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Genes, Volume 9, Issue 7 (July 2018)

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Open AccessArticle Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake
Genes 2018, 9(7), 357; https://doi.org/10.3390/genes9070357 (registering DOI)
Received: 16 June 2018 / Revised: 7 July 2018 / Accepted: 10 July 2018 / Published: 17 July 2018
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Abstract
Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus
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Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity. Full article
(This article belongs to the Special Issue Advances in Genetics of Regeneration in Metabesity)
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Open AccessArticle An Evolutionary Mechanism for the Generation of Competing RNA Structures Associated with Mutually Exclusive Exons
Genes 2018, 9(7), 356; https://doi.org/10.3390/genes9070356 (registering DOI)
Received: 10 May 2018 / Revised: 6 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
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Abstract
Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE
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Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE do so by using a mechanism that depends on RNA structure. Transcripts of these genes contain multiple sites called selector sequences that are all complementary to a regulatory element called the docking site; only one of the competing base pairings can form at a time, which exposes one exon from the cluster to the spliceosome. MXE tend to have similar lengths and sequence content and are believed to originate through tandem genomic duplications. Here, we report that pre-mRNAs of this class of exons have an increased capacity to fold into competing secondary structures. We propose an evolutionary mechanism for the generation of such structures via duplications that affect not only exons, but also their adjacent introns with stem-loop structures. If one of the two arms of a stem-loop is duplicated, it will generate two selector sequences that compete for the same docking site, a pattern that is associated with MXE splicing. A similar partial duplication of two independent stem-loops produces a pattern that is consistent with the so-called bidirectional pairing model. These models explain why tandem exon duplications frequently result in mutually exclusive splicing. Full article
(This article belongs to the Special Issue Computational Analysis of RNA Structure and Function)
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Open AccessArticle Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed
Genes 2018, 9(7), 355; https://doi.org/10.3390/genes9070355 (registering DOI)
Received: 19 June 2018 / Revised: 9 July 2018 / Accepted: 10 July 2018 / Published: 16 July 2018
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Abstract
HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis
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HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial food source), unaccompanied by significant defects in the requisite endocytic pathways. Despite its protective roles, we could not ectopically overexpress wild type HTRA2, suggesting that mitochondrial HTRA2 hyperactivity is lethal. This toxicity was abolished by replacing the essential catalytic serine S300 with alanine to ablate serine protease activity. Overexpression of protease-dead HTRA2 phenocopied the effects of knockdown, suggesting that the mutant protein competitively inhibits interactions between wild type HTRA2 and its binding partners. Our results show that cytopathological dysfunction can be caused either by too little or too much HTRA2 activity in the mitochondria and suggest that either could be a cause of PD. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
Open AccessArticle Genome Mining of Non-Conventional Yeasts: Search and Analysis of MAL Clusters and Proteins
Genes 2018, 9(7), 354; https://doi.org/10.3390/genes9070354 (registering DOI)
Received: 30 May 2018 / Revised: 9 July 2018 / Accepted: 12 July 2018 / Published: 16 July 2018
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Abstract
Genomic clustering of functionally related genes is rare in yeasts and other eukaryotes with only few examples available. Here, we summarize our data on a nontelomeric MAL cluster of a non-conventional methylotrophic yeast Ogataea (Hansenula) polymorpha containing genes for α-glucosidase MAL1,
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Genomic clustering of functionally related genes is rare in yeasts and other eukaryotes with only few examples available. Here, we summarize our data on a nontelomeric MAL cluster of a non-conventional methylotrophic yeast Ogataea (Hansenula) polymorpha containing genes for α-glucosidase MAL1, α-glucoside permease MAL2 and two hypothetical transcriptional activators. Using genome mining, we detected MAL clusters of varied number, position and composition in many other maltose-assimilating non-conventional yeasts from different phylogenetic groups. The highest number of MAL clusters was detected in Lipomyces starkeyi while no MAL clusters were found in Schizosaccharomyces pombe and Blastobotrys adeninivorans. Phylograms of α-glucosidases and α-glucoside transporters of yeasts agreed with phylogenesis of the respective yeast species. Substrate specificity of unstudied α-glucosidases was predicted from protein sequence analysis. Specific activities of Scheffersomycesstipitis α-glucosidases MAL7, MAL8, and MAL9 heterologously expressed in Escherichia coli confirmed the correctness of the prediction—these proteins were verified promiscuous maltase-isomaltases. α-Glucosidases of earlier diverged yeasts L. starkeyi, B. adeninivorans and S. pombe showed sequence relatedness with α-glucosidases of filamentous fungi and bacilli. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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Open AccessArticle Morphological Stasis and Proteome Innovation in Cephalochordates
Received: 24 May 2018 / Revised: 11 July 2018 / Accepted: 11 July 2018 / Published: 16 July 2018
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Abstract
