HCF-1 is cleaved in the active site of O-GlcNAc transferase.

Host cell factor-1 (HCF-1), a transcriptional co-regulator of human cell-cycle progression, undergoes proteolytic maturation in which any of six repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). We report that the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCF-1 proteolytic repeat into a glycosylation substrate. Thus, protein glycosylation and HCF-1 cleavage occur in the same active site.

Potential sources of biodynamically active natural products in Brazil

In contrast to China where vegatation is predominantly herbaceous, vegetation in Brazil is commonly arboreous. This fact may explain why Chinese drugs are usually acetate derived, while actual and potential natural therapeutic agents from Brazil are mostly shikimate derived. Only relatively few compounds isolated from Brazilian plants have been submitted to adequate pharmacological testing

A Survey of Active Learning Algorithms for Supervised Remote Sensing Image Classification

Defining an efficient training set is one of the most delicate phases for the success of remote sensing image classification routines. The complexity of the problem, the limited temporal and financial resources, as well as the high intraclass variance can make an algorithm fail if it is trained with a suboptimal dataset. Active learning aims at building efficient training sets by iteratively improving the model performance through sampling. A user-defined heuristic ranks the unlabeled pixels according to a function of the uncertainty of their class membership and then the user is asked to provide labels for the most uncertain pixels. This paper reviews and tests the main families of active learning algorithms: committee, large margin, and posterior probability-based. For each of them, the most recent advances in the remote sensing community are discussed and some heuristics are detailed and tested. Several challenging remote sensing scenarios are considered, including very high spatial resolution and hyperspectral image classification. Finally, guidelines for choosing the good architecture are provided for new and/or unexperienced user.

Transcriptional activation of the utrophin promoter B by a constitutively active Ets-transcription factor.

Duchenne muscular dystrophy is an X-linked genetic disease caused by the absence of functional dystrophin. Pharmacological upregulation of utrophin, the autosomal homologue of dystrophin, offers a potential therapeutic approach to treat Duchenne patients. Full-length utrophin mRNA is transcribed from two alternative promoters, called A and B. In contrast to the utrophin promoter A, little is known about the factors regulating the activity of the utrophin promoter B. Computer analysis of this second promoter revealed the presence of several conserved binding motives for Ets-transcription factors. Using electrotransfer of cDNA into mouse muscles, we demonstrate that a genetically modified beta-subunit of the Ets-transcription factor GA-binding protein potently activates a utrophin promoter B reporter construct in innervated muscle fibers in vivo. These results make the GA-binding protein and the signaling cascade regulating its activity in muscle cells, potential targets for the pharmacological modulation of utrophin expression in Duchenne patients.

A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.

AbstractBACKGROUND: KRAB-ZFPs (Krüppel-associated box domain-zinc finger proteins) are vertebrate-restricted transcriptional repressors encoded in the hundreds by the mouse and human genomes. They act via an essential cofactor, KAP1, which recruits effectors responsible for the formation of facultative heterochromatin. We have recently shown that KRAB/KAP1 can mediate long-range transcriptional repression through heterochromatin spreading, but also demonstrated that this process is at times countered by endogenous influences.METHOD: To investigate this issue further we used an ectopic KRAB-based repressor. This system allowed us to tether KRAB/KAP1 to hundreds of euchromatic sites within genes, and to record its impact on gene expression. We then correlated this KRAB/KAP1-mediated transcriptional effect to pre-existing genomic and chromatin structures to identify specific characteristics making a gene susceptible to repression.RESULTS: We found that genes that were susceptible to KRAB/KAP1-mediated silencing carried higher levels of repressive histone marks both at the promoter and over the transcribed region than genes that were insensitive. In parallel, we found a high enrichment in euchromatic marks within both the close and more distant environment of these genes.CONCLUSION: Together, these data indicate that high levels of gene activity in the genomic environment and the pre-deposition of repressive histone marks within a gene increase its susceptibility to KRAB/KAP1-mediated repression.

In the name of democracy: Disobedience and value-oriented citizenship

Recently, some scholars have highlighted a paradoxical phenomenon existing in democratic systems:Those people who show the greatest support for democracy are also those most willing to protestagainst the authority and to question it. However, if we consider the tasks of contemporary democraticcitizenship in a social-psychological perspective, this apparent paradox becomes understandable.Obedience to authority may ensure the continuity of social and group life, but disobedience may becrucial in stopping the authority relationship from degenerating into an authoritarian one. FollowingKelman and Hamilton's analysis of legitimacy dynamics, we consider how actions of disobediencemay serve the defence of democracy. In particular, by considering the different ways in which peoplerelate to the political system, the relevance of so-called value-oriented citizens in supportingdemocracy will be considered.

Best practice in the management of mild-to-moderately active ulcerative colitis and achieving maintenance of remission using mesalazine.

Optimizing treatment goals in ulcerative colitis requires recognizing the needs of patients. It is increasingly recognized that adapting treatment strategies aligned with patient needs can improve patient compliance and consequently minimize relapse rates. Tailoring of treatment strategies can improve not only patient quality of life, and decrease the number harmed by adverse events from more potent drugs, but can also save valuable healthcare costs by avoiding high-cost treatment interventions associated with acute ulcerative colitis. This review will consider several elements of mesalazine management from the patient perspective based on a range of clinical and patient-focused evidence. By highlighting patient preferences in disease management it is envisaged that this review will aid physicians to optimize treatment decisions with the different mesalazine preparations available.

Characteristic bimodal profiles of RNA polymerase II at thousands of active mammalian promoters.

BACKGROUND: In mammals, ChIP-seq studies of RNA polymerase II (PolII) occupancy have been performed to reveal how recruitment, initiation and pausing of PolII may control transcription rates, but the focus is rarely on obtaining finely resolved profiles that can portray the progression of PolII through sequential promoter states. RESULTS: Here, we analyze PolII binding profiles from high-coverage ChIP-seq on promoters of actively transcribed genes in mouse and humans. We show that the enrichment of PolII near transcription start sites exhibits a stereotypical bimodal structure, with one peak near active transcription start sites and a second peak 110 base pairs downstream from the first. Using an empirical model that reliably quantifies the spatial PolII signal, gene by gene, we show that the first PolII peak allows for refined positioning of transcription start sites, which is corroborated by mRNA sequencing. This bimodal signature is found both in mouse and humans. Analysis of the pausing-related factors NELF and DSIF suggests that the downstream peak reflects widespread pausing at the +1 nucleosome barrier. Several features of the bimodal pattern are correlated with sequence features such as CpG content and TATA boxes, as well as the histone mark H3K4me3. CONCLUSIONS: We thus show how high coverage DNA sequencing experiments can reveal as-yet unnoticed bimodal spatial features of PolII accumulation that are frequent at individual mammalian genes and reminiscent of transcription initiation and pausing. The initiation-pausing hypothesis is corroborated by evidence from run-on sequencing and immunoprecipitation in other cell types and species.