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Issue 6 2008
Issue 6 2008 / 3 December 2008 /
Recently, small RNAs such as microRNAs (miRNAs) have been demonstrated to be important regulators in both plants and animals. In animals miRNAs act as translational repressors of target genes through a combination of inhibition of translation and mRNA destabilisation. These molecules have been implicated in a multitude of diseases, including cancer and represent promising candidates for both diagnostics and therapeutics. While substantial progress has been made in the detection, sequencing and profiling of miRNAs, accurately delineating their targets remains difficult. Purely computational approaches hold much promise, yet they still suffer from over-prediction. In this article we will describe alternative approaches that utilise computational analysis combined with gene expression data to better detect miRNA effects and their targets. In particular we will describe Sylamer1 a new tool for the detection of miRNA targets and siRNA off-target effects from expression data.
Currently there are 695 confirmed miRNAs in Human (miRBase 12)2. One expects miRNAs to have multiple targets. However few miRNA targets have been experimentally confirmed so far. Currently, no accurate high-throughput experimental approaches exist for accurately determining miRNA target binding. Clearly, purely computational approaches are promising but while they have been shown to have high-sensitivity they can suffer from over-prediction issues3. The key issue faced by computational approaches is that miRNAs are short (21nt) and that the key region for binding specificity is even shorter (6-8nt). Finding complementary binding sites in the 3’UTRs of potential target transcripts is hence daunting as one can find 6nt complementary sites for any miRNA across the entire genome randomly at reasonably high frequencies. (more…)
Tagged with: Anton J. Enright, European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL), microRNA
Issue 6 2008 / 3 December 2008 /
The fluorescence-based quantitative real-time polymerase chain reaction (qPCR)1-3 has become firmly established as the preferred technology for the detection and quantification of nucleic acids in molecular diagnostics, life sciences, agriculture and medicine4,5.
The combination of conceptual and practical simplicity, large dynamic range of linear quantification, speed, sensitivity and specificity has made it the yardstick for nucleic acid quantification not just in basic research, but has engendered numerous uses ranging from basic research through diagnostic and forensic application to treatment monitoring in a clinical setting6-11. (more…)
Tagged with: qPCR, Stephen Bustin, University of London
Issue 6 2008 / 3 December 2008 /
In its Research Framework Programme 7 (2007-2013), the European Commission sets the focus in health research on bringing the huge high-throughput data collection efforts of earlier programmes to the systems level. The ultimate goal of systems biology is the integration of various types of experimental data into models that represent and simulate physiological cell function. To this end, information on gene and protein expression and its dynamics, protein localisation, modification states and activation, their interaction in larger supra-molecular complexes and functional roles need to be compiled from numerous sources and formats and brought into context using advanced computational tools.
PROSPECTS is a large collaborative project funded by the European Commission with €12 million over five years. It brings together leading experts in various disciplines to move the proteomics field to a ‘second generation’ state, where it will be able to deal with transient complexes and near complete descriptions of a proteome in time and space. The project will specifically focus on diseases related to folding stress. Unique insights into the molecular basis of multiple, in particular neurodegenerative, syndromes can therefore be expected. (more…)
Tagged with: Anne Katrin Werenskiold, Max Planck Institute, Proteomics
Issue 6 2008 / 3 December 2008 /
Date: 11-16 January 2009
Venue: Hotel Del Coronado, San Diego, California
Host: Cambridge Healthcare Institute
Website: http://www.chi-peptalk.com
The Definitive Protein-Focused Event is once again bringing together life science leaders from around the world to discuss the latest developments and successful strategies for pumping up the biopharm pipeline. Peptalk’s warm and welcoming atmosphere enhances the first-rate selection of in-depth presentations and abundant networking. (more…)
Tagged with: Peptalk, Show Preview
Issue 6 2008 / 3 December 2008 /
The development of pharmaceuticals and screening the biological activity of test compounds is a multi-staged process spanning from small molecule design and synthesis, in vitro testing, and compound evaluation in vivo using animal and human trials. The expense of this process escalates as a compound advances further into the development programme. Within each stage there are stringent criteria that must be satisfied before the decision to invest further in the compound and move its development forward is made.
The pharmaceutical industry is continually reviewing its practices and seeking novel ways in which to bring new drugs to market in a more efficient and cost effective manner. Part of this process will be to avoid investment in a potential drug candidate that fails at a later stage in the development process. The trick of course is spotting when to stop research and development of a particular candidate but at the same time to learn from the experience. (more…)
Tagged with: Durham University, Reinnervate Limited, Stefan Przyborski, Stem Cells
Issue 6 2008 / 3 December 2008 /
Date: 20-22 January 2009
Venue: The Wyndham Hotel, Palm Springs, California
Host: Select Biosciences
Website: http://www.selectbiosciences.com/conferences/SCWC2009/index.aspx
This year’s congress will include the Keynote Speakers Bernard Siegal, Executive Director at the Genetics Policy Institute, Jan Nolta, Director at the Stem Cell Programme in the University of California and Carolyn Compton, Director at the Biorepositories and Biospecimen Research in the National Cancer Institute. (more…)
Tagged with: Show Preview, Stem Cells
Issue 6 2008 / 3 December 2008 /
Approximately 45% of all deaths and 50% of all hospitalisations in the western world are a direct result of cardiovascular disease. Cardiomyocyte hypertrophy is a mechanism by which myocardial mass is increased to compensate for any elevated physical demands placed upon the heart, thus ensuring that adequate perfusion of body tissues is maintained during these periods. However, if the hypertrophic response persists, the heart enters a critical transition from compensatory to a patho-physiological de-compensatory state which eventually leads to heart failure.
The development of new therapeutic tools for the treatment of this condition has in many cases been hampered by the lack of biologically relevant experimental models on which new treatments can be tested.
