I co-authored some work that is to be presented at the ACS Congress next week in San Francicso, at the Fragment Based Drug Design: Success Stories due to Novel Computational Methods Applications session...
Ksenia Oguievetskaia, Laetitia Martin-Chanas, Artem Vorotyntsev, Olivia Doppelt-Azeroual, Xavier Brotel, Stewart Adcock, Alexandre de Brevern, Francois Delfaud, Fabrice Moriaud.
Eg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an
anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop5/helix a2.
Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to identify new fragments which fill this hydrophobic pocket and might be interesting chemical moieties to design new inhibitors.
If you'll be at the conference, put a squiggle in your schedule around Wednesday, March 24, 2010 at 3:15PM
The Eg5 allosteric binding site surface (Grey: hydrophobic, Blue: hydrophilic) showing co-crystallized monastrol (green) and mon-97 (blue) ligands, as superimposed with MED-SuMo.
At the beginning of Q3 2010, MEDIT plans to launch a Linux-based GUI for MED-SuMo, and we seek participants for the free beta-test program. Help bring our GUI products to Linux...
At the upcoming ACS Congress in San Francisco from the 21st to the 24th March, MEDIT will launch its latest range of products. You are invited visit us at booth 119 at the Moscone Center. (I can provide a free pass for the Expo, for anyone interested in that!)
MEDIT has distributed the premier software solution for searching and investigating interaction-based similarities on protein surfaces and in protein-ligand binding sites. To date, we've offered user-friendly interfaces for the Windows desktop, for CCG's MOE, for Tripos' Sybyl and more...
...and soon, we will launch a Linux-based GUI for MED-SuMo. Linux versions of our other new products are also planned.
Starting April 2010, we will undertake a beta-test programme on Linux for certain products. We invite you to participate in this beta-test programme. Get early access to the Linux version of the GUI, and have the opportunity to provide feedback directly into our development process. Following a planned three-month testing period, all beta-testers will be offered various incentives as thanks for their contributions.
As a Linux user myself since a PC magazine included RedHat 4.1 on the cover disk - nearly half a life-time ago - this is an exciting evolution of the MEDIT software for me.
For further information, visit us at our booth 119 at the ACS Congress in San Francisco, or visit our beta-teat website with no obligations for yourself.
My company offers a series of short internships to students each year. For the second year running it looks like we are heading for fewer good applicants than the number of projects and space that we have on offer. What can be done about that?
Each year MEDIT sponsors a handful of intern projects, mostly for French M2 Masters students. In practise this is a good way to complete small, standalone, projects that we otherwise wouldn't be able to justify the resources to complete. It also provides MEDIT with one mechanism for "giving back" to the academic community, fostering academic collaborations and allowing young scientists to gain valuable experience in a commercial research environment. We strictly believe that the best projects offer quantifiable benefits in two directions. If the student doesn't gain anything specific, then we won't attract the best students and the intern won't be dedicated. If the company doesn't achieve something definite from the project, even if it is tangential to our usual business, then the supervisor won't be engaged -and this will invariably lead to a project that drifts aimlessly.
It currently appears that this year, as last year, we will receive fewer good applications than we have either projects or space.
As MEDIT is primarily a software company, our projects can generally be grouped in one of two sets:
Research projects - these invariably apply our software to some scientific problem, often related in some way to an aspect of drug discovery.
Software development projects - Usually projects with a significant programming element, e.g. coding and validating an idea to extend one of our products.
Irrespective of the specific project, we generally require successful candidates to have a background in s biological or numerate science, and they must be highly computer literate though this can be demonstrated either through a clear extracurricular interest in computers, or though formal education.
All interns are based in our offices in Paris, although we are happy if the student wishes to share their time between our office and their academic institution. All things being equal, we prefer internships to be full-time, but part-time internships are a possibility. We provide a modest stipend, certainly not enough to pay a mortgage and raise a family on, but in line with the norm.
Given the above requirements, we don't think that finding good applicants would be a problem. This is the second year where we are on course for not receiving sufficient good applicants, with an appropriate background, to fill the available opportunities. Let's be clear - we don't accept second-rate applicants - we look for very good students. What are the possible causes for a lack of good applicants?
Our business is undesirable?
We don't advertise in the right places?
The Paris-area doesn't yield students with appropriate skills or training?
Science + Computers is an elusive mix?
What can we do to overcome any of the above factors that might be deterring or restricting applications?
1 - Is our business undesirable?
I don't think so. It is probably a fairly typical small, young company. The workforce is friendly and intimate - almost more like a family in many respects than just colleagues. If this is the problem, then we don't want to chage just to attract further interns! At the time of application, however, the students are unlikely to know much about the company beyond the information on our website. they don't know what stipend we might pay, they probably don't even know what projects they might be applying for (that depends on how their academic program is run).
