scholarly journals Functional and Structural Consequences of NineCYP21A2Mutations Ranging from Very Mild to Severe Effects

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Débora de Paula Michelatto ◽  
Leif Karlsson ◽  
Ana Letícia Gori Lusa ◽  
Camila D’Almeida Mgnani Silva ◽  
Linus Joakim Östberg ◽  
...  
Keyword(s):  
Enzyme Activities ◽  
Maximum Velocity ◽  
The Novel ◽  
Wild Type ◽  
Phenotype Correlation ◽  
Novel Variants ◽  
Order Of Magnitude ◽  
Classic Cah ◽  
17 Hydroxyprogesterone ◽  
Functional Analyses

We present the functional and structural effects of seven novel (p.Leu12Met, p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, p.Gln389_Ala391del, and p.Thr450Met) and two previously reported but not studied (p.Ser113Phe and p.Thr450Pro)CYP21A2mutations. Functional analyses were complemented within silicoprediction of mutation pathogenicity based on the recently crystallized human CYP21A2 structure. Mutated proteins were transiently expressed in COS-1 cells and enzyme activities towards 17-hydroxyprogesterone and progesterone were determined. Residual enzyme activities between 43% and 97% were obtained for p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met, similar to the activities of the well-known nonclassic mutations p.Pro453Ser and p.Pro482Ser, whereas the p.Leu12Met variant showed an activity of 100%. Conversely, the novel p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro mutations drastically reduced the enzyme function below 4%. TheKmvalues for all novel variants were in the same order of magnitude as for the wild-type protein except for p.The450Met. The maximum velocity was decreased for all mutants except for p.Leu12Met. We conclude that p.Leu12Met is a normal variant; the mutations p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met could be associated with very mild nonclassic CAH, and the mutations p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro are associated with classic CAH. The obtained residual activities indicated a good genotype-phenotype correlation.

scholarly journals Whole-Genome Sequence Analysis of Pseudorabies Virus Clinical Isolates from Pigs in China between 2012 and 2017 in China

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1322
Author(s):  
Ruiming Hu ◽  
Leyi Wang ◽  
Qingyun Liu ◽  
Lin Hua ◽  
Xi Huang ◽  
...  
Keyword(s):  
Selection Pressure ◽  
Pseudorabies Virus ◽  
Viral Evolution ◽  
Infectious Agent ◽  
Genomic Diversity ◽  
Whole Genome Sequence ◽  
Evolutionary Constraint ◽  
The Novel ◽  
Novel Variants ◽  
Pressure Analysis

Pseudorabies virus (PRV) is an economically significant swine infectious agent. A PRV outbreak took place in China in 2011 with novel virulent variants. Although the association of viral genomic variability with pathogenicity is not fully confirmed, the knowledge concerning PRV genomic diversity and evolution is still limited. Here, we sequenced 54 genomes of novel PRV variants isolated in China from 2012 to 2017. Phylogenetic analysis revealed that China strains and US/Europe strains were classified into two separate genotypes. PRV strains isolated from 2012 to 2017 in China are highly related to each other and genetically close to classic China strains such as Ea, Fa, and SC. RDP analysis revealed 23 recombination events within novel PRV variants, indicating that recombination contributes significantly to the viral evolution. The selection pressure analysis indicated that most ORFs were under evolutionary constraint, and 19 amino acid residue sites in 15 ORFs were identified under positive selection. Additionally, 37 unique mutations were identified in 19 ORFs, which distinguish the novel variants from classic strains. Overall, our study suggested that novel PRV variants might evolve from classical PRV strains through point mutation and recombination mechanisms.

scholarly journals Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals

2021 ◽  
Vol 11 (2) ◽  
pp. 94
Author(s):  
Masaki Kumondai ◽  
Akio Ito ◽  
Evelyn Marie Gutiérrez Rico ◽  
Eiji Hishinuma ◽  
Akiko Ueda ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Three Dimensional ◽  
Warfarin Dose ◽  
Catalytic Efficiency ◽  
Therapeutic Window ◽  
Wild Type ◽  
Drug Metabolizing Enzyme ◽  
Novel Variants ◽  
Metabolizing Enzyme ◽  
Almost All

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.