Lancelets, extant representatives of basal chordates, are prototypic examples of evolutionary stasis; they preserved a morphology and body-plan most similar to the fossil chordates from the early Cambrian. Such a low level of morphological evolution is in harmony with a low rate of
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Lancelets, extant representatives of basal chordates, are prototypic examples of evolutionary stasis; they preserved a morphology and body-plan most similar to the fossil chordates from the early Cambrian. Such a low level of morphological evolution is in harmony with a low rate of amino acid substitution; cephalochordate proteins were shown to evolve slower than those of the slowest evolving vertebrate, the elephant shark. Surprisingly, a study comparing the predicted proteomes of Chinese amphioxus, Branchiostoma belcheri and the Florida amphioxus, Branchiostoma floridae has led to the conclusion that the rate of creation of novel domain combinations is orders of magnitude greater in lancelets than in any other Metazoa, a finding that contradicts the notion that high rates of protein innovation are usually associated with major evolutionary innovations. Our earlier studies on a representative sample of proteins have provided evidence suggesting that the differences in the domain architectures of predicted proteins of these two lancelet species reflect annotation errors, rather than true innovations. In the present work, we have extended these studies to include a larger sample of genes and two additional lancelet species, Asymmetron lucayanum and Branchiostoma lanceolatum. These analyses have confirmed that the domain architecture differences of orthologous proteins of the four lancelet species are because of errors of gene prediction, the error rate in the given species being inversely related to the quality of the transcriptome dataset that was used to aid gene prediction. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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Open AccessFeature PaperReview Evolutionary Divergent Suppressor Mutations in Conformational Diseases
Received: 12 June 2018 / Revised: 9 July 2018 / Accepted: 11 July 2018 / Published: 13 July 2018
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Abstract
Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational
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Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational diseases. We have recently proposed that divergence at certain sites from the consensus (amino acid) state during mammalian evolution may have rendered some human proteins more vulnerable towards disease-associated mutations, primarily by decreasing their conformational stability. We herein extend and refine this hypothesis discussing results from phylogenetic and structural analyses, structure-based energy calculations and structure-function studies at molecular and cellular levels. As proof-of-principle, we focus on different mammalian orthologues of the NQO1 (NAD(P)H:quinone oxidoreductase 1) and AGT (alanine:glyoxylate aminotransferase) proteins. We discuss the different loss-of-function pathogenic mechanisms associated with diseases involving the two enzymes, including enzyme inactivation, accelerated degradation, intracellular mistargeting, and aggregation. Last, we take into account the potentially higher robustness of mammalian orthologues containing certain consensus amino acids as suppressors of human disease, and their relation with different intracellular post-translational modifications and protein quality control capacities, to be discussed as sources of phenotypic variability between human and mammalian models of disease and as tools for improving current therapeutic approaches. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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Open AccessReview Targeted Approaches for In Situ Gut Microbiome Manipulation
Received: 28 May 2018 / Revised: 7 July 2018 / Accepted: 9 July 2018 / Published: 12 July 2018
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Abstract
Microbial communities and their collective genomes form the gut microbiome, of which bacteria are the major contributor. Through their secreted metabolites, bacteria interact with the host, influencing human health and physiology. Perturbation of the microbiota and metabolome has been associated with various diseases
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Microbial communities and their collective genomes form the gut microbiome, of which bacteria are the major contributor. Through their secreted metabolites, bacteria interact with the host, influencing human health and physiology. Perturbation of the microbiota and metabolome has been associated with various diseases and metabolic conditions. As knowledge on fundamental host-microbiome interactions and genetic engineering tools becomes readily available, targeted manipulation of the gut microbiome for therapeutic applications gains favourable attention. Manipulation of the gut microbiome can be achieved by altering the microbiota population and composition, or by modifying the functional metabolic activity of the microbiome to promote health and restore the microbiome balance. In this article, we review current works that demonstrate various strategies employed to manipulate the gut microbiome in situ to various degrees of precision. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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Open AccessArticle Ensemble Consensus-Guided Unsupervised Feature Selection to Identify Huntington’s Disease-Associated Genes
Received: 30 May 2018 / Revised: 6 July 2018 / Accepted: 9 July 2018 / Published: 12 July 2018
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Abstract
Due to the complexity of the pathological mechanisms of neurodegenerative diseases, traditional differentially-expressed gene selection methods cannot detect disease-associated genes accurately. Recent studies have shown that consensus-guided unsupervised feature selection (CGUFS) performs well in feature selection for identifying disease-associated genes. Since the random