With the advent of laboratory automation technologies, it is now possible to screen libraries comprising of hundreds of thousands of potential therapeutic agents. These new technological innovations have increased the demand for cell based experimental models that can be used in conjunction with research platforms such as High Content Screening technologies. (more…)
Tagged with: Anthony Davies, HCS (High Content Screening), Paul J Spiers, Trinity College Dublin, Yuri Volkov
Issue 6 2008 / 3 December 2008 /
Date: 5-9 January 2009
Venue: The Fairmont Hotel, San Francisco, California
Host: Cambridge Healthtech Institute
Website: http://www.highcontent analysis.com/index.asp
Last year over 400 thought leaders gathered at the Fifth Annual High-Content Analysis meeting at the San Francisco Fairmont Hotel, on 14-17 January, to discuss the latest technologies and applications in high-content analysis. This year over 400 delegates are expected to attend and over sixty speakers will appear. (more…)
Tagged with: HCA (High Content Analysis), Show Preview
Issue 6 2008 / 3 December 2008 /
High Throughput Screening (HTS) has for many years now been playing a central role in drug discovery efforts to aid the identification of small molecule chemical entities that are capable of modifying the activity of disease relevant targets1. In order to make HTS a viable option to provide appropriate starting points for drug discovery efforts, large libraries of compounds are required that contain diverse chemical space.
These libraries are typically composed of 0.5 to 3.0 million distinct compounds in solution (usually DMSO) of which 10,000 to 100,000 are available in solid form. Subsequent to the execution of an HTS at an appropriate single concentration of compound, thousands of these are typically identified and are classified as actives. Some of these initial actives may be false positives, therefore their activities are usually confirmed in independent experiments carried out in duplicate followed by dose-response experiments to determine their potencies. The final set of confirmed actives is termed validated hits. Appropriate selectivity and liability assays enables annotation of these compounds and the most promising ones can be considered for structure-activity-relationship (SAR) studies. The SAR process is an iterative process in which new compounds are synthesised, their activities determined in appropriate assays, followed by further synthesis and compound profiling. Upon achieving the desired properties in the compound, potential starting points (lead like molecules) are obtained which would undergo a series of in-vivo validation studies. Subsequent lead optimisation could result in a pre-clinical candidate molecule which would enter a period of efficacy, safety and absorption, distribution, metabolism, excretion and toxicity (ADME-Tox)2 testing in animals and ultimately enter the various human clinical studies. The time period for a drug discovery program from its conception to initiation of human clinical trials is typically in excess of five years and consumes tens of millions of dollars. This article will overview how liquid handling technologies have aided the successful development of screening compatible assays. (more…)
Tagged with: European ScreeningPort GmbH, HTS (High Throughput Screening), Lab Automation, Sheraz Gul
Issue 6 2008 / 3 December 2008 /
Date: 24-28 January 2009
Venue: Palm Springs Convention Centre
Host: The Association for Laboratory Automation
Website: http://www.labautomation.org/LA09/index.cfm
From around the world, a diverse and highly innovative group of academicians, scientists, engineers, post-doctoral associates, graduate students, and business leaders will converge at LabAutomaton2009. The show will be held on 24-28 January 2009, at the Palm Springs Convention Centre, Palm Springs, California. (more…)
Tagged with: Lab Automation, Show Preview
Issue 6 2008 / 3 December 2008 /
Neurotoxicology is not a discipline that can expect to be popular in pharmaceutical circles. It is a not unreasonable prejudice amongst people working in drug development that even a suggestion that a candidate drug might be neurotoxic is enough to halt development, or at the least to stimulate a highly motivated search for an alternative. There are several good reasons for this. Firstly, neurotoxicity can be highly disabling and irreversible. Secondly, it is hard to detect (or rather to exclude) via high throughput systems. Thirdly, it is often hard to understand.
However, there are also good reasons not to over-react. Most neuro-active drugs have the potential to produce overdose neurotoxicity, and yet have made it successfully into the market. There is also a good pool of knowledge about neurotoxicity that can be drawn on by anyone in the industry who is unfortunate enough to need it. At this point, as past-President, I would like to briefly mention the International Neurotoxicology Association (INA). This is a non-profit making organisation with approximately 120 members world-wide who are dedicated to improving the academic discipline of neurotoxicology. Details of INA and its biennial scientific meetings can be found on the web at http://www.neurotoxicology.org. I would strongly recommend anyone who needs further information to contact INA, since its membership includes experimental scientists, physicians, and regulators – all with a wide range of expertise in the area. Whilst INA members may not be able to provide answers, they should be able to provide useful advice and put questions into a broader context. There are also a number of excellent (if sometimes intimidatingly thick) books that cover the topic of neurotoxicology. A very comprehensive description of most specific neurotoxicants and of general principles is given by Spencer et al.1, while clinical aspects are covered by Feldman2, and methodology by Chang and Slikker3. (more…)
Tagged with: David E. Ray, Toxicology, University of Nottingham
Issue 6 2008 / 3 December 2008 /
Freeze drying of pharmaceuticals requires an adequate formulation design to prevent low-temperature, freezing and drying stresses. The goal is to achieve a final product with long storage stability and elegant appearance. To meet these specifications the product temperature must be controlled below the critical formulation temperature during the freeze drying cycle. DSC is an established tool to measure this critical formulation property in the development of freeze dried pharmaceuticals as it allows rapid sample preparation and analysis time. The introduction of modulated DSC (MDSC) by Reading in 1992 has greatly facilitated the interpretation of DSC results. The overlapping transitions in the same temperature range can be distinguished and characterisation of the nature of transitions is facilitated. (more…)
Tagged with: Freeze Drying, Henning Gieseler, Jakob Beirowski, University of Erlangen-Nuremberg
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