Protecting exons from deleterious R-loops: a potential advantage of having introns

BACKGROUND: Accumulating evidence indicates that the nascent RNA can invade and pair with one strand of DNA, forming an R-loop structure that threatens the stability of the genome. In addition, the cost and benefit of introns are still in debate. RESULTS: At least three factors are likely required for the R-loop formation: 1) sequence complementarity between the nascent RNA and the target DNA, 2) spatial juxtaposition between the nascent RNA and the template DNA, and 3) accessibility of the template DNA and the nascent RNA. The removal of introns from pre-mRNA reduces the complementarity between RNA and the template DNA and avoids the spatial juxtaposition between the nascent RNA and the template DNA. In addition, the secondary structures of group I and group II introns may act as spatial obstacles for the formation of R-loops between nearby exons and the genomic DNA. CONCLUSION: Organisms may benefit from introns by avoiding deleterious R-loops. The potential contribution of this benefit in driving intron evolution is discussed. I propose that additional RNA polymerases may inhibit R-loop formation between preceding nascent RNA and the template DNA. This idea leads to a testable prediction: intermittently transcribed genes and genes with frequently prolonged transcription should have higher intron density. REVIEWERS: This article was reviewed by Dr. Eugene V. Koonin, Dr. Alexei Fedorov (nominated by Dr. Laura F Landweber), and Dr. Scott W. Roy (nominated by Dr. Arcady Mushegian)

Exon definition as a potential negative force against intron losses in evolution

<p>Abstract</p> <p>Background</p> <p>Previous studies have indicated that the wide variation in intron density (the number of introns per gene) among different eukaryotes largely reflects varying degrees of intron loss during evolution. The most popular model, which suggests that organisms lose introns through a mechanism in which reverse-transcribed cDNA recombines with the genomic DNA, concerns only one mutational force.</p> <p>Hypothesis</p> <p>Using exons as the units of splicing-site recognition, exon definition constrains the length of exons. An intron-loss event results in fusion of flanking exons and thus a larger exon. The large size of the newborn exon may cause splicing errors, i.e., exon skipping, if the splicing of pre-mRNAs is initiated by exon definition. By contrast, if the splicing of pre-mRNAs is initiated by intron definition, intron loss does not matter. Exon definition may thus be a selective force against intron loss. An organism with a high frequency of exon definition is expected to experience a low rate of intron loss throughout evolution and have a high density of spliceosomal introns.</p> <p>Conclusion</p> <p>The majority of spliceosomal introns in vertebrates may be maintained during evolution not because of potential functions, but because of their splicing mechanism (i.e., exon definition). Further research is required to determine whether exon definition is a negative force in maintaining the high intron density of vertebrates.</p> <p>Reviewers</p> <p>This article was reviewed by Dr. Scott W. Roy (nominated by Dr. John Logsdon), Dr. Eugene V. Koonin, and Dr. Igor B. Rogozin (nominated by Dr. Mikhail Gelfand). For the full reviews, please go to the Reviewers' comments section.</p

Resource Allocation for Device-to-Device Communications Underlaying Heterogeneous Cellular Networks Using Coalitional Games

Heterogeneous cellular networks (HCNs) with millimeter wave (mmWave) communications included are emerging as a promising candidate for the fifth generation mobile network. With highly directional antenna arrays, mmWave links are able to provide several-Gbps transmission rate. However, mmWave links are easily blocked without line of sight. On the other hand, D2D communications have been proposed to support many content based applications, and need to share resources with users in HCNs to improve spectral reuse and enhance system capacity. Consequently, an efficient resource allocation scheme for D2D pairs among both mmWave and the cellular carrier band is needed. In this paper, we first formulate the problem of the resource allocation among mmWave and the cellular band for multiple D2D pairs from the view point of game theory. Then, with the characteristics of cellular and mmWave communications considered, we propose a coalition formation game to maximize the system sum rate in statistical average sense. We also theoretically prove that our proposed game converges to a Nash-stable equilibrium and further reaches the near-optimal solution with fast convergence rate. Through extensive simulations under various system parameters, we demonstrate the superior performance of our scheme in terms of the system sum rate compared with several other practical schemes.Comment: 13 pages, 12 figure

