P2TF: a comprehensive resource for analysis of prokaryotic transcription factors

BACKGROUND: Transcription factors (TFs) are DNA-binding proteins that regulate gene expression by activating or repressing transcription. Some have housekeeping roles, while others regulate the expression of specific genes in response to environmental change. The majority of TFs are multi-domain proteins, and they can be divided into families according to their domain organisation. There is a need for user-friendly, rigorous and consistent databases to allow researchers to overcome the inherent variability in annotation between genome sequences. DESCRIPTION: P2TF (Predicted Prokaryotic Transcription Factors) is an integrated and comprehensive database relating to transcription factor proteins. The current version of the database contains 372,877 TFs from 1,987 completely sequenced prokaryotic genomes and 43 metagenomes. The database provides annotation, classification and visualisation of TF genes and their genetic context, providing researchers with a one-stop shop in which to investigate TFs. The P2TF database analyses TFs in both predicted proteomes and reconstituted ORFeomes, recovering approximately 3% more TF proteins than just screening predicted proteomes. Users are able to search the database with sequence or domain architecture queries, and resulting hits can be aligned to investigate evolutionary relationships and conservation of residues. To increase utility, all searches can be filtered by taxonomy, TF genes can be added to the P2TF cart, and gene lists can be exported for external analysis in a variety of formats. CONCLUSIONS: P2TF is an open resource for biologists, allowing exploration of all TFs within prokaryotic genomes and metagenomes. The database enables a variety of analyses, and results are presented for user exploration as an interactive web interface, which provides different ways to access and download the data. The database is freely available at http://www.p2tf.org/

An ontological model for the reality-based 3D annotation of heritage building conservation state

The conservation and restoration of historical monuments require a diagnostic analysis carried out by amultidisciplinary team. The results of the diagnosis include data produced by different techniques andprotocols, which are used by conservation scientists to assess the built heritage. Nowadays, together withthe aforementioned data, a great deal of heterogeneous information is also available, including descriptiveand contextual information, as well as 2D/3D geometrical restitution of the studied object. However, theintegration of these diverse data into a unique information model capable of fully describing the buildingconservation state, as well as integrating future data, is still an open issue within the Cultural Heritagecommunity. It is of paramount importance to correlate these data and spatialize them in order to providescientists in charge of our heritage with a practical and easy means to explore the information usedduring their assessment, as well as a way to record their scientific observation and share them withintheir community of practice. In order to resolve this issue, we developed a correlation pipeline for theintegration of the semantic, spatial and morphological dimension of a built heritage. The pipeline uses anontological model for recording and integrating multidisciplinary observations of the conservation stateinto structural data spatialized into a semantic-aware 3D representation. The pipeline was successfullytested on the Saint Maurice church of Caromb in the south of France, integrating into a unique spatialrepresentation information about material and alteration phenomena, providing users with a means tocorrelate, and more importantly retrieve several types of information

Hydrophobically Modified let-7b miRNA Enhances Biodistribution to NSCLC and Downregulates HMGA2 In Vivo

MicroRNAs (miRNAs) have increasingly been shown to be involved in human cancer, and interest has grown about the potential use of miRNAs for cancer therapy. miRNA levels are known to be altered in cancer cells, including in non-small cell lung cancer (NSCLC), a subtype of lung cancer that is the most prevalent form of cancer worldwide and that lacks effective therapies. The let-7 miRNA is involved in the regulation of oncogene expression in cells and directly represses cancer growth in the lung. let-7 is therefore a potential molecular target for tumor therapy. However, applications of RNA interference for cancer research have been limited by a lack of simple and efficient methods to deliver oligonucleotides (ONs) to cancer cells. In this study, we have used in vitro and in vivo approaches to show that HCC827 cells internalize hydrophobically modified let-7b miRNAs (hmiRNAs) added directly to the culture medium without the need for lipid formulation. We identified functional let-7b hmiRNAs targeting the HMGA2 mRNA, one of the let-7 target genes upregulated in NSCLC, and show that direct uptake in HCC827 cells induced potent and specific gene silencing in vitro and in vivo. Thus, hmiRNAs constitute a novel class of ONs that enable functional studies of genes involved in cancer biology and are potentially therapeutic molecules

Vers une ontologie de domaine pour l’analyse de l’état de conservation du bâti patrimonial

