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Genes, Volume 9, Issue 11 (November 2018)

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Cover Story (view full-size image) The concept for cystic fibrosis (CF) gene therapy was established nearly 30 years ago. Despite the [...] Read more.
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Open AccessReview Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes
Genes 2018, 9(11), 566; https://doi.org/10.3390/genes9110566
Received: 25 October 2018 / Revised: 13 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes
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DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated factors that mediate the crosstalk between DNA methylation and chromatin modifications. Finally, we describe recent advances regarding the methylation of non-CpG sites, methylation of adenine residues in human cells and methylation of mitochondrial DNA. At several places, we highlight controversial findings or open questions demanding future experimental work. Full article
(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)
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Open AccessReview Coping with Reactive Oxygen Species to Ensure Genome Stability in Escherichia coli
Genes 2018, 9(11), 565; https://doi.org/10.3390/genes9110565
Received: 26 October 2018 / Revised: 15 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
The facultative aerobic bacterium Escherichia coli adjusts its cell cycle to environmental conditions. Because of its lifestyle, the bacterium has to balance the use of oxygen with the potential lethal effects of its poisonous derivatives. Oxidative damages perpetrated by molecules such as hydrogen
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The facultative aerobic bacterium Escherichia coli adjusts its cell cycle to environmental conditions. Because of its lifestyle, the bacterium has to balance the use of oxygen with the potential lethal effects of its poisonous derivatives. Oxidative damages perpetrated by molecules such as hydrogen peroxide and superoxide anions directly incapacitate metabolic activities relying on enzymes co-factored with iron and flavins. Consequently, growth is inhibited when the bacterium faces substantial reactive oxygen insults coming from environmental or cellular sources. Although hydrogen peroxide and superoxide anions do not oxidize DNA directly, these molecules feed directly or indirectly the generation of the highly reactive hydroxyl radical that damages the bacterial chromosome. Oxidized bases are normally excised and the single strand gap repaired by the base excision repair pathway (BER). This process is especially problematic in E. coli because replication forks do not sense the presence of damages or a stalled fork ahead of them. As consequence, single-strand breaks are turned into double-strand breaks (DSB) through replication. Since E. coli tolerates the presence of DSBs poorly, BER can become toxic during oxidative stress. Here we review the repair strategies that E. coli adopts to preserve genome integrity during oxidative stress and their relation to cell cycle control of DNA replication. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11
Genes 2018, 9(11), 564; https://doi.org/10.3390/genes9110564
Received: 31 October 2018 / Revised: 17 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome
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DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle Legume Cytosolic and Plastid Acetyl-Coenzyme—A Carboxylase Genes Differ by Evolutionary Patterns and Selection Pressure Schemes Acting before and after Whole-Genome Duplications
Genes 2018, 9(11), 563; https://doi.org/10.3390/genes9110563
Received: 11 October 2018 / Revised: 9 November 2018 / Accepted: 15 November 2018 / Published: 21 November 2018
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Abstract
Acetyl-coenzyme A carboxylase (ACCase, E.C.6.4.1.2) catalyzes acetyl-coenzyme A carboxylation to malonyl coenzyme A. Plants possess two distinct ACCases differing by cellular compartment and function. Plastid ACCase contributes to de novo fatty acid synthesis, whereas cytosolic enzyme to the synthesis of very long chain
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Acetyl-coenzyme A carboxylase (ACCase, E.C.6.4.1.2) catalyzes acetyl-coenzyme A carboxylation to malonyl coenzyme A. Plants possess two distinct ACCases differing by cellular compartment and function. Plastid ACCase contributes to de novo fatty acid synthesis, whereas cytosolic enzyme to the synthesis of very long chain fatty acids, phytoalexins, flavonoids, and anthocyanins. The narrow leafed lupin (Lupinus angustifolius L.) represents legumes, a plant family which evolved by whole-genome duplications (WGDs). The study aimed on the contribution of these WGDs to the multiplication of ACCase genes and their further evolutionary patterns. The molecular approach involved bacterial artificial chromosome (BAC) library screening, fluorescent in situ hybridization, linkage mapping, and BAC sequencing. In silico analysis encompassed sequence annotation, comparative mapping, selection pressure calculation, phylogenetic inference, and gene expression profiling. Among sequenced legumes, the highest number of ACCase genes was identified in lupin and soybean. The most abundant plastid ACCase subunit genes were accB. ACCase genes in legumes evolved by WGDs, evidenced by shared synteny and Bayesian phylogenetic inference. Transcriptional activity of almost all copies was confirmed. Gene duplicates were conserved by strong purifying selection, however, positive selection occurred in Arachis (accB2) and Lupinus (accC) lineages, putatively predating the WGD event(s). Early duplicated accA and accB genes underwent transcriptional sub-functionalization. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Molecular Factors of Hypochlorite Tolerance in the Hypersaline Archaeon Haloferax volcanii
Genes 2018, 9(11), 562; https://doi.org/10.3390/genes9110562
Received: 8 October 2018 / Revised: 7 November 2018 / Accepted: 13 November 2018 / Published: 20 November 2018
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Abstract
Halophilic archaea thrive in hypersaline conditions associated with desiccation, ultraviolet (UV) irradiation and redox active compounds, and thus are naturally tolerant to a variety of stresses. Here, we identified mutations that promote enhanced tolerance of halophilic archaea to redox-active compounds using Haloferax volcanii
