The analysis of regulatory regions in genome sequences is strongly based on the detection of potential transcription factor binding sites. The preferred models for representation of transcription ...factor binding specificity have been termed position‐specific scoring matrices. JASPAR is an open‐access database of annotated, high‐quality, matrix‐based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome‐wide and comparative genomic analysis of regulatory regions. JASPAR is available at http://jaspar. cgb.ki.se.
ConSite is a user-friendly, web-based tool for finding cis-regulatory elements in genomic sequences. Predictions are based on the integration of binding site prediction generated with high-quality ...transcription factor models and cross-species comparison filtering (phylogenetic footprinting). By incorporating evolutionary constraints, selectivity is increased by an order of magnitude as compared to single-sequence analysis. ConSite offers several unique features, including an interactive expert system for retrieving orthologous regulatory sequences. Programming modules and biological databases that form the foundation of the ConSite service are freely available to the research community. ConSite is available at http:/www.phylofoot.org/consite.
JASPAR is a popular open-access database for matrix models describing DNA-binding preferences for transcription factors and other DNA patterns. With its third major release, JASPAR has been expanded ...and equipped with additional functions aimed at both casual and power users. The heart of the JASPAR database--the JASPAR CORE sub-database--has increased by 12% in size, and three new specialized sub-databases have been added. New functions include clustering of matrix models by similarity, generation of random matrices by sampling from selected sets of existing models and a language-independent Web Service applications programming interface for matrix retrieval. JASPAR is available at http://jaspar.genereg.net.
Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced ...spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity.
Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability.
This analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper-excitability, the manipulation of which potentially could be used to alter the transcriptional response to prevent the motor neurons from entering a state of hyper-excitability.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims/hypothesis
We hypothesised that the blunted baroreflex sensitivity (BRS) typical of type 1 diabetes is caused by a higher degree of tissue hypoxia in diabetes, and tested whether oxygen ...increased BRS and ventilation less, equally or more than in healthy control participants (the latter suggesting higher tissue hypoxia). In addition, we also considered the possible interference between oxygen and breathing pattern.
Methods
In 96 participants with type 1 diabetes and 40 age-matched healthy controls, we measured BRS (average of six different standard methods), oxygen saturation, end-tidal carbon dioxide and ventilation changes during spontaneous and controlled breathing at 15 and six breaths/min, in normoxia and during 5 l/min oxygen administration.
Results
BRS was blunted and blood pressure higher in diabetic participants during spontaneous breathing (
p
< 0.05). BRS increased with oxygen during spontaneous breathing in diabetic (
p
< 0.001) but not in control participants, and with oxygen the difference in BRS was no longer significant. Slow breathing in normoxia restored BRS to a similar extent to giving oxygen. Oxygen increased systolic and diastolic blood pressure, RR interval, heart rate variability, minute ventilation and tidal volume to a greater extent in diabetic patients than in controls, and decreased carbon dioxide similarly to controls.
Conclusions/interpretation
The increased response to hyperoxia suggests a pre-existing condition of tissue hypoxia that functionally restrains parasympathetic activity in patients with type 1 diabetes. Autonomic abnormalities can be partially and temporarily reversed by functional manoeuvres such as slow breathing or oxygen administration through enhancement of parasympathetic activity and/or correction of tissue hypoxia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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•Direct applications of fatty acids or geraniol control horn flies on cattle for periods of 1–3d.•Cattle exhibit fly defensive behaviors (head throws, leg stamps, paniculus reflex, ...tail flicks) under horn fly attack.•Reduced defensive behaviors appear only when horn fly densities are reduced to extremely low levels after treatment.•Defensive behaviors cannot be used to estimate fluctuating fly numbers under normal summer field attack rates.•These repellents applied at 1-2 d intervals should keep fly densities below the economic threshold.
Adult horn fly populations were tracked on cattle for 2-week periods before, during and after multiple treatments (every 3–4days) with two repellents in a mineral oil carrier. Cattle were sprayed four times in a two-week period either with 2% geraniol (125ml/cow) or a 15% mixture of short chain fatty acids (C8-C9-C10)(250ml/cow), and there were untreated control cattle. Trials were conducted in California and North Carolina for 3 summers. Short-term fly counts (same day) on treated cattle were reduced by 61–99%, depending on material and trial, and the fatty acid mixture provided better control than geraniol. Horn fly counts were suppressed for 1–3 d and rebounded somewhat after both treatments. Consecutive treatments showed evidence of persistent impact in California where herds were more isolated. Rebounds to pre-treatment levels 3–4 d after treatment occurred more often in North Carolina, where other infested cattle were closer to treated herds. By 3–4 d post-treatment, horn flies were reduced by 29–61% in California and 0–83% in North Carolina, relative to pre-treatment. Background behavior frequencies were assessed from hundreds of counts on untreated, infested California cattle, where horn flies were the only abundant biting fly. Behavior averages were 16.5 tail flicks, 7.6 skin twitches, 1.2 head throws, or 0.2 leg stamps per 2min observation period. At horn fly densities from about 200 to more than 1000 flies per animal (moderate to high numbers), fly defensive behaviors on control cattle were poorly related (or unrelated) to fly numbers. Immediately after repellent application, however, flies were almost absent and behavior frequencies dropped distinctly. Cattle fly defensive behaviors therefore seem to be quite sensitive to low (less than 100 flies/animal) horn fly densities, and behaviors would be a poor quantitative tool to track fly stress at moderate densities and above. Both geraniol and the fatty acids show promise for horn fly control, especially in organic agriculture. Treatments at 1–2 d intervals probably would keep infestations below the economic threshold (200 flies/cow).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the ...promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The compilation of multiple metazoan genome sequences and the deluge of large-scale expression data have combined to motivate the maturation of bioinformatics methods for the analysis of sequences ...that regulate gene transcription. Historically, these bioinformatics methods have been plagued by poor predictive specificity, but new bioinformatics algorithms that accelerate the identification of regulatory regions are drawing disgruntled users back to their keyboards. However, these new approaches and software are not without problems. Here, we introduce the purpose and mechanisms of the leading algorithms, with a particular emphasis on metazoan sequence analysis. We identify key issues that users should take into consideration in interpreting the results and provide an online training example to help researchers who wish to test online tools before taking an independent foray into the bioinformatics of transcription regulation.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous “nuclear ...exosome targeting” (NEXT) and “human silencing hub” (HUSH) complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively. Knocking out the NEXT component ZCCHC8 in embryonic stem cells results in elevated TE RNA levels. We identify a physical interaction between ZCCHC8 and the MPP8 protein of HUSH and establish that HUSH recruits NEXT to chromatin at MPP8-bound TE loci. However, while NEXT and HUSH both dampen TE RNA expression, their activities predominantly affect shorter non-polyadenylated and full-length polyadenylated transcripts, respectively. Indeed, our data suggest that the repressive action of HUSH promotes a condition favoring NEXT RNA decay activity. In this way, transcriptional and post-transcriptional machineries synergize to suppress the genotoxic potential of TE RNAs.
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•The NEXT complex targets transposable element (TE) RNAs•NEXT, via its ZCCHC8 subunit, physically interacts with the HUSH complex•The HUSH factor MPP8 is required to recruit NEXT to chromatin at TE loci•HUSH and NEXT function regulate pA+ and pA− RNAs, respectively
Garland et al. report a physical and functional connection between the NEXT complex, involved in RNA decay, and the HUSH complex, involved in chromatin regulation. Together, NEXT and HUSH cooperate to control transposable element (TE) RNA expression in embryonic stem cells, suppressing pA− and pA+ transcripts, respectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The importance of microRNAs and long noncoding RNAs in the regulation of pluripotency has been documented; however, the noncoding components of stem cell gene networks remain largely unknown. Here we ...investigate the role of noncoding RNAs in the pluripotent state, with particular emphasis on nuclear and retrotransposon-derived transcripts. We have performed deep profiling of the nuclear and cytoplasmic transcriptomes of human and mouse stem cells, identifying a class of previously undetected stem cell-specific transcripts. We show that long terminal repeat (LTR)-derived transcripts contribute extensively to the complexity of the stem cell nuclear transcriptome. Some LTR-derived transcripts are associated with enhancer regions and are likely to be involved in the maintenance of pluripotency.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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