scholarly journals DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients

2019 ◽  
Vol 28 (1) ◽  
pp. 64-75 ◽  
Author(s):  
Roser Urreizti ◽  
Klaus Mayer ◽  
Gilad D. Evrony ◽  
Edith Said ◽  
Laura Castilla-Vallmanya ◽  
...  
Keyword(s):  
Missense Variants ◽  
Novel Variants ◽  
Functional Analyses

Novel variants in GUCY2D causing retinopathy and the genotype-phenotype correlation

2021 ◽  
pp. 108637
Author(s):  
Zhen Yi ◽  
Wenmin Sun ◽  
Xueshan Xiao ◽  
Shiqiang Li ◽  
Xiaoyun Jia ◽  
...  
Keyword(s):  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Novel Variants

Characterization of novel ybjG and dacC variants in Escherichia coli

2013 ◽  
Vol 62 (11) ◽  
pp. 1728-1734 ◽  
Author(s):  
Dongguo Wang ◽  
Enping Hu ◽  
Jiayu Chen ◽  
Xiulin Tao ◽  
Katelyn Gutierrez ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
The Novel ◽  
Conventional Pcr ◽  
E Coli ◽  
Novel Variants ◽  
Restriction Sites ◽  
Genetic Structures

A total of 69 strains of Escherichia coli from patients in the Taizhou Municipal Hospital, China, were isolated, and 11 strains were identified that were resistant to bacitracin, chloramphenicol, tetracycline and erythromycin. These strains were PCR positive for at least two out of three genes, ybjG, dacC and mdfA, by gene mapping with conventional PCR detection. Conjugation experiments demonstrated that these genes existed in plasmids that conferred resistance. Novel ybjG and dacC variants were isolated from E. coli strains EC2163 and EC2347, which were obtained from the sputum of intensive care unit patients. Genetic mapping showed that the genes were located on 8200 kb plasmid regions flanked by EcoRI restriction sites. Three distinct genetic structures were identified among the 11 PCR-positive strains of E. coli, and two contained the novel ybjG and dacC variants. The putative amino acid differences in the ybjG and dacC gene variants were characterized. These results provide evidence for novel variants of ybjG and dacC, and suggest that multiple drug resistance in hospital strains of E. coli depends on the synergistic function of ybjG, dacC and mdfA within three distinct genetic structures in conjugative plasmids.

scholarly journals RON-Gauss: Enhancing Utility in Non-Interactive Private Data Release

2019 ◽  
Vol 2019 (1) ◽  
pp. 26-46 ◽  
Author(s):  
Thee Chanyaswad ◽  
Changchang Liu ◽  
Prateek Mittal
Keyword(s):  
Machine Learning ◽  
Real World ◽  
Differential Privacy ◽  
Real Data ◽  
The Novel ◽  
Private Data ◽  
Data Release ◽  
Machine Learning Applications ◽  
Order Of Magnitude ◽  
Real World Datasets

Abstract A key challenge facing the design of differential privacy in the non-interactive setting is to maintain the utility of the released data. To overcome this challenge, we utilize the Diaconis-Freedman-Meckes (DFM) effect, which states that most projections of high-dimensional data are nearly Gaussian. Hence, we propose the RON-Gauss model that leverages the novel combination of dimensionality reduction via random orthonormal (RON) projection and the Gaussian generative model for synthesizing differentially-private data. We analyze how RON-Gauss benefits from the DFM effect, and present multiple algorithms for a range of machine learning applications, including both unsupervised and supervised learning. Furthermore, we rigorously prove that (a) our algorithms satisfy the strong ɛ-differential privacy guarantee, and (b) RON projection can lower the level of perturbation required for differential privacy. Finally, we illustrate the effectiveness of RON-Gauss under three common machine learning applications – clustering, classification, and regression – on three large real-world datasets. Our empirical results show that (a) RON-Gauss outperforms previous approaches by up to an order of magnitude, and (b) loss in utility compared to the non-private real data is small. Thus, RON-Gauss can serve as a key enabler for real-world deployment of privacy-preserving data release.

scholarly journals Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Cesar Sierra ◽  
Ilario De Toma ◽  
Lorenzo Lo Cascio ◽  
Esteban Vegas ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Object Recognition ◽  
Environmental Factors ◽  
Mouse Models ◽  
Recognition Task ◽  
Novel Object Recognition ◽  
The Novel ◽  
Wild Type ◽  
Male And Female ◽  
Novel Object

