TFBSTools: an R/bioconductor package for transcription factor binding site analysis.

Summary: The ability to efficiently investigate transcription factor binding sites (TFBSs) genome-wide is central to computational studies of gene regulation. TFBSTools is an R/Bioconductor package for the analysis and manipulation of TFBSs and their associated transcription factor profile matrices. TFBStools provides a toolkit for handling TFBS profile matrices, scanning sequences and alignments including whole genomes, and querying the JASPAR database. The functionality of the package can be easily extended to include advanced statistical analysis, data visualization and data integration. Availability and implementation: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/TFBSTools/). Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Legendrian contact homology in R3\mathbb{R}^3

This is an introduction to Legendrian contact homology and the Chekanov-Eliashberg differential graded algebra, with a focus on the setting of Legendrian knots in $\mathbb{R}^3$.Comment: v3: 59 pages, 27 figures; introduction rewritten, sections 5 and 6 switched, many small revision

Legendrian and transverse twist knots

In 1997, Chekanov gave the first example of a Legendrian nonsimple knot type: the $m(5_2)$ knot. Epstein, Fuchs, and Meyer extended his result by showing that there are at least $n$ different Legendrian representatives with maximal Thurston--Bennequin number of the twist knot $K_{-2n}$ with crossing number $2n+1$. In this paper we give a complete classification of Legendrian and transverse representatives of twist knots. In particular, we show that $K_{-2n}$ has exactly $\lceil\frac{n^2}2\rceil$ Legendrian representatives with maximal Thurston--Bennequin number, and $\lceil\frac{n}{2}\rceil$ transverse representatives with maximal self-linking number. Our techniques include convex surface theory, Legendrian ruling invariants, and Heegaard Floer homology.Comment: 27 pages, v3: added figure, other minor changes, to appear in JEM

Distinct core promoter codes drive transcription initiation at key developmental transitions in a marine chordate

BACKGROUND: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates. RESULTS: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box. CONCLUSIONS: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome-wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa

Invariants of Legendrian Knots and Coherent Orientations

We provide a translation between Chekanov's combinatorial theory for invariants of Legendrian knots in the standard contact R^3 and a relative version of Eliashberg and Hofer's Contact Homology. We use this translation to transport the idea of ``coherent orientations'' from the Contact Homology world to Chekanov's combinatorial setting. As a result, we obtain a lifting of Chekanov's differential graded algebra invariant to an algebra over Z[t,t^{-1}] with a full Z grading.Comment: 32 pages, 17 figures; small technical corrections to proof of Thm 3.7 and example 4.

Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome

Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes

Evaluating an analytical model to predict subsurface LNAPL distributions and transmissivity from current and historic fluid levels in groundwater wells: Comparing results to numerical simulations

A recent analytical model predicts free, entrapped, and residual LNAPL saturations and the LNAPL transmissivity in the subsurface from current and historic fluid levels in groundwater wells. As such, the model accounts for effects of fluid level fluctuations in a well. The model was developed to predict LNAPL specific volumes and transmissivities from current fluid level measurements in wells and either recorded historic fluid level fluctuations in wells or estimates. An assumption is made in the model that the predictions are not dependent on whether the historic highest or lowest fluid level elevations in a well occur first. To test the assumption, we conduct two simulations with a modified multiphase flow numerical code TMVOC that incorporates relative permeability-saturation-capillary head relations employed in the model. In one simulation, the initial condition is for fluid levels in a well at the historic highest elevations. In the other simulation, the initial condition is for fluid levels in a well at the historic lowest elevations. We change the boundary conditions so both historical conditions occur followed by generating the current condition. Results from the numerical simulations are compared to model predictions and show the assumption in the analytical model is reasonable. The analytical model can be used to develop/refine conceptual site models and for assessing potential LNAPL recovery endpoints, especially on sites with fluctuating fluid levels in wells

Naturally Occurring Isoleucyl-tRNA Synthetase without tRNA-dependent Pre-transfer Editing

Isoleucyl-tRNA synthetase (IleRS) is unusual among aminoacyl-tRNA synthetases in having a tRNA-dependent pre-transfer editing activity. Alongside the typical bacterial IleRS (such as Escherichia coli IleRS), some bacteria also have the enzymes (eukaryote-like) that cluster with eukaryotic IleRSs and exhibit low sensitivity to the antibiotic mupirocin. Our phylogenetic analysis suggests that the ileS1 and ileS2 genes of contemporary bacteria are the descendants of genes that might have arisen by an ancient duplication event before the separation of bacteria and archaea. We present the analysis of evolutionary constraints of the synthetic and editing reactions in eukaryotic/eukaryote-like IleRSs, which share a common origin but diverged through adaptation to different cell environments. The enzyme from the yeast cytosol exhibits tRNA-dependent pre-transfer editing analogous to E. coli IleRS. This argues for the presence of this proofreading in the common ancestor of both IleRS types and an ancient origin of the synthetic site-based quality control step. Yet surprisingly, the eukaryote-like enzyme from Streptomyces griseus IleRS lacks this capacity; at the same time, its synthetic site displays the 10(3)-fold drop in sensitivity to antibiotic mupirocin relative to the yeast enzyme. The discovery that pre-transfer editing is optional in IleRSs lends support to the notion that the conserved post-transfer editing domain is the main checkpoint in these enzymes. We substantiated this by showing that under error-prone conditions S. griseus IleRS is able to rescue the growth of an E. coli lacking functional IleRS, providing the first evidence that tRNA-dependent pre-transfer editing in IleRS is not essential for cell viability

Off-label use in germany - a current appraisal of gynaecologic university departments

<p>Abstract</p> <p>Objective</p> <p>The off-label use, referring to the applicability of pharmaceutical drugs beyond the submitted and from the Federal Institute for Drugs and Medical Devices (BfArM, Bundesamt für Arzneimittel und Medizinprodukte) certified and approved administration, is the subject of controversial discussions. the application can be considered in case of severe illness - if no therapeutic alternatives are available - or it exists as a founded perspective for achieving therapeutic success.</p> <p>Methods</p> <p>A latitudinal study for evaluating the application of off-label use supplements was performed at 43 German university and academic teaching hospitals. Five doctors at each hospital applied off-label pharmaceutical drugs and were called upon to share their personal experience to the application of those medications.</p> <p>Results</p> <p>75 (35%) questionnaires were returned out of 22 (51%) medical centres with 215 contacted physicians. Off-label use was common for 65 (91%) of the physicians. Only 9% of them obviate the application of off-label drugs. About a half of the medication is related to application in obstetrics (54%) and in most cases on an every day basis. Uterotonics were the most commonly used off-label medications (34%). The main part of information about off-label use is obtained from personal information of colleagues (66%) and personal experience (58%). 34% of physicians think that off label use is risky. Interestingly, the view about off label use of medication varies considerably among physicians from various hospitals.</p> <p>Conclusions</p> <p>The application of off-label pharmaceutical drugs in Germany seems to be a well established practice. More than 90% of participators of our trial use at least one medication outside the administration. This includes particularly prostaglandins, anti-hyper-tonic therapeutics and chemotherapeutics.</p

Ancestrally duplicated conserved noncoding element suggests dual regulatory roles of HOTAIR in <i>cis </i>and <i>trans</i>

HOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans. We propose a dual modality of HOTAIR regulation where transcription of HOTAIR and its embedded enhancer regulates HOXC11 in cis and sequence complementarity between paralogous CNEs suggests HOXD11 regulation in trans.publishedVersio