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Due to the complexity of the pathological mechanisms of neurodegenerative diseases, traditional differentially-expressed gene selection methods cannot detect disease-associated genes accurately. Recent studies have shown that consensus-guided unsupervised feature selection (CGUFS) performs well in feature selection for identifying disease-associated genes. Since the random initialization of the feature selection matrix in CGUFS results in instability of the final disease-associated gene set, for the purposes of this study we proposed an ensemble method based on CGUFS—namely, ensemble consensus-guided unsupervised feature selection (ECGUFS) in order to further improve the accuracy of disease-associated genes and the stability of feature gene sets. We also proposed a bagging integration strategy to integrate the results of CGUFS. Lastly, we conducted experiments with Huntington’s disease RNA sequencing (RNA-Seq) data and obtained the final feature gene set, where we detected 287 disease-associated genes. Enrichment analysis on these genes has shown that postsynaptic density and the postsynaptic membrane, synapse, and cell junction are all affected during the disease’s progression. However, ECGUFS greatly improved the accuracy of disease-associated gene prediction and the stability of the disease-associated gene set. We conducted a classification of samples with labels based on the linear support vector machine with 10-fold cross-validation. The average accuracy is 0.9, which suggests the effectiveness of the feature gene set. Full article
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Open AccessArticle Description of Genetic Variants in BRCA Genes in Mexican Patients with Ovarian Cancer: A First Step towards Implementing Personalized Medicine
Received: 18 May 2018 / Revised: 11 July 2018 / Accepted: 11 July 2018 / Published: 11 July 2018
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Abstract
Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe
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Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)
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Open AccessFeature PaperPerspective The Multiplanetary Future of Plant Synthetic Biology
Received: 30 May 2018 / Revised: 6 July 2018 / Accepted: 9 July 2018 / Published: 10 July 2018
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Abstract
The interest in human space journeys to distant planets and moons has been re-ignited in recent times and there are ongoing plans for sending the first manned missions to Mars in the near future. In addition to generating oxygen, fixing carbon, and recycling
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The interest in human space journeys to distant planets and moons has been re-ignited in recent times and there are ongoing plans for sending the first manned missions to Mars in the near future. In addition to generating oxygen, fixing carbon, and recycling waste and water, plants could play a critical role in producing food and biomass feedstock for the microbial manufacture of materials, chemicals, and medicines in long-term interplanetary outposts. However, because life on Earth evolved under the conditions of the terrestrial biosphere, plants will not perform optimally in different planetary habitats. The construction or transportation of plant growth facilities and the availability of resources, such as sunlight and liquid water, may also be limiting factors, and would thus impose additional challenges to efficient farming in an extraterrestrial destination. Using the framework of the forthcoming human missions to Mars, here we discuss a series of bioengineering endeavors that will enable us to take full advantage of plants in the context of a Martian greenhouse. We also propose a roadmap for research on adapting life to Mars and outline our opinion that synthetic biology efforts towards this goal will contribute to solving some of the main agricultural and industrial challenges here on Earth. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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Open AccessFeature PaperArticle Possible Role of Envelope Components in the Extreme Copper Resistance of the Biomining Acidithiobacillus ferrooxidans
Received: 30 May 2018 / Revised: 30 June 2018 / Accepted: 3 July 2018 / Published: 10 July 2018
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Abstract
Acidithiobacillus ferrooxidans resists extremely high concentrations of copper. Strain ATCC 53993 is much more resistant to the metal compared with strain ATCC 23270, possibly due to the presence of a genomic island in the former one. The global response of strain ATCC 53993
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Acidithiobacillus ferrooxidans resists extremely high concentrations of copper. Strain ATCC 53993 is much more resistant to the metal compared with strain ATCC 23270, possibly due to the presence of a genomic island in the former one. The global response of strain ATCC 53993 to copper was analyzed using iTRAQ (isobaric tag for relative and absolute quantitation) quantitative proteomics. Sixty-seven proteins changed their levels of synthesis in the presence of the metal. On addition of CusCBA efflux system proteins, increased levels of other envelope proteins, such as a putative periplasmic glucan biosynthesis protein (MdoG) involved in the osmoregulated synthesis of glucans and a putative antigen O polymerase (Wzy), were seen in the presence of copper. The expression of A. ferrooxidansmdoG or wzy genes in a copper sensitive Escherichia coli conferred it a higher metal resistance, suggesting the possible role of these components in copper resistance of A. ferrooxidans. Transcriptional levels of genes wzy, rfaE and wzz also increased in strain ATCC 23270 grown in the presence of copper, but not in strain ATCC 53993. Additionally, in the absence of this metal, lipopolysaccharide (LPS) amounts were 3-fold higher in A. ferrooxidans ATCC 53993 compared with strain 23270. Nevertheless, both strains grown in the presence of copper contained similar LPS quantities, suggesting that strain 23270 synthesizes higher amounts of LPS to resist the metal. On the other hand, several porins diminished their levels in the presence of copper. The data presented here point to an essential role for several envelope components in the extreme copper resistance by this industrially important acidophilic bacterium. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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Open AccessArticle The Genetics of a Behavioral Speciation Phenotype in an Island System
Received: 25 May 2018 / Revised: 3 July 2018 / Accepted: 3 July 2018 / Published: 10 July 2018