Improving Top- N

Recommender systems become increasingly significant in solving the information explosion problem. Data sparse is a main challenge in this area. Massive unrated items constitute missing data with only a few observed ratings. Most studies consider missing data as unknown information and only use observed data to learn models and generate recommendations. However, data are missing not at random. Part of missing data is due to the fact that users choose not to rate them. This part of missing data is negative examples of user preferences. Utilizing this information is expected to leverage the performance of recommendation algorithms. Unfortunately, negative examples are mixed with unlabeled positive examples in missing data, and they are hard to be distinguished. In this paper, we propose three schemes to utilize the negative examples in missing data. The schemes are then adapted with SVD++, which is a state-of-the-art matrix factorization recommendation approach, to generate recommendations. Experimental results on two real datasets show that our proposed approaches gain better top-N performance than the baseline ones on both accuracy and diversity

Evidence against the energetic cost hypothesis for the short introns in highly expressed genes

<p>Abstract</p> <p>Background</p> <p>In animals, the moss <it>Physcomitrella patens </it>and the pollen of <it>Arabidopsis thaliana</it>, highly expressed genes have shorter introns than weakly expressed genes. A popular explanation for this is selection for transcription efficiency, which includes two sub-hypotheses: to minimize the energetic cost or to minimize the time cost.</p> <p>Results</p> <p>In an individual human, different organs may differ up to hundreds of times in cell number (for example, a liver versus a hypothalamus). Considered at the individual level, a gene specifically expressed in a large organ is actually transcribed tens or hundreds of times more than a gene with a similar expression level (a measure of mRNA abundance per cell) specifically expressed in a small organ. According to the energetic cost hypothesis, the former should have shorter introns than the latter. However, in humans and mice we have not found significant differences in intron length between large-tissue/organ-specific genes and small-tissue/organ-specific genes with similar expression levels. Qualitative estimation shows that the deleterious effect (that is, the energetic burden) of long introns in highly expressed genes is too negligible to be efficiently selected against in mammals.</p> <p>Conclusion</p> <p>The short introns in highly expressed genes should not be attributed to energy constraint. We evaluated evidence for the time cost hypothesis and other alternatives.</p

Why eukaryotic cells use introns to enhance gene expression: Splicing reduces transcription-associated mutagenesis by inhibiting topoisomerase I cutting activity

<p>Abstract</p> <p>Background</p> <p>The costs and benefits of spliceosomal introns in eukaryotes have not been established. One recognized effect of intron splicing is its known enhancement of gene expression. However, the mechanism regulating such splicing-mediated expression enhancement has not been defined. Previous studies have shown that intron splicing is a time-consuming process, indicating that splicing may not reduce the time required for transcription and processing of spliced pre-mRNA molecules; rather, it might facilitate the later rounds of transcription. Because the densities of active RNA polymerase II on most genes are less than one molecule per gene, direct interactions between the splicing apparatus and transcriptional complexes (from the later rounds of transcription) are infrequent, and thus unlikely to account for splicing-mediated gene expression enhancement.</p> <p>Presentation of the hypothesis</p> <p>The serine/arginine-rich protein SF2/ASF can inhibit the DNA topoisomerase I activity that removes negative supercoiling of DNA generated by transcription. Consequently, splicing could make genes more receptive to RNA polymerase II during the later rounds of transcription, and thus affect the frequency of gene transcription. Compared with the transcriptional enhancement mediated by strong promoters, intron-containing genes experience a lower frequency of cut-and-paste processes. The cleavage and religation activity of DNA strands by DNA topoisomerase I was recently shown to account for transcription-associated mutagenesis. Therefore, intron-mediated enhancement of gene expression could reduce transcription-associated genome instability.</p> <p>Testing the hypothesis</p> <p>Experimentally test whether transcription-associated mutagenesis is lower in intron-containing genes than in intronless genes. Use bioinformatic analysis to check whether exons flanking lost introns have higher frequencies of short deletions.</p> <p>Implications of the hypothesis</p> <p>The mechanism of intron-mediated enhancement proposed here may also explain the positive correlation observed between intron size and gene expression levels in unicellular organisms, and the greater number of intron containing genes in higher organisms.</p> <p>Reviewers</p> <p>This article was reviewed by Dr Arcady Mushegian, Dr Igor B Rogozin (nominated by Dr I King Jordan) and Dr Alexey S Kondrashov. For the full reviews, please go to the Reviewer's Reports section.</p

