Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs. © 2013 Song et al

EAD - enabling armchair delivery : approaches to encoding finding aids at the University of Liverpool

EAD is increasingly being selected as the primary data format for constructing archival finding aids in the British Archive Community as the new technologies and know-how required to encode lists are being embraced in many repositories. One major problem facing archivists, though, is how to convert finding aids held in a variety of formats (including databases, word processed documents and paper lists with no machine readable form) into EAD. This article will discuss the methods used in Special Collections and Archives at the University of Liverpool Library in converting finding aids into EAD. Two main examples will be discussed: firstly, designing database output styles which automatically generate EAD tags to wrap around database fields using the ProCite bibliographic database and secondly, offshore keying of paper lists with the addition of basic EAD tags following a rigorous template designed by Special Collections and Archives staff. Both methods have proved effective and have facilitated the generation of EAD encoded lists for a number of our largest collections. Finally, there will be a brief discussion of our use of native EAD generation using AdeptEdit software and our continuing use of conversion methods

Marked increase in the incidence rate of esophageal adenocarcinoma in a high-risk area for esophageal cancer

BACKGROUND: Esophageal cancer (EC) is the eighth common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAD) are the most common histologic types of EC. Many recent reports showed an increasing trend in EAD and a decreasing trend in ESCC in many Western countries. Golestan Province in northeastern Iran has been known as a high-risk area for EC. The aim of this study was to describe the time trend of EAD in this area between 2000-2009. METHODS: Data on cancer cases were obtained from Golestan Population-based Cancer Registry. Analysis was done using Joinpoint software. To examine the incidence trends, the annual percent change was calculated. The possibilities of anatomic and histologic misclassification were considered by assessing the trend of ESCC and gastric adenocarcinoma. RESULTS: A total number of 1186 histologically-confirmed EC cases were recruited. The incidence rate of EAD showed a significant increasing trend. There was no significant trend in the incidence of ESCC during the study period. A significant increase in the incidence rate of gastric adenocarcinoma was observed during the period of 2000-2005, followed by a plateau during the period of 2005-2009. CONCLUSIONS: We found a significant increasing trend in the incidence rate of EAD. We find no evidence to support an alternative explanation including anatomic and histologic misclassification. So, the observed rise in the incidence of EAD seems to be real. Therefore, designing and implementation of control programs, including control of preventable risk factors of EAD, should be considered in this high- risk area

Radical increase of the parametric X-ray intensity under condition of extremely asymmetric diffraction

Parametric X-ray radiation (PXR) from relativistic electrons moving in a crystal along the crystal-vacuum interface is considered. In this geometry the emission of photons is happening in the regime of extremely asymmetric diffraction (EAD). In the EAD case the whole crystal length contributes to the formation of X-ray radiation opposed to Laue and Bragg geometries, where the emission intensity is defined by the X-ray absorption length. We demonstrate that this phenomenon should be described within the dynamical theory of diffraction and predict a radical increase of the PXR intensity. In particular, under realistic electron-beam parameters, an increase of two orders of magnitude in PXR-EAD intensity can be obtained in comparison with conventional experimental geometries of PXR. In addition we discuss in details the experimental feasibility of the detection of PXR-EAD.Comment: 9 pages, 5 figure

XQuery for Archivists: Understanding EAD Finding Aids as Data

[Excerpt] XQuery is a simple, yet powerful, scripting language designed to enable users without formal programming training to extract, transform, and manipulate XML data. Moreover, the language is an accepted standard and a W3C recommendation much like its sister standards, XML and XSLT. In other words, XQuery’s raison d’etre coincides perfectly with the needs of today’s archivists. What follows is a brief, pragmatic, overview of XQuery for archivists that will enable archivists with a keen understanding of XML, XPath, and EAD to begin experimenting with manipulating EAD data using XQuery

EAD calibration for corporate credit lines

Managing the credit risk inherent to a corporate credit line is similar to that of a term loan, but with one key difference. For both instruments, the bank should know the borrower's probability of default (PD) and the facility's loss given default (LGD). However, since a credit line allows the borrowers to draw down the committed funds according to their own needs, the bank must also have a measure of the line's exposure at default (EAD). Our study, which is based on a census of all corporate lending within Spain over the last 20 years, provides the most comprehensive overview of corporate credit line use and EAD calculations to date. Our analysis shows that defaulting firms have significantly higher credit line usage rates and EAD values up to five years prior to their actual default. Furthermore, we find that there are important variations in EAD values due to credit line size, collateralization, and maturity. While our results are derived from data for a single country, they should provide useful benchmarks for further academic, business and policy research into this underdeveloped area of credit risk management.Commercial loans ; Bank loans ; Credit

Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk.

Population-based computational approaches have been developed in recent years and helped to gain insight into arrhythmia mechanisms, and intra- and inter-patient variability (e.g., in drug responses). Here, we illustrate the use of multivariable logistic regression to analyze the factors that enhance or reduce the susceptibility to cellular arrhythmogenic events. As an example, we generate 1000 model variants by randomly modifying ionic conductances and maximal rates of ion transports in our atrial myocyte model and simulate an arrhythmia-provoking protocol that enhances early afterdepolarization (EAD) proclivity. We then treat EAD occurrence as a categorical, yes or no variable, and perform logistic regression to relate perturbations in model parameters to the presence/absence of EADs. We find that EAD formation is sensitive to the conductance of the voltage-gated Na+, the acetylcholine-sensitive and ultra-rapid K+ channels, and the Na+/Ca2+ exchange current, which matches our mechanistic understanding of the process and preliminary sensitivity analysis. The described technique: •allows investigating the factors underlying dichotomous outcomes, and is therefore a useful tool improve our understanding of arrhythmic risk;•is valid for analyzing both deterministic and stochastic models, and various phenomena (e.g., delayed afterdepolarizations and Ca2+ sparks);•is computationally more efficient than one-at-a-time parameter sensitivity analysis

Early afterdepolarisations and ventricular arrhythmias in cardiac tissue: a computational study

Afterdepolarisations are associated with arrhythmias in the heart, but are difficult to study experimentally. In this study we used a simplified computational model of 1D and 2D cardiac ventricular tissue, where we could control the size of the region generating afterdepolarisations, as well as the properties of the afterdepolarisation waveform. Provided the size of the afterdepolarisation region was greater than around 1 mm, propagating extrasystoles were produced in both 1D and 2D. The number of extrasystoles produced depended on the amplitude, period, and duration of the oscillatory EAD waveform. In 2D, re-entry was also initiated for specific combinations of EAD amplitude, period, and duration, with the afterdepolarisation region acting as a common pathway. The main finding from this modelling study is therefore that afterdepolarisations can act as potent sources of propagating extrasystoles, as well as a source of re-entrant activation