Les pratiques de conservation et restauration de monuments historiques requièrent l’élaboration de diagnostics impliquant une multitude d’experts au sein de contextes d’études pluridisciplinaires. L’état de conservation d’un objet patrimonial est décrit au moyen d’observations directes impliquant des sources documentaires et des données analytiques hétérogènes. Parallèlement, si de nouveaux outils permettent aux différents experts de mémoriser et d’analyser leurs observations sur différents supports, les données générées par ces différents acteurs ne sont généralement ni reliées ni spatialisées autour d’un unique support de référence. De plus, aujourd’hui, il est possible de générer des entités 3D denses et précises, mais isolées, ces représentations spatiales ne sont pas suffisantes pour répondre aux exigences d’observation réelle des acteurs de la conservation. Ce constat montre l’absence de cadres opérationnels pour l’extraction d’informations pertinentes pour l’analyse et l’interprétation de l’état de conservation. La nécessité de créer un support d’analyse commun est donc au centre des préoccupations. C’est la raison pour laquelle la création d’une ontologie dans le domaine de la conservation semble être une solution innovante non seulement pour rendre intelligibles des représentations spatiales brutes, mais également pour permettre d’introduire la notion de continuum informationnel. Par l’interconnexion de descripteurs qualitatifs (par une formalisation des connaissances partagées) et quantitatifs, l’ontologie de domaine constitue l’échafaudage conceptuel pour clarifier l’ensemble des interrelations qui permettent par combinaison de décrire les phénomènes de dégradation du bâti.The conservation and restoration of historic monuments require diagnostic analysis carried out by multidisciplinary teams. The elaboration of this diagnosis of a cultural heritage object involves direct observation, the examination of documentary sources and of diverse types of analytical data. While new tools now allow various experts to store and analyse their observations on different media, the data generated by these different actors is generally not linked to a unique reference, nor spatialized around it. Today, it is possible to generate dense and precise 3D models, but these spatial representations are not adequate for the requirements of real observations of conservation actors. This observation pinpoints the lack of operational frameworks for the capture of information pertaining to the analysis and interpretation of a state of conservation. The need to create a common analytical support is therefore central to these concerns. This is why the creation of an ontology in the field of conservation seems to be an innovative solution not only for making raw spatial representations intelligible, but also for introducing the notion of an informational continuum. By the interconnection of descriptors that are both qualitative (formalising shared knowledge) and quantitative, domain ontology constitutes the conceptual scaffolding which can help clarify all the interrelationships that, by combination, allow for a description of building degradation phenomena

Modelling and Simulation of Asynchronous Real-Time Systems using Timed Rebeca

In this paper we propose an extension of the Rebeca language that can be used to model distributed and asynchronous systems with timing constraints. We provide the formal semantics of the language using Structural Operational Semantics, and show its expressiveness by means of examples. We developed a tool for automated translation from timed Rebeca to the Erlang language, which provides a first implementation of timed Rebeca. We can use the tool to set the parameters of timed Rebeca models, which represent the environment and component variables, and use McErlang to run multiple simulations for different settings. Timed Rebeca restricts the modeller to a pure asynchronous actor-based paradigm, where the structure of the model represents the service oriented architecture, while the computational model matches the network infrastructure. Simulation is shown to be an effective analysis support, specially where model checking faces almost immediate state explosion in an asynchronous setting.Comment: In Proceedings FOCLASA 2011, arXiv:1107.584

Phase II study (KAMELEON) of single-agent T-DM1 in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma

The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types.</p

International Expert Consensus on Switching Platelet P2Y(12) Receptor-Inhibiting Therapies

Dual antiplatelet therapy with aspirin and a P2Y(12) inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y(12) inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y(12) inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y(12) inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y(12) inhibitors

Tat-human immunodeficiency virus-1 induces human monocyte chemotaxis by activation of vascular endothelial growth factor receptor-1.

Human immunodeficiency virus-1 (HIV-1) Tat protein can be released by infected cells and activates mesenchymal cells. Among these, monocytes respond to Tat by migrating into tissues and releasing inflammatory mediators. In the present study, we have examined the molecular mechanism of monocyte activation by Tat, showing that this viral protein signals inside the cells through the tyrosine kinase receptor for vascular endothelial growth factor encoded by fms-like tyrosine kinase gene (VEGFR-1/Flt-1). Subnanomolar concentrations of Tat induced monocyte chemotaxis, which was inhibited by cell preincubation with vascular-endothelial growth factor-A (VEGF-A). This desensitisation was specific for VEGF-A, because it not was observed with FMLP. In addition, the soluble form of VEGFR-1 specifically inhibited polarization and migration induced by Tat and VEGF-A, thus confirming the common use of this receptor. Binding studies performed at equilibrium by using radiolabeled Tat showed that monocytes expressed a unique class of binding site, with a kd of approximately 0.2 nmol/L. The binding of radiolabeled Tat to monocyte surface and the cross-linking to a protein of 150 kD was inhibited specifically by an excess of cold Tat or VEGF-A. Western blot analysis with an antibody anti-VEGFR-1/Flt-1 performed on monocyte phosphoproteins immunoprecipitated by an monoclonal antibody anti-phosphotyrosine showed that Tat induced a rapid phosphorylation in tyrosine residue of the 150-kD VEGFR-1/Flt-1. Taken together, these results suggest that biologic activities of HIV-1 Tat in human monocytes may, at least in part, be elicited by activation of VEGFR-1/Flt-1

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference