Century-of-Information Research (CIR): a strategy for research and innovation in the century of information

More data will be produced in the next five years than in the entire history of human kind, a digital deluge that marks the beginning of the Century of Information. Through a year-long consultation with UK researchers, a coherent strategy has been developed, which will nurture Century-of-Information Research (CIR); it crystallises the ideas developed by the e-Science Directors' Forum Strategy Working Group. This paper is an abridged version of their latest report which can be found at: http://wikis.nesc.ac.uk/escienvoy/Century_of_Information_Research_Strategy which also records the consultation process and the affiliations of the authors. This document is derived from a paper presented at the Oxford e-Research Conference 2008 and takes into account suggestions made in the ensuing panel discussion. The goals of the CIR Strategy are to facilitate the growth of UK research and innovation that is data and computationally intensive and to develop a new culture of 'digital-systems judgement' that will equip research communities, businesses, government and society as a whole, with the skills essential to compete and prosper in the Century of Information. The CIR Strategy identifies a national requirement for a balanced programme of coordination, research, infrastructure, translational investment and education to empower UK researchers, industry, government and society. The Strategy is designed to deliver an environment which meets the needs of UK researchers so that they can respond agilely to challenges, can create knowledge and skills, and can lead new kinds of research. It is a call to action for those engaged in research, those providing data and computational facilities, those governing research and those shaping education policies. The ultimate aim is to help researchers strengthen the international competitiveness of the UK research base and increase its contribution to the economy. The objectives of the Strategy are to better enable UK researchers across all disciplines to contribute world-leading fundamental research; to accelerate the translation of research into practice; and to develop improved capabilities, facilities and context for research and innovation. It envisages a culture that is better able to grasp the opportunities provided by the growing wealth of digital information. Computing has, of course, already become a fundamental tool in all research disciplines. The UK e-Science programme (2001-06)—since emulated internationally—pioneered the invention and use of new research methods, and a new wave of innovations in digital-information technologies which have enabled them. The Strategy argues that the UK must now harness and leverage its own, plus the now global, investment in digital-information technology in order to spread the benefits as widely as possible in research, education, industry and government. Implementing the Strategy would deliver the computational infrastructure and its benefits as envisaged in the Science & Innovation Investment Framework 2004-2014 (July 2004), and in the reports developing those proposals. To achieve this, the Strategy proposes the following actions: support the continuous innovation of digital-information research methods; provide easily used, pervasive and sustained e-Infrastructure for all research; enlarge the productive research community which exploits the new methods efficiently; generate capacity, propagate knowledge and develop skills via new curricula; and develop coordination mechanisms to improve the opportunities for interdisciplinary research and to make digital-infrastructure provision more cost effective. To gain the best value for money strategic coordination is required across a broad spectrum of stakeholders. A coherent strategy is essential in order to establish and sustain the UK as an international leader of well-curated national data assets and computational infrastructure, which is expertly used to shape policy, support decisions, empower researchers and to roll out the results to the wider benefit of society. The value of data as a foundation for wellbeing and a sustainable society must be appreciated; national resources must be more wisely directed to the collection, curation, discovery, widening access, analysis and exploitation of these data. Every researcher must be able to draw on skills, tools and computational resources to develop insights, test hypotheses and translate inventions into productive use, or to extract knowledge in support of governmental decision making. This foundation plus the skills developed will launch significant advances in research, in business, in professional practice and in government with many consequent benefits for UK citizens. The Strategy presented here addresses these complex and interlocking requirements.

eIF5A binds to translational machinery components and affects translation in yeast

The putative translation factor eIF5A is essential for cell viability and is highly conserved from archebacteria to mammals. Although this protein was originally identified as a translation initiation factor, subsequent experiments did not support a role for eIF5A in general translation. In this work, we demonstrate that eIF-5A interacts with structural components of the 80S ribosome, as well as with the translation elongation factor 2 (eEF2). Moreover, eIF5A is further shown to cofractionate with monosomes in a translation-dependent manner. Finally, eIF5A mutants show altered polysome profiles and are sensitive to translation inhibitors. Our results re-establish a function for eIF5A in translation and suggest a role for this factor in translation elongation instead of translation initiation. (c) 2006 Elsevier B.V. All rights reserved.