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Halophilic archaea thrive in hypersaline conditions associated with desiccation, ultraviolet (UV) irradiation and redox active compounds, and thus are naturally tolerant to a variety of stresses. Here, we identified mutations that promote enhanced tolerance of halophilic archaea to redox-active compounds using Haloferax volcanii as a model organism. The strains were isolated from a library of random transposon mutants for growth on high doses of sodium hypochlorite (NaOCl), an agent that forms hypochlorous acid (HOCl) and other redox acid compounds common to aqueous environments of high concentrations of chloride. The transposon insertion site in each of twenty isolated clones was mapped using the following: (i) inverse nested two-step PCR (INT-PCR) and (ii) semi-random two-step PCR (ST-PCR). Genes that were found to be disrupted in hypertolerant strains were associated with lysine deacetylation, proteasomes, transporters, polyamine biosynthesis, electron transfer, and other cellular processes. Further analysis revealed a ΔpsmA1 (α1) markerless deletion strain that produces only the α2 and β proteins of 20S proteasomes was hypertolerant to hypochlorite stress compared with wild type, which produces α1, α2, and β proteins. The results of this study provide new insights into archaeal tolerance of redox active compounds such as hypochlorite. Full article
(This article belongs to the Special Issue Genetics of Halophilic Microorganisms)
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Open AccessReview The Plant Circadian Clock and Chromatin Modifications
Genes 2018, 9(11), 561; https://doi.org/10.3390/genes9110561
Received: 3 October 2018 / Revised: 27 October 2018 / Accepted: 5 November 2018 / Published: 20 November 2018
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Abstract
The circadian clock is an endogenous timekeeping network that integrates environmental signals with internal cues to coordinate diverse physiological processes. The circadian function depends on the precise regulation of rhythmic gene expression at the core of the oscillators. In addition to the well-characterized
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The circadian clock is an endogenous timekeeping network that integrates environmental signals with internal cues to coordinate diverse physiological processes. The circadian function depends on the precise regulation of rhythmic gene expression at the core of the oscillators. In addition to the well-characterized transcriptional feedback regulation of several clock components, additional regulatory mechanisms, such as alternative splicing, regulation of protein stability, and chromatin modifications are beginning to emerge. In this review, we discuss recent findings in the regulation of the circadian clock function in Arabidopsis thaliana. The involvement of chromatin modifications in the regulation of the core circadian clock genes is also discussed. Full article
(This article belongs to the Special Issue Genetic Regulation of Circadian Rhythm in Plants)
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Open AccessArticle Association of Candidate Genes with Response to Heat and Newcastle Disease Virus
Genes 2018, 9(11), 560; https://doi.org/10.3390/genes9110560
Received: 19 September 2018 / Revised: 12 November 2018 / Accepted: 13 November 2018 / Published: 19 November 2018
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Abstract
Newcastle disease is considered the number one disease constraint to poultry production in low and middle-income countries, however poultry that is raised in resource-poor areas often experience multiple environmental challenges. Heat stress has a negative impact on production, and immune response to pathogens
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Newcastle disease is considered the number one disease constraint to poultry production in low and middle-income countries, however poultry that is raised in resource-poor areas often experience multiple environmental challenges. Heat stress has a negative impact on production, and immune response to pathogens can be negatively modulated by heat stress. Candidate genes and regions chosen for this study were based on previously reported associations with response to immune stimulants, pathogens, or heat, including: TLR3, TLR7, MX, MHC-B (major histocompatibility complex, gene complex), IFI27L2, SLC5A1, HSPB1, HSPA2, HSPA8, IFRD1, IL18R1, IL1R1, AP2A2, and TOLLIP. Chickens of a commercial egg-laying line were infected with a lentogenic strain of NDV (Newcastle disease virus); half the birds were maintained at thermoneutral temperature and the other half were exposed to high ambient temperature before the NDV challenge and throughout the remainder of the study. Phenotypic responses to heat, to NDV, or to heat + NDV were measured. Selected SNPs (single nucleotide polymorphisms) within 14 target genes or regions were genotyped; and genotype effects on phenotypic responses to NDV or heat + NDV were tested in each individual treatment group and the combined groups. Seventeen significant haplotype effects, among seven genes and seven phenotypes, were detected for response to NDV or heat or NDV + heat. These findings identify specific genetic variants that are associated with response to heat and/or NDV which may be useful in the genetic improvement of chickens to perform favorably when faced with pathogens and heat stress. Full article
(This article belongs to the Special Issue Genomics of Avian Viral Infections)
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Open AccessArticle Molecular Characterization of Annexin B2, B3 and B12 in Taenia multiceps
Genes 2018, 9(11), 559; https://doi.org/10.3390/genes9110559
Received: 23 October 2018 / Revised: 8 November 2018 / Accepted: 12 November 2018 / Published: 19 November 2018
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Abstract
Coenurus cerebralis, the metacestode of Taenia multiceps, causes coenurosis, a disease severely affecting goat, sheep, cattle and yak farming and resulting in huge economic losses annually. Annexins bind calcium ions and play an important role in flatworm parasite development. To explore
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Coenurus cerebralis, the metacestode of Taenia multiceps, causes coenurosis, a disease severely affecting goat, sheep, cattle and yak farming and resulting in huge economic losses annually. Annexins bind calcium ions and play an important role in flatworm parasite development. To explore potential functions of annexins in T. multiceps, three homologous genes, namely, TmAnxB2, TmAnxB3 and TmAnxB12, were screened from the transcriptome dataset, amplified from C. cerebralis cDNA and subjected to bioinformatics analysis. Then, polyclonal antibodies recognizing the recombinant TmAnxB2 (rTmAnxB2) and rTmAnxB3 were prepared for localization of TmAnxB2 and TmAnxB3 in different tissues and developmental stages by immunofluorescence. The transcription of all three genes was also measured by relative fluorescent quantitative PCR. The sizes of rTmAnxB2, rTmAnxB3 and rTmAnxB12 were 58.00, 53.06 and 53.51 kDa, respectively, and rTmAnxB12 was unstable. Both rTmAnxB2 and rTmAnxB3 were recognized by goat-positive T. multiceps sera in Western blots. Immunofluorescence revealed that TmAnxB2 and TmAnxB3 were localized in the protoscolex and cyst wall and TmAnxB3 was also detected in adult cortex. TmAnxB2 and TmAnxB12 mRNA levels were determined to be highest in oncospheres and protoscolex, whereas transcription of TmAnxB3 was highest in scolex and immature segments. Taken together, these findings indicate that TmAnxB2 and TmAnxB12 may play critical roles in T. multiceps larvae, while TmAnxB3 may have important functions in adults. These results will lay the foundation for functional research of annexins in T. multiceps. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle Fanconi Anaemia-Like Mph1 Helicase Backs up Rad54 and Rad5 to Circumvent Replication Stress-Driven Chromosome Bridges
Genes 2018, 9(11), 558; https://doi.org/10.3390/genes9110558
Received: 25 October 2018 / Revised: 13 November 2018 / Accepted: 13 November 2018 / Published: 17 November 2018
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Abstract
Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure-selective endonucleases
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Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure-selective endonucleases (SSEs), helicases and topoisomerases. Previously, we showed that yeast double mutants for the Mus81-Mms4 and Yen1 SSEs lead to anaphase bridges (ABs) after replication stress. Here, we have studied the role of the Mph1 helicase in preventing these anaphase aberrations. Mph1, the yeast ortholog of Fanconi anaemia protein M (FANCM), is involved in the removal of the D-loop, the first JM to arise in canonical HR. Surprisingly, the absence of Mph1 alone did not increase ABs; rather, it blocked cells in G2. Interestingly, in the search for genetic interactions with functionally related helicases and translocases, we found additive effects on the G2 block and post-G2 aberrations between mph1Δ and knockout mutants for Srs2, Rad54 and Rad5. Based on these interactions, we suggest that Mph1 acts coordinately with these helicases in the non-canonical HR-driven fork regression mechanism to bypass stalled replication forks. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Cyclic Peptides: Promising Scaffolds for Biopharmaceuticals
Genes 2018, 9(11), 557; https://doi.org/10.3390/genes9110557
Received: 22 October 2018 / Revised: 8 November 2018 / Accepted: 8 November 2018 / Published: 16 November 2018
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Abstract
To date, small molecules and macromolecules, including antibodies, have been the most pursued substances in drug screening and development efforts. Despite numerous favorable features as a drug, these molecules still have limitations and are not complementary in many regards. Recently, peptide-based chemical structures
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To date, small molecules and macromolecules, including antibodies, have been the most pursued substances in drug screening and development efforts. Despite numerous favorable features as a drug, these molecules still have limitations and are not complementary in many regards. Recently, peptide-based chemical structures that lie between these two categories in terms of both structural and functional properties have gained increasing attention as potential alternatives. In particular, peptides in a circular form provide a promising scaffold for the development of a novel drug class owing to their adjustable and expandable ability to bind a wide range of target molecules. In this review, we discuss recent progress in methodologies for peptide cyclization and screening and use of bioactive cyclic peptides in various applications. Full article
(This article belongs to the Special Issue Synthetic DNA and RNA Programming)
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Open AccessReview Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions
Genes 2018, 9(11), 556; https://doi.org/10.3390/genes9110556
Received: 12 October 2018 / Revised: 6 November 2018 / Accepted: 7 November 2018 / Published: 16 November 2018
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Abstract
Heparan sulfate proteoglycan 2 (HSPG2) is an essential, highly conserved gene whose expression influences many developmental processes including the formation of the heart and brain. The gene is widely expressed throughout the musculoskeletal system including cartilage, bone marrow and skeletal muscle.
[...] Read more.
Heparan sulfate proteoglycan 2 (HSPG2) is an essential, highly conserved gene whose expression influences many developmental processes including the formation of the heart and brain. The gene is widely expressed throughout the musculoskeletal system including cartilage, bone marrow and skeletal muscle. The HSPG2 gene product, perlecan is a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Given HSPG2’s expression pattern and its role in so many fundamental processes, it is not surprising that relatively few gene mutations have been identified in viable organisms. Mutations to the perlecan gene are rare, with effects ranging from a relatively mild condition to a more severe and perinatally lethal form. This review will summarize the important studies characterizing mutations and variants of HSPG2 and discuss how these genomic modifications affect expression, function and phenotype. Additionally, this review will describe the clinical findings of reported HSPG2 mutations and their observed phenotypes. Finally, the evolutionary aspects that link gene integrity to function are discussed, including key findings from both in vivo animal studies and in vitro systems. We also hope to facilitate discussion about perlecan/HSPG2 and its role in normal physiology, to explain how mutation can lead to pathology, and to point out how this information can suggest pathways for future mechanistic studies. Full article
(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)
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Open AccessArticle Genetic Dissection of Azuki Bean Weevil (Callosobruchus chinensis L.) Resistance in Moth Bean (Vigna aconitifolia [Jaqc.] Maréchal)
Genes 2018, 9(11), 555; https://doi.org/10.3390/genes9110555
Received: 3 September 2018 / Revised: 9 November 2018 / Accepted: 12 November 2018 / Published: 15 November 2018
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Abstract
The azuki bean weevil (Callosobruchus chinensis L.) is an insect pest responsible for serious postharvest seed loss in leguminous crops. In this study, we performed quantitative trait locus (QTL) mapping of seed resistance to C. chinensis in moth bean (Vigna aconitifolia
[...] Read more.