Viability of Non-Coplanar VMAT for Liver SBRT as Compared to Coplanar VMAT and Beam Orientation Optimized 4π IMRT.

PurposeThe 4π static non-coplanar radiotherapy delivery technique has demonstrated better normal tissue sparing and dose conformity than the clinically used volumetric modulated arc therapy (VMAT). It is unclear whether this is a fundamental limitation of VMAT delivery or the coplanar nature of its typical clinical plans. The dosimetry and the limits of normal tissue toxicity constrained dose escalation of coplanar VMAT, non-coplanar VMAT and 4π radiotherapy are quantified in this study.Methods and materialsClinical stereotactic body radiation therapy plans for 20 liver patients receiving 30-60 Gy using coplanar VMAT (cVMAT) were re-planned using 3-4 partial non-coplanar arcs (nVMAT) and 4π with 20 intensity-modulated non-coplanar fields. The conformity number (CN), homogeneity index (HI), 50% dose spillage volume (R50), normal liver volume receiving &gt;15 Gy (VL&gt;15), dose to organs at risk (OARs), and tumor control probability (TCP) were compared for all three treatment plans. The maximum tolerable dose (MTD) yielding a normal liver normal tissue control probability (NTCP) below 1%, 5%, and 10% was calculated with the Lyman-Kutcher-Burman model for each plan, as well as the resulting survival fractions at one, two, three, and four years.ResultsCompared to cVMAT, the nVMAT and 4π plans reduced VL&gt;15 by an average of 5 cm3 and 80 cm3, respectively. 4π reduced the 50% dose spillage volume by ~23% compared to both VMAT plans, and either significantly decreased or maintained OAR doses. The 4π MTDs and survival fractions were significantly higher than both cVMAT and nVMAT (p&lt;0.05) for all normal liver NTCP limits used in this study.ConclusionsThe 4π technique provides significantly better OAR sparing than both cVMAT and vMAT and enables more clinically relevant dose escalation for tumor local control. Therefore, despite the current accessibility of nVMAT, it is not a viable alternative to 4π for liver SBRT

Transient ligand‐enabled transition metal‐catalysed C‐H functionalisation

Transition metal‐catalysed C‐H bond functionalisation is one of the most efficient and powerful strategies in synthetic organic chemistry to derivatize otherwise inert sites of organic molecules for the construction of C‐C and C‐heteroatom bonds. However, additional steps are often required in order to install the directing groups to realize the positional functionalisation of the substrates. These tedious steps run counter to the step‐economical nature of the C‐H activation. In contrast, direct functionalisation of the substrate, utilizing the transient ligands, avoids the unnecessary steps for the prefunctionalisation of the substrates. In this mini review, we will provide a short journey for the major progress made in this field for the C‐H functionalisation on sp2 and sp3 carbon centres with different transient working modes, including the covalent, hydrogen, and ionic bonds

Benzisothiazol‐3‐ones through a Metal‐Free Intramolecular N–S Bond Formation

The highly efficient synthesis of benzoisothiazol‐3‐ones from thiobenzamides has been described with good functional group compatibility and excellent yields. This work represents the first example of selectfluor‐promoted N–S bond formation processes. This method provides a facile approach to access various important bioactive benzoisothiazol‐3‐ones