Using Proteomic Strategies for Sequencing and Post-Translational Modifications Assignment of Antigen-5, a Major Allergen from the Venom of the Social Wasp Polybia paulista

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

Translation from research to applications

The article summarizes the collective views expressed at the fourth session of the workshop Tissue Engineering-the Next Generation, which was devoted to the translation of results of tissue engineering research into applications. Ernst Hunziker described the paradigm of a dual translational approach, and argued that tissue engineering should be guided by the dimensions and physiological setting of the bodily compartment to be repaired. Myron Spector discussed collagen-glycosaminoglycan (GAG) scaffolds for musculoskeletal tissue engineering. Jeanette Libera focused on the biological and clinical aspects of cartilage tissue engineering, and described a completely autologous procedure for engineering cartilage using the patient's own chondrocytes and blood serum. Arthur Gertzman reviewed the applications of allograft tissues in orthopedic surgery, and outlined the potential of allograft tissues as models for biological and medical studies. Savio Woo discussed a list of functional tissue engineering approaches designed to restore the biochemical and biomechanical properties of injured ligaments and tendons to be closer to that of the normal tissues. Specific examples of using biological scaffolds that have chemoattractants as well as growth factors with unique contact guidance properties to improve their healing process were shown. Anthony Ratcliffe discussed the translation of the results of research into products that are profitable and meet regulatory requirements. Michael Lysaght challenged the proposition that commercial and clinical failures of early tissue engineering products demonstrate a need for more focus on basic research. Arthur Coury described the evolution of tissue engineering products based on the example of Genzyme, and how various definitions of success and failure can affect perceptions and policies relative to the status and advancement of the field of tissue engineering.

Improving outcome after stroke: overcoming the translational roadblock

Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.

A rat model for orthodontic translational expansive tooth movement

OBJECTIVES To present the development of an experimental model in rats for translational expansive tooth movement. SETTING AND SAMPLE Section of Periodontology at Department of Dentistry Aarhus University. Twenty male Wistar rats in two pilot experimental settings plus seven animals without any intervention serving as controls. MATERIAL AND METHODS The second molar (group P1) or the second and third molar (group P2) in the maxillae of the animals were moved buccally using transpalatal β-titanium springs. In the group P2, two spring types (high force and low force) and two preangulations (0° passive or 30° torsion moment) were tested. The amount and type of tooth movement achieved and the resulting skeletal effect were assessed on microCT images, histological analysis was performed on few selected specimens. RESULTS Expansive translational root movement amounting half a tooth width was achieved. Comparison of the amount of tooth movement at the right and left side of the maxilla showed that the expansion was rather symmetrical in the P2 group. Skeletal widening of the maxilla contributed in the P2 group to approximately one-third of the total root movement, whereas two-thirds were dental movement. CONCLUSION With the model used in the P2 group, further research on translational expansive tooth movement and its effect on the periodontium can be pursued. In models for orthodontic expansion, it is strongly recommended to separately evaluate skeletal and dental effects.

Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

AIMS:Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. METHODS AND RESULTS:Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak. CONCLUSION:Our findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.

Scp160p is required for translational efficiency of codon-optimized mRNAs in yeast

The budding yeast multi-K homology domain RNA-binding protein Scp160p binds to > 1000 messenger RNAs (mRNAs) and polyribosomes, and its mammalian homolog vigilin binds transfer RNAs (tRNAs) and translation elongation factor EF1alpha. Despite its implication in translation, studies on Scp160p's molecular function are lacking to date. We applied translational profiling approaches and demonstrate that the association of a specific subset of mRNAs with ribosomes or heavy polysomes depends on Scp160p. Interaction of Scp160p with these mRNAs requires the conserved K homology domains 13 and 14. Transfer RNA pairing index analysis of Scp160p target mRNAs indicates a high degree of consecutive use of iso-decoding codons. As shown for one target mRNA encoding the glycoprotein Pry3p, Scp160p depletion results in translational downregulation but increased association with polysomes, suggesting that it is required for efficient translation elongation. Depletion of Scp160p also decreased the relative abundance of ribosome-associated tRNAs whose codons show low potential for autocorrelation on mRNAs. Conversely, tRNAs with highly autocorrelated codons in mRNAs are less impaired. Our data indicate that Scp160p might increase the efficiency of tRNA recharge, or prevent diffusion of discharged tRNAs, both of which were also proposed to be the likely basis for the translational fitness effect of tRNA pairing.

