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951.
Sapna Pandey Kalyani Dhusia Pramod Katara Satendra Singh 《Journal of biomolecular structure & dynamics》2020,38(14):4259-4272
Abstract Mutation in two genes deglycase gene (DJ-1) and retromer complex component gene (VPS35) are linked with neurodegenerative disorder such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. DJ-1 gene located at 1p36 chromosomal position and involved in PD pathogenesis through many pathways including mitochondrial dysfunction and oxidative injury. VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for basis of VPS35 related PD. The study focuses on identifying most deleterious SNPs through computational analysis. Result obtained from various bioinformatics tools shows that D149A is most deleterious in DJ-1 and A54W, R365H, and V717M are most deleterious in VPS35. To understand the functionality of protein comparative modeling of DJ-1 and VPS35 native and mutants was done by MODELLER. The generated structures are validated by two web servers–ProSa and RAMPAGE. Molecular dynamic simulation (MDS) analysis done for the most validated structures to know the functional and structural nature of native and mutants protein of DJ-1 and VPS35. Native structure of DJ-1 and VPS35 show more flexibility through MDS analysis. DJ-1 D149A mutant structures become more compact which shows the structural perturbation and loss of DJ-1 protein function which in turn are probable cause for PD. A54W, R365H, and V717M mutant protein of VPS35 also shows compactness which cause structure perturbation and absence of retromer function which likely to be linked to PD pathogenesis. This in silico study may provide a new insight for fundamental molecular mechanism involved in Parkinson’s disease. Communicated by Ramaswamy H. Sarma 相似文献
952.
953.
Liu et al. (Journal of Biogeography, 2018, 45 :164–176) presented an approach to detect outliers in species distribution data by developing virtual species created using the threshold approach. Meynard et al. (Journal of biogeography, 2019, 46 :2141–2144) raised concerns about this approach stating that ‘using a probabilistic approach … may significantly change results’. Here we provide a new series of simulations using the two approaches and demonstrate that the outlier detection approach based on pseudo species distribution models was still effective when using the probabilistic approach, although the detection rate was lower than when using the threshold approach. 相似文献
954.
1. The course and outcome of many wildlife diseases are context-dependent, and therefore change depending on the behaviour of hosts and environmental response of the pathogen.2. Contemporary declines in amphibian populations are widely attributed to chytridiomycosis, caused by the pathogenic fungus Batrachochytrium dendrobatidis. Despite the thermal sensitivity of the pathogen and its amphibian hosts, we do not understand how host thermal regimes experienced by frogs in the wild directly influence pathogen growth.3. We tested how thermal regimes experienced by the rainforest frog Litoria rheocola in the wild influence pathogen growth in the laboratory, and whether these responses differ from pathogen growth under available environmental thermal regimes.4. Frog thermal regimes mimicked in the laboratory accelerated pathogen growth during conditions representative of winter at high elevations more so than if temperatures matched air or stream water temperatures. By contrast, winter frog thermal regimes at low elevations slowed pathogen growth relative to air temperatures, but not water temperatures.5. The growth pattern of the fungus under frog thermal regimes matches field prevalence and intensity of infections for this species (high elevation winter > high elevation summer > low elevation winter > low elevation summer), whereas pathogen growth trajectories under environmental temperatures did not match these patterns.6. If these laboratory results translate into field responses, tropical frogs may be able to reduce disease impacts by regulating their body temperatures to limit pathogen growth (e.g., by using microhabitats that facilitate basking to reach high temperatures); in other cases, the environment may limit the ability of frogs to thermoregulate such that individuals are more vulnerable to this pathogen (e.g., in dense forests at high elevations).7. Species-specific thermoregulatory behaviour, and interactions with and constraints imposed by the environment, are therefore essential to understanding and predicting the spatial and temporal impacts of this global disease. 相似文献
955.
Timm Intemann Kirsten Mehlig Stefaan De Henauw Alfonso Siani Tassos Constantinou Luis A. Moreno Dénes Molnár Toomas Veidebaum Iris Pigeot 《Biometrical journal. Biometrische Zeitschrift》2020,62(1):221-237
Modelling dietary data, and especially 24-hr dietary recall (24HDR) data, is a challenge. Ignoring the inherent measurement error (ME) leads to biased effect estimates when the association between an exposure and an outcome is investigated. We propose an adapted simulation extrapolation (SIMEX) algorithm for modelling dietary exposures. For this purpose, we exploit the ME model of the NCI method where we assume the assumption of normally distributed errors of the reported intake on the Box-Cox transformed scale and of unbiased recalls on the original scale. According to the SIMEX algorithm, remeasurements of the observed data with additional ME are generated in order to estimate the association between the level of ME and the resulting effect estimate. Subsequently, this association is extrapolated to the case of zero ME to obtain the corrected estimate. We show that the proposed method fulfils the key property of the SIMEX approach, that is, that the MSE of the generated data will converge to zero if the ME variance converges to zero. Furthermore, the method is applied to real 24HDR data of the I.Family study to correct the effects of salt and alcohol intake on blood pressure. In a simulation study, the method is compared with the NCI method resulting in effect estimates with either smaller MSE or smaller bias in certain situations. In addition, we found our method to be more informative and easier to implement. Therefore, we conclude that the proposed method is useful to promote the dissemination of ME correction methods in nutritional epidemiology. 相似文献
956.
Many late-phase clinical trials recruit subjects at multiple study sites. This introduces a hierarchical structure into the data that can result in a power-loss compared to a more homogeneous single-center trial. Building on a recently proposed approach to sample size determination, we suggest a sample size recalculation procedure for multicenter trials with continuous endpoints. The procedure estimates nuisance parameters at interim from noncomparative data and recalculates the sample size required based on these estimates. In contrast to other sample size calculation methods for multicenter trials, our approach assumes a mixed effects model and does not rely on balanced data within centers. It is therefore advantageous, especially for sample size recalculation at interim. We illustrate the proposed methodology by a study evaluating a diabetes management system. Monte Carlo simulations are carried out to evaluate operation characteristics of the sample size recalculation procedure using comparative as well as noncomparative data, assessing their dependence on parameters such as between-center heterogeneity, residual variance of observations, treatment effect size and number of centers. We compare two different estimators for between-center heterogeneity, an unadjusted and a bias-adjusted estimator, both based on quadratic forms. The type 1 error probability as well as statistical power are close to their nominal levels for all parameter combinations considered in our simulation study for the proposed unadjusted estimator, whereas the adjusted estimator exhibits some type 1 error rate inflation. Overall, the sample size recalculation procedure can be recommended to mitigate risks arising from misspecified nuisance parameters at the planning stage. 相似文献
957.
Guihai Zhang Erxi Fan Guojun Yue Qiuyue Zhong Yu Shuai Mingna Wu Guangyong Feng Qiying Chen Xiaoxia Gou 《Journal of cellular biochemistry》2020,121(8-9):3804-3813
In this study, we purpose to investigate a novel five-gene signature for predicting the prognosis of patients with laryngeal cancer. The laryngeal cancer datasets were obtained from The Cancer Genome Atlas (TCGA). Both univariate and multivariate Cox regression analysis was applied to screening for prognostic differential expressed genes (DEGs), and a novel gene signature was obtained. The performance of this Cox regression model was tested by receiver operating characteristic (ROC) curves and area under the curve (AUC). Further survival analysis for each of the five genes was carried out through the Kaplan-Meier curve and Log-rank test. Totally, 622 DEGs were screened from the TCGA datasets in this study. We construct a five-gene signature through Cox survival analysis. Patients were divided into low- and high-risk groups depending on the median risk score, and a significant difference of the 5-year overall survival was found between these two groups (P < .05). ROC curves verified that this five-gene signature had good performance to predict the prognosis of laryngeal cancer (AUC = 0.862, P < .05). In conclusion, the five-gene signature consist of EMP1, HOXB9, DPY19L2P1, MMP1, and KLHDC7B might be applied as an independent prognosis predictor of laryngeal cancer. 相似文献
958.
Long-term balancing selection typically leaves narrow footprints of increased genetic diversity, and therefore most detection approaches only achieve optimal performances when sufficiently small genomic regions (i.e., windows) are examined. Such methods are sensitive to window sizes and suffer substantial losses in power when windows are large. Here, we employ mixture models to construct a set of five composite likelihood ratio test statistics, which we collectively term B statistics. These statistics are agnostic to window sizes and can operate on diverse forms of input data. Through simulations, we show that they exhibit comparable power to the best-performing current methods, and retain substantially high power regardless of window sizes. They also display considerable robustness to high mutation rates and uneven recombination landscapes, as well as an array of other common confounding scenarios. Moreover, we applied a specific version of the B statistics, termed B2, to a human population-genomic data set and recovered many top candidates from prior studies, including the then-uncharacterized STPG2 and CCDC169–SOHLH2, both of which are related to gamete functions. We further applied B2 on a bonobo population-genomic data set. In addition to the MHC-DQ genes, we uncovered several novel candidate genes, such as KLRD1, involved in viral defense, and SCN9A, associated with pain perception. Finally, we show that our methods can be extended to account for multiallelic balancing selection and integrated the set of statistics into open-source software named BalLeRMix for future applications by the scientific community. 相似文献
959.
AbstractIn the current contribution, a multicomplex-based pharmacophore modeling approach was employed on the structural proteome of Plasmodium falciparum orotidine-5-monophosphate decarboxylase enzyme (PfOMPDC). Among the constructed pharmacophore models, the representative hypotheses were selected as the primary filter to screen the molecules with the complementary features responsible for showing inhibition. Thereafter, auxiliary evaluations were performed on the screened candidates via drug-likeness and molecular docking studies. Subsequently, the stability of the docked protein-ligand complexes was scrutinized by employing molecular dynamics simulations and molecular mechanics-Poisson Boltzmann surface area based free binding energy calculations. The stability the docked candidates was compared with the highly active crystallized inhibitor (3S9Y-FNU) to seek more potential candidates. All the docked molecules displayed stable dynamic behavior and high binding free energy in comparison to 3S9Y-FNU. The employed workflow resulted in the retrieval of five drug-like candidates with diverse scaffolds that may show inhibitory activity against PfOMPDC and could be further used as the novel scaffold to develop novel antimalarials.Communicated by Ramaswamy H. Sarma 相似文献
960.
Many proteins are composed of several domains that pack together into a complex tertiary structure. Multidomain proteins can be challenging for protein structure modeling, particularly those for which templates can be found for individual domains but not for the entire sequence. In such cases, homology modeling can generate high quality models of the domains but not for the orientations between domains. Small-angle X-ray scattering (SAXS) reports the structural properties of entire proteins and has the potential for guiding homology modeling of multidomain proteins. In this article, we describe a novel multidomain protein assembly modeling method, SAXSDom that integrates experimental knowledge from SAXS with probabilistic Input-Output Hidden Markov model to assemble the structures of individual domains together. Four SAXS-based scoring functions were developed and tested, and the method was evaluated on multidomain proteins from two public datasets. Incorporation of SAXS information improved the accuracy of domain assembly for 40 out of 46 critical assessment of protein structure prediction multidomain protein targets and 45 out of 73 multidomain protein targets from the ab initio domain assembly dataset. The results demonstrate that SAXS data can provide useful information to improve the accuracy of domain-domain assembly. The source code and tool packages are available at https://github.com/jianlin-cheng/SAXSDom . 相似文献