The azuki bean weevil (Callosobruchus chinensis L.) is an insect pest responsible for serious postharvest seed loss in leguminous crops. In this study, we performed quantitative trait locus (QTL) mapping of seed resistance to C. chinensis in moth bean (Vigna aconitifolia [Jaqc.] Maréchal). An F2 population of 188 plants developed by crossing resistant accession ‘TN67’ (wild type from India; male parent) and susceptible accession ‘IPCMO056’ (cultivated type from India; female parent) was used for mapping. Seeds of the F2 population from 2014 and F2:3 populations from 2016 and 2017 were bioassayed with C. chinensis, and the percentage of damaged seeds and progress of infestation severity were measured. Segregation analysis suggested that C. chinensis resistance in TN176 is controlled by a single dominant gene, designated as Rcc. QTL analysis revealed one principal and one modifying QTL for the resistance, named qVacBrc2.1 and qVacBrc5.1, respectively. qVacBrc2.1 was located on linkage group 2 between simple sequence repeat markers CEDG261 and DMB-SSR160 and accounted for 50.41% to 64.23% of resistance-related traits, depending on the trait and population. Comparative genomic analysis suggested that qVacBrc2.1 is the same as QTL Brc2.1 conferring C. chinensis resistance in wild azuki bean (V. nepalensis Tateishi and Maxted). Markers CEDG261 and DMB-SSR160 should be useful for marker-assisted selection for C. chinensis resistance in moth bean. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Cryptic Diversity Hidden within the Leafminer Genus Liriomyza (Diptera: Agromyzidae)
Genes 2018, 9(11), 554; https://doi.org/10.3390/genes9110554
Received: 17 September 2018 / Revised: 24 October 2018 / Accepted: 12 November 2018 / Published: 15 November 2018
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Abstract
Leafminer insects of the genus Liriomyza are small flies whose larvae feed on the internal tissue of some of the most important crop plants for the human diet. Several of these pest species are highly uniform from the morphological point of view, meaning
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Leafminer insects of the genus Liriomyza are small flies whose larvae feed on the internal tissue of some of the most important crop plants for the human diet. Several of these pest species are highly uniform from the morphological point of view, meaning molecular data represents the only reliable taxonomic tool useful to define cryptic boundaries. In this study, both mitochondrial and nuclear molecular markers have been applied to investigate the population genetics of some Tunisian populations of the polyphagous species Liriomyza cicerina, one of the most important pest of chickpea cultivars in the whole Mediterranean region. Molecular data have been collected on larvae isolated from chickpea, faba bean, and lentil leaves, and used for population genetics, phylogenetics, and species delimitation analyses. Results point toward high differentiation levels between specimens collected on the three different legume crops, which, according to the species delimitation methods, are also sufficient to define incipient species differentiation and cryptic species occurrence, apparently tied up with host choice. Genetic data have also been applied for a phylogenetic comparison among Liriomyza species, further confirming their decisive role in the systematic studies of the genus. Full article
(This article belongs to the Special Issue Tools for Population and Evolutionary Genetics)
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Open AccessArticle Large-Scale Analyses of Site-Specific Evolutionary Rates across Eukaryote Proteomes Reveal Confounding Interactions between Intrinsic Disorder, Secondary Structure, and Functional Domains
Genes 2018, 9(11), 553; https://doi.org/10.3390/genes9110553
Received: 1 October 2018 / Revised: 9 November 2018 / Accepted: 9 November 2018 / Published: 14 November 2018
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Abstract
Various structural and functional constraints govern the evolution of protein sequences. As a result, the relative rates of amino acid replacement among sites within a protein can vary significantly. Previous large-scale work on Metazoan (Animal) protein sequence alignments indicated that amino acid replacement
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Various structural and functional constraints govern the evolution of protein sequences. As a result, the relative rates of amino acid replacement among sites within a protein can vary significantly. Previous large-scale work on Metazoan (Animal) protein sequence alignments indicated that amino acid replacement rates are partially driven by a complex interaction among three factors: intrinsic disorder propensity; secondary structure; and functional domain involvement. Here, we use sequence-based predictors to evaluate the effects of these factors on site-specific sequence evolutionary rates within four eukaryotic lineages: Metazoans; Plants; Saccharomycete Fungi; and Alveolate Protists. Our results show broad, consistent trends across all four Eukaryote groups. In all four lineages, there is a significant increase in amino acid replacement rates when comparing: (i) disordered vs. ordered sites; (ii) random coil sites vs. sites in secondary structures; and (iii) inter-domain linker sites vs. sites in functional domains. Additionally, within Metazoans, Plants, and Saccharomycetes, there is a strong confounding interaction between intrinsic disorder and secondary structure—alignment sites exhibiting both high disorder propensity and involvement in secondary structures have very low average rates of sequence evolution. Analysis of gene ontology (GO) terms revealed that in all four lineages, a high fraction of sequences containing these conserved, disordered-structured sites are involved in nucleic acid binding. We also observe notable differences in the statistical trends of Alveolates, where intrinsically disordered sites are more variable than in other Eukaryotes and the statistical interactions between disorder and other factors are less pronounced. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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Open AccessReview The Emerging Role of Epitranscriptomics in Cancer: Focus on Urological Tumors
Genes 2018, 9(11), 552; https://doi.org/10.3390/genes9110552
Received: 28 September 2018 / Revised: 27 October 2018 / Accepted: 8 November 2018 / Published: 13 November 2018
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Abstract
Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs. m6A has been demonstrated to
[...] Read more.
Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs. m6A has been demonstrated to play important roles in many physiological processes and several disease states, including various cancer models (from solid to liquid tumors). Tumor cells’ epitranscriptome is indeed disrupted in a way to promote cancer-prone features, by means of up/downregulating m6A-related players: the so-called writers, readers and erasers. These proteins modulate m6A establishment, removal and determine mRNAs fate, acting in a context-dependent manner, so that a single player may act as an oncogenic signal in one tumor model (methyltransferase like 3 (METTL3) in lung cancer) and as a tumor suppressor in another context (METTL3 in glioblastoma). Despite recent advances, however, little attention has been directed towards urological cancer. By means of a thorough analysis of the publicly available TCGA (The Cancer Genome Atlas) database, we disclosed the most relevant players in four major urogenital neoplasms—kidney, bladder, prostate and testicular cancer—for prognostic, subtype discrimination and survival purposes. In all tumor models assessed, the most promising player was shown to be Vir like m6A methyltransferase associated (VIRMA), which could constitute a potential target for personalized therapies. Full article
(This article belongs to the Special Issue The Epitranscriptome in Human Disease)
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Open AccessArticle Unintentional Genomic Changes Endow Cupriavidus metallidurans with an Augmented Heavy-Metal Resistance
Genes 2018, 9(11), 551; https://doi.org/10.3390/genes9110551
Received: 6 October 2018 / Revised: 1 November 2018 / Accepted: 8 November 2018 / Published: 13 November 2018
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Abstract
For the past three decades, Cupriavidus metallidurans has been one of the major model organisms for bacterial tolerance to heavy metals. Its type strain CH34 contains at least 24 gene clusters distributed over four replicons, allowing for intricate and multilayered metal responses. To
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For the past three decades, Cupriavidus metallidurans has been one of the major model organisms for bacterial tolerance to heavy metals. Its type strain CH34 contains at least 24 gene clusters distributed over four replicons, allowing for intricate and multilayered metal responses. To gain organic mercury resistance in CH34, broad-spectrum mer genes were introduced in a previous work via conjugation of the IncP-1β plasmid pTP6. However, we recently noted that this CH34-derived strain, MSR33, unexpectedly showed an increased resistance to other metals (i.e., Co2+, Ni2+, and Cd2+). To thoroughly investigate this phenomenon, we resequenced the entire genome of MSR33 and compared its DNA sequence and basal gene expression profile to those of its parental strain CH34. Genome comparison identified 11 insertions or deletions (INDELs) and nine single nucleotide polymorphisms (SNPs), whereas transcriptomic analysis displayed 107 differentially expressed genes. Sequence data implicated the transposition of IS1088 in higher Co2+ and Ni2+ resistances and altered gene expression, although the precise mechanisms of the augmented Cd2+ resistance in MSR33 remains elusive. Our work indicates that conjugation procedures involving large complex genomes and extensive mobilomes may pose a considerable risk toward the introduction of unwanted, undocumented genetic changes. Special efforts are needed for the applied use and further development of small nonconjugative broad-host plasmid vectors, ideally involving CRISPR-related and advanced biosynthetic technologies. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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Open AccessArticle Root-Specific Expression of a Jacalin Lectin Family Protein Gene Requires a Transposable Element Sequence in the Promoter
Genes 2018, 9(11), 550; https://doi.org/10.3390/genes9110550
Received: 17 October 2018 / Revised: 6 November 2018 / Accepted: 7 November 2018 / Published: 13 November 2018
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Abstract
Transposable elements (TEs) are widespread in the plant genome and can impact on the expression of neighbouring genes. Our previous studies have identified a number of DNA demethylase-regulated defence-related genes that contain TE sequences in the promoter and show tissue-specific expression in Arabidopsis.
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Transposable elements (TEs) are widespread in the plant genome and can impact on the expression of neighbouring genes. Our previous studies have identified a number of DNA demethylase-regulated defence-related genes that contain TE sequences in the promoter and show tissue-specific expression in Arabidopsis. In this study we investigated the role of the promoter TE insertions in the root-specific expression of a DNA demethylase-regulated gene, AT5G38550, encoding a Jacalin lectin family protein. Using a promoter:GUS fusion reporter gene approach, we first demonstrated that the full-length promoter fragment, carrying four TE sequences, contained the essential regulatory information required for root-specific expression and DNA demethylase regulation in Arabidopsis. By successive deletion of the four TE sequences, we showed that one of the four TE insertions, a 201-bp TE fragment of the hAT DNA transposon family, was required for root-specific expression: Deletion of this TE, but not the first two TE sequences, converted the root-specific expression pattern to a constitutive expression pattern in Arabidopsis plants. Our study provides an example indicating an important role of TE insertions in tissue-specific expression of plant defence-related genes. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessEditorial Special Issue: Coevolution of Hosts and Their Microbiome
Genes 2018, 9(11), 549; https://doi.org/10.3390/genes9110549
Received: 5 November 2018 / Accepted: 7 November 2018 / Published: 13 November 2018
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Abstract
The evolution of life-history traits in plants and animals has taken place in the midst of complex microbial communities. [...] Full article
(This article belongs to the Special Issue Coevolution of Hosts and their Microbiome)
Open AccessReview De-Extinction
Genes 2018, 9(11), 548; https://doi.org/10.3390/genes9110548
Received: 26 September 2018 / Revised: 1 November 2018 / Accepted: 7 November 2018 / Published: 13 November 2018
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De-extinction projects for species such as the woolly mammoth and passenger pigeon have greatly stimulated public and scientific interest, producing a large body of literature and much debate. To date, there has been little consistency in descriptions of de-extinction technologies and purposes. In