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Abstract
Mating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we
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Mating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we use quantitative trait locus (QTL) mapping to infer the number, distribution, and effect size of mating song rhythm variations in the crickets Laupala eukolea and Laupala cerasina, which occur on different islands (Maui and Hawaii). We then compare these results with a similar study of an independently evolving species pair that diverged within the same island. Finally, we annotate the L. cerasina transcriptome and test whether the QTL fall in functionally enriched genomic regions. We document a polygenic architecture behind the song rhythm divergence in the inter-island species pair that is remarkably similar to that previously found for an intra-island species pair in the same genus. Importantly, the QTL regions were significantly enriched for potential homologs of the genes involved in pathways that may be modulating the cricket song rhythm. These clusters of loci could constrain the spatial genomic distribution of the genetic variation underlying the cricket song variation and harbor several candidate genes that merit further study. Full article
(This article belongs to the Special Issue Evolutionary Genetics of Reproductive Isolation)
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Open AccessArticle A Novel Probability Model for LncRNA–Disease Association Prediction Based on the Naïve Bayesian Classifier
Received: 26 May 2018 / Revised: 24 June 2018 / Accepted: 3 July 2018 / Published: 8 July 2018
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Abstract
An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover
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An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover potential associations between lncRNAs and diseases by integrating multiple heterogeneous biological data; this has become a hot topic in biological research. In this article, we constructed a global tripartite network by integrating a variety of biological information including miRNA–disease, miRNA–lncRNA, and lncRNA–disease associations and interactions. Then, we constructed a global quadruple network by appending gene–lncRNA interaction, gene–disease association, and gene–miRNA interaction networks to the global tripartite network. Subsequently, based on these two global networks, a novel approach was proposed based on the naïve Bayesian classifier to predict potential lncRNA–disease associations (NBCLDA). Comparing with the state-of-the-art methods, our new method does not entirely rely on known lncRNA–disease associations, and can achieve a reliable performance with effective area under ROC curve (AUCs)in leave-one-out cross validation. Moreover, in order to further estimate the performance of NBCLDA, case studies of colorectal cancer, prostate cancer, and glioma were implemented in this paper, and the simulation results demonstrated that NBCLDA can be an excellent tool for biomedical research in the future. Full article
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Open AccessFeature PaperArticle Using a Chemical Genetic Screen to Enhance Our Understanding of the Antibacterial Properties of Silver
Received: 7 June 2018 / Revised: 30 June 2018 / Accepted: 3 July 2018 / Published: 6 July 2018
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Abstract
It is essential to understand the mechanisms by which a toxicant is capable of poisoning the bacterial cell. The mechanism of action of many biocides and toxins, including numerous ubiquitous compounds, is not fully understood. For example, despite the widespread clinical and commercial
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It is essential to understand the mechanisms by which a toxicant is capable of poisoning the bacterial cell. The mechanism of action of many biocides and toxins, including numerous ubiquitous compounds, is not fully understood. For example, despite the widespread clinical and commercial use of silver (Ag), the mechanisms describing how this metal poisons bacterial cells remains incomplete. To advance our understanding surrounding the antimicrobial action of Ag, we performed a chemical genetic screen of a mutant library of Escherichia coli—the Keio collection, in order to identify Ag sensitive or resistant deletion strains. Indeed, our findings corroborate many previously established mechanisms that describe the antibacterial effects of Ag, such as the disruption of iron-sulfur clusters containing proteins and certain cellular redox enzymes. However, the data presented here demonstrates that the activity of Ag within the bacterial cell is more extensive, encompassing genes involved in cell wall maintenance, quinone metabolism and sulfur assimilation. Altogether, this study provides further insight into the antimicrobial mechanism of Ag and the physiological adaption of E. coli to this metal. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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Open AccessArticle Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms
Received: 27 March 2018 / Accepted: 29 June 2018 / Published: 6 July 2018
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Abstract
Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A
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Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A resistance-associated mutations (RAMs) have been described at baseline and after therapy failure. A mutation from glutamine to arginine at position 30 (Q30R) is a characteristic RAM for the HCV sub/genotype (GT) 1a, but arginine corresponds to the wild type in the GT-1b; still, GT-1b strains are susceptible to NS5A-inhibitors. In this study, we show that GT-1b strains with R30Q often display other specific NS5A substitutions, particularly in positions 24 and 34. We demonstrate that in GT-1b secondary substitutions usually happen after initial R30Q development in the phylogeny, and that the chemical properties of the corresponding amino acids serve to restore the positive charge in this region, acting as compensatory mutations. These findings may have implications for RAVs treatment. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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