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death.

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Nanoinformatics: a new area of research in nanomedicine

Over a decade ago, nanotechnologists began research on applications of nanomaterials for medicine. This research has revealed a wide range of different challenges, as well as many opportunities. Some of these challenges are strongly related to informatics issues, dealing, for instance, with the management and integration of heterogeneous information, defining nomenclatures, taxonomies and classifications for various types of nanomaterials, and research on new modeling and simulation techniques for nanoparticles. Nanoinformatics has recently emerged in the USA and Europe to address these issues. In this paper, we present a review of nanoinformatics, describing its origins, the problems it addresses, areas of interest, and examples of current research initiatives and informatics resources. We suggest that nanoinformatics could accelerate research and development in nanomedicine, as has occurred in the past in other fields. For instance, biomedical informatics served as a fundamental catalyst for the Human Genome Project, and other genomic and ?omics projects, as well as the translational efforts that link resulting molecular-level research to clinical problems and findings.

Actin Depolymerization Affects Stress-Induced Translational Activity of Potato Tuber Tissue1

Changes in polymerized actin during stress conditions were correlated with potato (Solanum tuberosum L.) tuber protein synthesis. Fluorescence microscopy and immunoblot analyses indicated that filamentous actin was nearly undetectable in mature, quiescent aerobic tubers. Mechanical wounding of postharvest tubers resulted in a localized increase of polymerized actin, and microfilament bundles were visible in cells of the wounded periderm within 12 h after wounding. During this same period translational activity increased 8-fold. By contrast, low-oxygen stress caused rapid reduction of polymerized actin coincident with acute inhibition of protein synthesis. Treatment of aerobic tubers with cytochalasin D, an agent that disrupts actin filaments, reduced wound-induced protein synthesis in vivo. This effect was not observed when colchicine, an agent that depolymerizes microtubules, was used. Neither of these drugs had a significant effect in vitro on run-off translation of isolated polysomes. However, cytochalasin D did reduce translational competence in vitro of a crude cellular fraction containing both polysomes and cytoskeletal elements. These results demonstrate the dependence of wound-induced protein synthesis on the integrity of microfilaments and suggest that the dynamics of the actin cytoskeleton may affect translational activity during stress conditions.

Synthesis and Phosphorylation of Maize Acidic Ribosomal Proteins1 : Implications in Translational Regulation

The objective of this research was to determine the role of acidic ribosomal protein (ARP) phosphorylation in translation. Ribosomes (Rbs) from germinated maize (Zea mays L.) axes had four ARP bands within 4.2 to 4.5 isoelectric points when analyzed by isoelectric focusing. Two of these bands disappeared after alkaline phosphatase hydrolysis. During germination a progressive change from nonphosphorylated (0 h) to phosphorylated ARP (24 h) forms was observed in the Rbs; a free cytoplasmic pool of nonphosphorylated ARPs was also identified by immunoblot and isoelectric focusing experiments. De novo ARP synthesis initiated very slowly early in germination, whereas ARP phosphorylation occurred rapidly within this period. ARP-phosphorylated versus ARP-nonphosphorylated Rbs were tested in an in vitro reticulocyte lysate translation system. Greater in vitro mRNA translation rates were demonstrated for the ARP-phosphorylated Rbs than for the non-ARP-phosphorylated ones. Rapamycin application to maize axes strongly inhibited S6 ribosomal protein phosphorylation, but did not interfere with the ARP phosphorylation reaction. We conclude that ARP phosphorylation does not depend on ARP synthesis or on ARP assembly into Rbs. Rather, this process seems to be part of a translational regulation mechanism.