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De-extinction projects for species such as the woolly mammoth and passenger pigeon have greatly stimulated public and scientific interest, producing a large body of literature and much debate. To date, there has been little consistency in descriptions of de-extinction technologies and purposes. In 2016, a special committee of the International Union for the Conservation of Nature (IUCN) published a set of guidelines for de-extinction practice, establishing the first detailed description of de-extinction; yet incoherencies in published literature persist. There are even several problems with the IUCN definition. Here I present a comprehensive definition of de-extinction practice and rationale that expounds and reconciles the biological and ecological inconsistencies in the IUCN definition. This new definition brings together the practices of reintroduction and ecological replacement with de-extinction efforts that employ breeding strategies to recover unique extinct phenotypes into a single “de-extinction” discipline. An accurate understanding of de-extinction and biotechnology segregates the restoration of certain species into a new classification of endangerment, removing them from the purview of de-extinction and into the arena of species’ recovery. I term these species as “evolutionarily torpid species”; a term to apply to species falsely considered extinct, which in fact persist in the form of cryopreserved tissues and cultured cells. For the first time in published literature, all currently active de-extinction breeding programs are reviewed and their progress presented. Lastly, I review and scrutinize various topics pertaining to de-extinction in light of the growing body of peer-reviewed literature published since de-extinction breeding programs gained public attention in 2013. Full article
(This article belongs to the Special Issue Conservation Genetics and Genomics)
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Open AccessArticle Assembly of a Complete Mitogenome of Chrysanthemum nankingense Using Oxford Nanopore Long Reads and the Diversity and Evolution of Asteraceae Mitogenomes
Genes 2018, 9(11), 547; https://doi.org/10.3390/genes9110547
Received: 21 October 2018 / Revised: 3 November 2018 / Accepted: 7 November 2018 / Published: 12 November 2018
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Abstract
Diversity in structure and organization is one of the main features of angiosperm mitochondrial genomes (mitogenomes). The ultra-long reads of Oxford Nanopore Technology (ONT) provide an opportunity to obtain a complete mitogenome and investigate the structural variation in unprecedented detail. In this study,
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Diversity in structure and organization is one of the main features of angiosperm mitochondrial genomes (mitogenomes). The ultra-long reads of Oxford Nanopore Technology (ONT) provide an opportunity to obtain a complete mitogenome and investigate the structural variation in unprecedented detail. In this study, we compared mitogenome assembly methods using Illumina and/or ONT sequencing data and obtained the complete mitogenome (208 kb) of Chrysanthemum nankingense based on the hybrid assembly method. The mitogenome encoded 19 transfer RNA genes, three ribosomal RNA genes, and 34 protein-coding genes with 21 group II introns disrupting eight intron-contained genes. A total of seven medium repeats were related to homologous recombination at different frequencies as supported by the long ONT reads. Subsequently, we investigated the variations in gene content and constitution of 28 near-complete mitogenomes from Asteraceae. A total of six protein-coding genes were missing in all Asteraceae mitogenomes, while four other genes were not detected in some lineages. The core fragments (~88 kb) of the Asteraceae mitogenomes had a higher GC content (~46.7%) than the variable and specific fragments. The phylogenetic topology based on the core fragments of the Asteraceae mitogenomes was highly consistent with the topologies obtained from the corresponding plastid datasets. Our results highlighted the advantages of the complete assembly of the C. nankingense mitogenome and the investigation of its structural variation based on ONT sequencing data. Moreover, the method based on local collinear blocks of the mitogenomes could achieve the alignment of highly rearrangeable and variable plant mitogenomes as well as construct a robust phylogenetic topology. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Dissecting the Contribution of Release Factor Interactions to Amber Stop Codon Reassignment Efficiencies of the Methanocaldococcus jannaschii Orthogonal Pair
Genes 2018, 9(11), 546; https://doi.org/10.3390/genes9110546
Received: 18 October 2018 / Revised: 5 November 2018 / Accepted: 5 November 2018 / Published: 12 November 2018
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Abstract
Non-canonical amino acids (ncAAs) are finding increasing use in basic biochemical studies and biomedical applications. The efficiency of ncAA incorporation is highly variable, as a result of competing system composition and codon context effects. The relative quantitative contribution of the multiple factors affecting
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Non-canonical amino acids (ncAAs) are finding increasing use in basic biochemical studies and biomedical applications. The efficiency of ncAA incorporation is highly variable, as a result of competing system composition and codon context effects. The relative quantitative contribution of the multiple factors affecting incorporation efficiency are largely unknown. This manuscript describes the use of green fluorescent protein (GFP) reporters to quantify the efficiency of amber codon reassignment using the Methanocaldococcus jannaschii orthogonal pair system, commonly employed for ncAA incorporation, and quantify the contribution of release factor 1 (RF1) to the overall efficiency of amino acid incorporation. The efficiencies of amber codon reassignments were quantified at eight positions in GFP and evaluated in multiple combinations. The quantitative contribution of RF1 competition to reassignment efficiency was evaluated through comparisons of amber codon suppression efficiencies in normal and genomically recoded Escherichia coli strains. Measured amber stop codon reassignment efficiencies for eight single stop codon GFP variants ranged from 51 to 117% in E. coli DH10B and 76 to 104% in the RF1 deleted E. coli C321.ΔA.exp. Evaluation of efficiency changes in specific sequence contexts in the presence and absence of RF1 suggested that RF1 specifically interacts with +4 Cs and that the RF1 interactions contributed approximately half of the observed sequence context-dependent variation in measured reassignment efficiency. Evaluation of multisite suppression efficiencies suggests that increasing demand for translation system components limits multisite incorporation in cells with competing RF1. Full article
(This article belongs to the Special Issue Synthetic DNA and RNA Programming)
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Open AccessArticle miRNA Mediated Noise Making of 3′UTR Mutations in Cancer
Genes 2018, 9(11), 545; https://doi.org/10.3390/genes9110545
Received: 18 October 2018 / Revised: 1 November 2018 / Accepted: 6 November 2018 / Published: 12 November 2018
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Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic
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Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic mutations located in the 3′UTRs of messenger RNAs (mRNAs) which can alter miRNA–mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3′UTR mutations may play an important role in tumor development. Full article
(This article belongs to the Special Issue Non-coding RNAs)
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Open AccessArticle Population Connectivity and Traces of Mitochondrial Introgression in New Zealand Black-Billed Gulls (Larus bulleri)
