Predicting the accuracy of protein-ligand docking on homology models

Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand-protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target-template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics.Contract/grant sponsor: National Institutes of Health; contract/grant numbers: ES00768

Reforming public service employment relations: past, present and future prospects

In most countries public sector employment relations have traditionally been regulated by special rules and institutions, separate and distinct from those governing private sector employment relations. The reasons for this distinctiveness are rooted, according to many scholars, in the unique role of the state as employer and as service provider, and in a number of structural factors which on average give public employees and trade unions a stronger bargaining power than private sector employees and unions. Since the mid-late 1980s public service employment relations have undergone in many countries a continuous process of transformation, often within a context of public administration reform inspired by the New Public Management approach. The traditional distinctiveness of public service employment relations, with separate institutions and practices from the private sector, has been challenged, although to varying degrees and with different effects across countries. Based on the new institutional economics (transaction costs theory and agency theory), NPM aimed at removing any difference between the private and public sector as the only way to improve efficiency and effectiveness of public service. Changing the traditional patterns of public sector employment relations and HRM practices was an essential part of this program. The promise was a fundamental transformation, with a double process of convergence: between different countries and between public and private sectors within each country. However, after more than two decades of NPM inspired reforms, these processes of convergence did not occur, if not to a limited extent. In many cases, the na\uefve adoption into the public sector of private sector institutions and practices brought about unintended and even perverse effects, rather than improved quality and lower costs. The fundamental transformation which NPM promised did not materialize, quite defferently from what occurred in private sector employment relations approximately in the same period. However, in many advanced countries, but also in some emerging economies, the 2008 crisis altered the picture in a crucial feature. Namely, it challenged the traditional configuration of public sector employment relations as sheltered from international market pressures and supranational actors, operating in a relatively closed environment mostly shaped by the regulatory power of the state and other domestic actors. The key effect of this greater role of external and international forces is to strengthen governments in their relations with unions and employees, possibly altering the traditional balance of powers in public sector employment relations like globalization and the intensified competition did four in management\u2019s favour in the private sector in recent decades. These changes in the traditional environment of public sector employment relations do not appear to be just transitory, but seem likely to last over time, at least in the medium term. Whether they will be strong enough to bring about the fundamental transformation of public sector employment relations that NPM promised but failed to deliver, remains to be seen. Much will depend on the evolution of the crisis itself, and on the responses to the crisis by international authorities and national governments

Public sector industrial relations in transition

The economic environment of recent years has had a transformatory effect on public sector industrial relations, with the crisis serving to accelerate and deepen changes that were already in train. The effects of this include a revival of unilateralism in the public sector, a recentralisation of wage-setting systems, an acceleration of the introduction of private sector-style HRM practices, and a general weakening of trade union influence over governments struggling to adapt to tough economic conditions

Improved Molecular Diagnosis of McCune-Albright Syndrome and Bone Fibrous Dysplasia by Digital PCR

McCune-Albright syndrome (MAS) is a rare congenital disorder characterized by the association of endocrine and nonendocrine anomalies caused by somatic activating variants of GNAS. The mosaic state of variants makes the clinical presentation extremely heterogeneous depending on involved tissues. Biological samples bearing a low level of mosaicism frequently lead to false-negative results with an underestimation of causative molecular alterations, and the analysis of biopsies is often needed to obtain a molecular diagnosis. To date, no reliable analytical method for the noninvasive testing of blood is available. This study was aimed at validating a novel and highly sensitive technique, the digital PCR (dPCR), to increase the detection rate of GNAS alterations in patients with a clinical suspicion of MAS and, in particular, in blood. We screened different tissues (blood, bone, cutis, ovary, and ovarian cyst) collected from 54 MAS patients by different technical approaches. Considering blood, Sanger was unable to detect mutations, the allele-specific PCR and the co-amplification at lower denaturation temperature had a 9.1% and 18.1% detection rate, respectively, whereas the dPCR reached a 37.8% detection rate. In conclusion, the dPCR resulted in a cost-effective, reliable, and rapid method allowing the selective amplification of low-frequency variants and able to improve GNAS mutant allele detection, especially in the blood

2q37 deletions in patients with an albright hereditary osteodystrophy phenotype and PTH resistance

Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP pathway by the parathyroid hormone secondary to GNAS molecular defects. PHP subtypes are defined by the presence/absence of specific clinical/biochemical features. PHP1A is characterized by resistance to multiple hormones with features of Albright hereditary osteodystrophy (AHO), while pseudopseudohypoparathyroidism (PPHP) is characterized by AHO in the absence of PTH resistance. Small subsets of PHP and PPHP patients without known molecular defects have been re-diagnosed as being affected by the brachydactyly-mental retardation syndrome (BDMR), also known as the AHO-like syndrome. This study aimed to analyse 24 PHP1A and 51 PPHP patients without a molecular diagnosis for the presence of BDMR-associated 2q37 deletions to improve the differential diagnosis and to identify features that might help to avoid a misdiagnosis. Molecular investigations identified 4 deletions in 4 unrelated patients. The affected patients showed a combination of the most pathognomonic AHO features. Of note, 3 of the patients also displayed mild PTH resistance, and none of the patients developed ectopic ossifications. Our work confirmed the rarity of the misdiagnosis of BDMR in PHP patients through the identification of 4 patients bearing a 2q37 deletion in a cohort of 73 PHP patients (5.3%). Three patients with the deletion presented a PHP1A phenotype in the absence of any BDMR-specific findings. Further studies on larger case series are needed to elucidate the overlap between these clinical entities and to allow the early identification of patients

Transnational higher education partnerships and the role of operational faculty members: developing an alternative theoretical approach for empirical research

For too long, transnational higher education (TNE) has been linked to discourse predominately focused upon strategic implementation, quality assurance and pedagogy. Whilst these aspects are important when designing and managing overseas provisions, there is a lack of research focusing on the social interactions that influence the pace and development of TNE partnerships. This gap is particularly evident at the operational phase of TNE partnerships. This conceptual article therefore offers an alternative way in which to research TNE partnerships, in relation to the interactions of faculty members delivering at the operational level. It provides an integrated theoretical framework, comprising of three different theoretical approaches in order to provide a conceptual tool in which to investigate and evaluate TNE partnership development. The article concludes that by understanding how relationships develop between faculty members tasked with delivering TNE, international partnerships can be significantly strengthened in terms of their progression and value

Нейросекреторная активность супраоптического ядра переднего гипоталамуса кроликов под действием транскутанной электростимуляции зрительного анализатора

На 8 кролях породи Метелик вивчали вплив непрямої черезшкірної електростимуляції зорового аналізатора на нейросекреторну активність магноцелюлярних клітин супраоптичного ядра переднього гіпоталамусу. На мікропрепаратах інтактних тварин переважали нейрони II морфофункціонального типу, що перебувають у стадії синтезу нейросекрету. Показано, що за дії электростимуляції спостерігається перерозподіл головних морфо-функціональних типів нейронів. Відзначено збільшення змісту клітин I й III типів, відповідно у стадіях спокою після виведення секрету й накопичення, що вказує на активацію процесів звільнення нейросекрету і його акумуляції. Виразність реакції нервової тканини однакова при силі стимулюючого струму 100 мкА й 300 мкА.The influence of indirect through-skin electrostimulation (different doses) of the optical analyser on neurosecretory activity of anterior hypothalamus magnocellular nucleus was stading during chronic experiment. The stady was carried out on rabbits. Five morphological types of neurons was exposed in the supraoptical nucleus of control animal groop: I type- phase of rest after neurosecrets leading, II- phase of synthesis, III- phase of accumulation, IV - leading phase, V - phase of degerneration, but neurons of II types was prevalenced (51%). The indirect electrostimulation of the optical analyser provokes quantitative changes of keeping same neurons types. The number of I and III types neurons increases (on 20% and 7%) . The kind of changes is indicative of electrostimulation activation influense on neurosecrets leading and accumulation. Expression of nervous tissue reaction was identical under different doses (100 mkA and 300 mkA) of afferent electrostimulation

Community resilience : a policy tool for local government?

In many countries, local government has been a prime target of austerity measures. In response, local authorities are exploring a new repertoire of policy approaches in a bid to provide more with less. In England, local authorities have been drawn to community resilience as a pragmatic response to the challenge of deploying shrinking resources to support communities exposed to social and economic disruption. This application of resilience thinking is not without its challenges. It demands a working definition of community resilience that recognises the potential for communities to prove resilient to shocks and disruptions, but avoids blaming them for their predicament. There is also the practical challenge of developing and targeting interventions to promote and protect resilience. This paper sets out to explore these issues and establish the potential utility of community resilience as a policy tool through case study analysis in the city of Sheffield

A Survey of Volunteered Open Geo-Knowledge Bases in the Semantic Web

Over the past decade, rapid advances in web technologies, coupled with innovative models of spatial data collection and consumption, have generated a robust growth in geo-referenced information, resulting in spatial information overload. Increasing 'geographic intelligence' in traditional text-based information retrieval has become a prominent approach to respond to this issue and to fulfill users' spatial information needs. Numerous efforts in the Semantic Geospatial Web, Volunteered Geographic Information (VGI), and the Linking Open Data initiative have converged in a constellation of open knowledge bases, freely available online. In this article, we survey these open knowledge bases, focusing on their geospatial dimension. Particular attention is devoted to the crucial issue of the quality of geo-knowledge bases, as well as of crowdsourced data. A new knowledge base, the OpenStreetMap Semantic Network, is outlined as our contribution to this area. Research directions in information integration and Geographic Information Retrieval (GIR) are then reviewed, with a critical discussion of their current limitations and future prospects

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society