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

scholarly journals Microgeographic variation in locomotor traits among lizards in a human-built environment

2016 ◽  
Author(s):  
Colin Donihue
Keyword(s):  
Built Environment ◽  
Habitat Structure ◽  
Vertical Structure ◽  
Maximum Velocity ◽  
The Novel ◽  
Novel Habitat ◽  
Microgeographic Variation ◽  
And Performance ◽  
Locomotor Capacity

Microgeographic variation in fitness-relevant traits may be more common than previously appreciated. The fitness of many vertebrates is directly related to their locomotor capacity, a whole-organism trait integrating behavior, morphology, and physiology. Because locomotion is inextricably related to context, I hypothesized that it might vary with habitat structure in a wide-ranging lizard, Podarcis erhardii, found in the Greek Cyclade Islands. I compared lizard populations living on human-built rock walls, a novel habitat with complex vertical structure, with nearby lizard populations that are naive to human-built infrastructure and live in flat, loose-substrate habitat. I tested for differences in morphology, behavior, and performance. Lizards from built sites were larger and had significantly (and relatively) longer forelimbs and hindlimbs. The differences in hindlimb morphology were especially pronounced for distal components – the foot and longest toe. These morphologies facilitated a significant behavioral shift in jumping propensity across a rocky experimental substrate. I found no difference in maximum velocity between these populations, however females originating from wall sites potentially accelerated faster over the rocky experimental substrate. The variation between these closely neighboring populations suggests that the lizards inhabiting walls have experienced a suite of trait changes enabling them to take advantage of the novel habitat structure created by humans.

scholarly journals The novel dipeptide ligand of TASP

2019 ◽  
Vol 484 (2) ◽  
pp. 228-232
Author(s):  
O. A. Deeva ◽  
A. S. Pantileev ◽  
I. V. Rybina ◽  
M. A. Yarkova ◽  
T. A. Gudasheva ◽  
...  
Keyword(s):  
Elevated Plus Maze ◽  
Open Field Test ◽  
Anxiolytic Activity ◽  
The Novel ◽  
Minimum Effective Dose ◽  
Elevated Plus Maze Test ◽  
Maze Test ◽  
Plus Maze ◽  
Order Of Magnitude ◽  
Preliminary Administration

Using the previously obtained first dipeptide ligand TSPO the N‑carbobenzoxy-L‑tryptophanyl-L‑isoleucine amide (GD‑23) as a basis, the new dipeptide was synthesized — the N‑phenylpropionyl–L‑tryptophanyl-L‑leucine amide (GD‑102). GD‑102 expressed anxiolytic activity in the open field test in BALB/c mice and in the elevated plus maze test in ICR mice. The minimum effective dose of GD‑102 was an order of magnitude lower than that of GD‑23. Preliminary administration of the TSPO selective antagonist, compound PK11195, completely blocked the anxiolytic activity of GD‑102, that indicated the participation of TSPO in the realization of the anxiolytic action GD‑102. The results were confirmed by molecular docking data.

scholarly journals TOXIFY: a deep learning approach to classify animal venom proteins

2019 ◽  
Author(s):  
T Jeffrey Cole ◽  
Michael S Brewer
Keyword(s):  
Protein Sequence ◽  
Software Package ◽  
Shotgun Proteomics ◽  
Learning Approach ◽  
The Novel ◽  
Venom Protein ◽  
Order Of Magnitude ◽  
Gated Recurrent Units ◽  
Venom Proteins ◽  
Generation Sequencing

In the era of Next-Generation Sequencing and shotgun proteomics, the sequences of animal toxigenic proteins are being generated at rates exceeding the pace of traditional means for empirical toxicity verification. To facilitate the automation of toxin identification from protein sequences, we trained Recurrent Neural Networks with Gated Recurrent Units on publicly available datasets. The resulting models are available via the novel software package TOXIFY, allowing users to infer the probability of a given protein sequence being a venom protein. TOXIFY is more than 20X faster and uses over an order of magnitude less memory than previously published methods. Additionally, TOXIFY is more accurate, precise, and sensitive at classifying venom proteins. Availability: https://www.github.com/tijeco/toxify

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