Genes 2018, 9(11), 544; https://doi.org/10.3390/genes9110544
Received: 12 October 2018 / Revised: 25 October 2018 / Accepted: 29 October 2018 / Published: 9 November 2018
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Abstract
Black-billed gulls (Larus bulleri) are endemic to New Zealand and are suspected to be undergoing substantial population declines. They primarily breed on open gravel beds in braided rivers of the South Island—a habitat that is diminishing and becoming increasingly modified. Although
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Black-billed gulls (Larus bulleri) are endemic to New Zealand and are suspected to be undergoing substantial population declines. They primarily breed on open gravel beds in braided rivers of the South Island—a habitat that is diminishing and becoming increasingly modified. Although management of this species is increasing, little has been published on their movements and demographics. In this study, both mitochondrial DNA (mtDNA) control region domain I and nuclear single nucleotide polymorphisms (SNPs) were examined to help understand the connectivity and population structure of black-billed gulls across the country and to help inform management decisions. Mitochondrial DNA showed no population structure, with high haplotype and low nucleotide diversity, and analyses highlighted mitochondrial introgression with the closely related red-billed gulls (Larus novaehollandiae scopulinus). Nuclear DNA analyses, however, identified two groups, with Rotorua birds in the North Island being distinct from the rest of New Zealand, and isolation-by-distance evident across the South Island populations. Gene flow primarily occurs between nearby colonies with a stepwise movement across the landscape. The importance from a genetic perspective of the more isolated North Island birds (1.6% of total population) needs to be further evaluated. From our results, we infer that the South Island black-billed gull management should focus on maintaining several populations within each region rather than focusing on single specific colonies or river catchments. Future study is needed to investigate the genetic structure of populations at the northern limit of the species’ range, and identify the mechanisms behind, and extent of, the hybridisation between red-billed and black-billed gulls. Full article
(This article belongs to the Special Issue Conservation Genetics and Genomics)
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Open AccessArticle The MAPKKK CgMck1 Is Required for Cell Wall Integrity, Appressorium Development, and Pathogenicity in Colletotrichum gloeosporioides
Genes 2018, 9(11), 543; https://doi.org/10.3390/genes9110543
Received: 16 October 2018 / Revised: 4 November 2018 / Accepted: 5 November 2018 / Published: 8 November 2018
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Abstract
Mitogen-activated protein kinase (MAPK) signaling pathway plays key roles in sensing extracellular signals and transmitting them from the cell membrane to the nucleus in response to various environmental stimuli. A MAPKKK protein CgMck1 in Colletotrichum gloeosporioides was characterized. Phenotypic analyses of the ∆
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Mitogen-activated protein kinase (MAPK) signaling pathway plays key roles in sensing extracellular signals and transmitting them from the cell membrane to the nucleus in response to various environmental stimuli. A MAPKKK protein CgMck1 in Colletotrichum gloeosporioides was characterized. Phenotypic analyses of the ∆Cgmck1 mutant showed that the CgMck1 was required for vegetative growth, fruiting body development, and sporulation. Additionally, the CgMCK1 deletion mutant showed significant defects in cell wall integrity, and responses to osmotic stresses. The mutant abolished the ability to develop appressorium, and lost pathogenicity to host plants. The ∆Cgmck1 mutant also exhibited a higher sensitivity to antifungal bacterium agent Bacillus velezensis. The deletion mutants of downstream MAPK cascades components CgMkk1 and CgMps1 showed similar defects to the ∆Cgmck1 mutant. In conclusion, CgMck1 is involved in the regulation of vegetative growth, asexual development, cell wall integrity, stresses resistance, and infection morphogenesis in C. gloeosporioides. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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Open AccessReview Harnessing Rhizobia to Improve Heavy-Metal Phytoremediation by Legumes
Genes 2018, 9(11), 542; https://doi.org/10.3390/genes9110542
Received: 28 September 2018 / Revised: 5 November 2018 / Accepted: 6 November 2018 / Published: 8 November 2018
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Abstract
Rhizobia are bacteria that can form symbiotic associations with plants of the Fabaceae family, during which they reduce atmospheric di-nitrogen to ammonia. The symbiosis between rhizobia and leguminous plants is a fundamental contributor to nitrogen cycling in natural and agricultural ecosystems. Rhizobial microsymbionts
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Rhizobia are bacteria that can form symbiotic associations with plants of the Fabaceae family, during which they reduce atmospheric di-nitrogen to ammonia. The symbiosis between rhizobia and leguminous plants is a fundamental contributor to nitrogen cycling in natural and agricultural ecosystems. Rhizobial microsymbionts are a major reason why legumes can colonize marginal lands and nitrogen-deficient soils. Several leguminous species have been found in metal-contaminated areas, and they often harbor metal-tolerant rhizobia. In recent years, there have been numerous efforts and discoveries related to the genetic determinants of metal resistance by rhizobia, and on the effectiveness of such rhizobia to increase the metal tolerance of host plants. Here, we review the main findings on the metal resistance of rhizobia: the physiological role, evolution, and genetic determinants, and the potential to use native and genetically-manipulated rhizobia as inoculants for legumes in phytoremediation practices. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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Open AccessReview Epidemiology of Hepatitis B Virus Infection in Bangladesh: Prevalence among General Population, Risk Groups and Genotype Distribution
Genes 2018, 9(11), 541; https://doi.org/10.3390/genes9110541
Received: 5 September 2018 / Revised: 26 October 2018 / Accepted: 29 October 2018 / Published: 8 November 2018
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Despite a considerable body of published research on hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about hepatitis B virus (HBV) infection epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus
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Despite a considerable body of published research on hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about hepatitis B virus (HBV) infection epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus on a number of epidemiological questions, as well as a commentary on the trends of hepatitis B research as it has taken place in Bangladesh. The key themes to emerge from this review are: first, beyond noting a declining trend, it is difficult to provide conclusive estimates about HBV prevalence in the general population of Bangladesh. The majority of the studies, even the ones conducted on apparently healthy populations, fail to be adequately representative for the reasons explored in the article. Secondly, HBV infection in Bangladesh is sharply stratified across sociodemographic lines, which speaks to the role of awareness and risk exposure in HBV prevalence. Third, more research on occult infection rates is required to estimate the extent of risk posed by the current blood donation screening program, which relies exclusively on hepatitis B surface antigen as a biomarker. The same considerations apply for the comparative importance of vertical versus horizontal transmission and prevalence among particular risk groups like healthcare workers with high occupational exposure. Finally, while recent studies do allow us, albeit with some ambiguity, to draw conclusions about distribution of HBV genotypes in Bangladesh, there needs to be an added emphasis on molecular epidemiology. It is hoped that the present review, the first of its kind in Bangladesh, will serve as an up-to-date summary of the course HBV epidemiology research in Bangladesh has taken thus far, as well as crucial gaps to address going forward. Full article
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Open AccessReview Transcriptomic and Genomic Approaches for Unravelling Candida albicans Biofilm Formation and Drug Resistance—An Update
Genes 2018, 9(11), 540; https://doi.org/10.3390/genes9110540
Received: 21 September 2018 / Revised: 29 October 2018 / Accepted: 30 October 2018 / Published: 7 November 2018
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Abstract
Candida albicans is an opportunistic fungal pathogen, which causes a plethora of superficial, as well as invasive, infections in humans. The ability of this fungus in switching from commensalism to active infection is attributed to its many virulence traits. Biofilm formation is a
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Candida albicans is an opportunistic fungal pathogen, which causes a plethora of superficial, as well as invasive, infections in humans. The ability of this fungus in switching from commensalism to active infection is attributed to its many virulence traits. Biofilm formation is a key process, which allows the fungus to adhere to and proliferate on medically implanted devices as well as host tissue and cause serious life-threatening infections. Biofilms are complex communities of filamentous and yeast cells surrounded by an extracellular matrix that confers an enhanced degree of resistance to antifungal drugs. Moreover, the extensive plasticity of the C. albicans genome has given this versatile fungus the added advantage of microevolution and adaptation to thrive within the unique environmental niches within the host. To combat these challenges in dealing with C. albicans infections, it is imperative that we target specifically the molecular pathways involved in biofilm formation as well as drug resistance. With the advent of the -omics era and whole genome sequencing platforms, novel pathways and genes involved in the pathogenesis of the fungus have been unraveled. Researchers have used a myriad of strategies including transcriptome analysis for C. albicans cells grown in different environments, whole genome sequencing of different strains, functional genomics approaches to identify critical regulatory genes, as well as comparative genomics analysis between C. albicans and its closely related, much less virulent relative, C. dubliniensis, in the quest to increase our understanding of the mechanisms underlying the success of C. albicans as a major fungal pathogen. This review attempts to summarize the most recent advancements in the field of biofilm and antifungal resistance research and offers suggestions for future directions in therapeutics development. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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Open AccessReview Genome Instability Induced by Low Levels of Replicative DNA Polymerases in Yeast
Genes 2018, 9(11), 539; https://doi.org/10.3390/genes9110539
Received: 24 October 2018 / Revised: 4 November 2018 / Accepted: 5 November 2018 / Published: 7 November 2018
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Abstract
Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have
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Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have examined genome instability in yeast strains that have low levels of two of the replicative DNA polymerases: DNA polymerase α and DNA polymerase δ (Polα and Polδ). We show that low levels of either of these DNA polymerases results in greatly elevated levels of mitotic recombination, chromosome rearrangements, and deletions/duplications. The spectrum of events in the two types of strains, however, differs in a variety of ways. For example, a reduced level of Polδ elevates single-base alterations and small deletions considerably more than a reduced level of Polα. In this review, we will summarize the methods used to monitor genome instability in yeast, and how this analysis contributes to understanding the linkage between genome instability and DNA replication stress. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward
Genes 2018, 9(11), 538; https://doi.org/10.3390/genes9110538
Received: 27 September 2018 / Revised: 30 October 2018 / Accepted: 31 October 2018 / Published: 7 November 2018
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Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung
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Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality. Full article
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
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Open AccessReview Versatility of Synthetic tRNAs in Genetic Code Expansion
Genes 2018, 9(11), 537; https://doi.org/10.3390/genes9110537
Received: 16 October 2018 / Revised: 31 October 2018 / Accepted: 5 November 2018 / Published: 7 November 2018
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Abstract
Transfer RNA (tRNA) is a dynamic molecule used by all forms of life as a key component of the translation apparatus. Each tRNA is highly processed, structured, and modified, to accurately deliver amino acids to the ribosome for protein synthesis. The tRNA molecule
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Transfer RNA (tRNA) is a dynamic molecule used by all forms of life as a key component of the translation apparatus. Each tRNA is highly processed, structured, and modified, to accurately deliver amino acids to the ribosome for protein synthesis. The tRNA molecule is a critical component in synthetic biology methods for the synthesis of proteins designed to contain non-canonical amino acids (ncAAs). The multiple interactions and maturation requirements of a tRNA pose engineering challenges, but also offer tunable features. Major advances in the field of genetic code expansion have repeatedly demonstrated the central importance of suppressor tRNAs for efficient incorporation of ncAAs. Here we review the current status of two fundamentally different translation systems (TSs), selenocysteine (Sec)- and pyrrolysine (Pyl)-TSs. Idiosyncratic requirements of each of these TSs mandate how their tRNAs are adapted and dictate the techniques used to select or identify the best synthetic variants. Full article
(This article belongs to the Special Issue Synthetic DNA and RNA Programming)
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