2 - Do we advertise in the right places?
We tend to notify universities/departments and some select academics in the Paris-area directly of opportunities. We certainly could advertise more widely - oh! is that what this blog post is doing?
3 - Are courses producing students with the required training?
Maybe many applicants do have the required skills, but these are not clearly discernible from the application? My argument is that if somebody can't write an effective CV and cover letter, then they won't be able to write an effective report. Communication is key, and the application can be considered as a test of communication skills.
There's lots of noise on the web suggesting that modern courses are not producing students with the necessary skills for the workplace. My view is that the chief skill required is the ability to learn and research independently. If the potential employee can efficiently solve problems, and can continue to develop their skill base, then they are more suited to working in a real commercial organisation than any potential employee who knows everything about topics W, X and Y, but who can't overcome simple problems or quickly learn about new topic Z. At this level, good numeracy and literacy are important, but the application screening adequately filters on this point!
4 - Are Science and Computing skills mutually exclusive?
There's plenty of courses that mesh computing and science: Bioinformatics and Cheminformatics are two popular subjects for Masters courses. I'm sure the programming elements of these courses leave a lot to be desired - but that's not important because people who are really interested will teach themselves how to program effectively (as opposed to how to write source code to express some contrived but simple logic). Further, many of our projects don't require any significant programming. Therefore, I don't think this is the problem.
The above analysis suggests that poor advertising is an aspect that we might benefit from improving. With that in mind...
Do you want an Internship Project?
My company currently has at least 6 available projects, some focused on research related to drug discovery, and some focused on validating or programming or prototyping algorithms and software. We have space in our offices in Paris for around 3 simultaneous interns, but the exact number we will accept depends on various criteria. It is safe to say we want to find at least 2 more interns for 2010. Each project usually takes between 3 and 6 months.
Do you come from a Scientific Background?
For a research project, you would be expected to be very comfortable with spreadsheets and maybe with some experience of basic shell scripting. Sometimes, knowledge of SQL is useful but we can teach you that.
For a software project, you would need some demonstrable experience in a modern programming language (e.g. Java, C#, OCaml). You could explain to me what the difference between an object and a class is. Maybe, you can explain to me how a relational database works. Maybe, you can create a webpage by hand, using (X)HTML.
Do you come from a Computing Background?
You'll be given a software project, and that'll almost certainly include a large element of hands-on programming and testing. You can categorise a set of simple molecules according to those which are aromatic and which aren't (I would offer a variety of representations, but there would be no complicated or borderline cases). You'll be able to explain protein structure to me, in terms of primary, secondary, and tertiary structure. You can explain to me the basic concepts of Molecular Mechanics. You'll be familiar with Unit tests.
Why should you want to work at MEDIT?
We are friendly ; During your project, we will try to push you but that's good for both of us ; You'll gain experience in a real commercial environment, doing a meaningful, useful project.
Historically, a high proportion of our interns progress on to complete PhDs, some of which we even fund ourselves.
Our offices have reasonable access to Fontainebleau.
Interested?
If your application is accepted, we are very flexible. We will adapt a project to suit you.
Email me. Your first test is to find my work email address. I'll give you a clue. It starts with "stewart" and ends with "medit.fr". Include a CV and a cover letter. Tell me something interesting that you've done recently. Tell me whether you want a "mainly-scientific" project or a "mainly-software" project.
The Portable Document Format (PDF) is a widely-used format to publish documents. There are several different variants of it, some qualifying as an Open Standard, some certified by ISO and some sadly encumbered by software patents. It is important to promote the versions that are Open Standards, because Open Standards lead to better interoperability, competition and ultimately choice.
There is a lot of software available for reading and writing PDF documents, but few people know about any of these. All of the PDF readers listed on the pdfreaders.org site are Free Software, respecting your basic freedom to use, study, share and improve these. This maintains your control over your own computer and helps to protect your privacy, wallet and sanity. That's not all, many of the programs listed are actually better than Adobe Acrobat and other propriety programs. Smaller, faster, easier to use. Do you have any reason to not try them?
Here is a simple, minimal, but efficient solution to supporting multi-core processors in your software with older versions of the .NET framework.
Introduction
In case you haven't noticed, computer processors aren't getting faster any more. There was a time when every few months a new range of chips would be available from Intel, or AMD, and their friends, boasting new faster processing. Nowadays, we can still get new chips but now they provide improvements other than raw speed increases.
To take advantage of the new "multi-core" chips, we need to write our software a bit differently. This is quite straightforward when using modern programming languages and frameworks, but less so for legacy systems. For example, current versions of Microsoft's .Net framework offers something known as the Parallel Task Library. It is lovely. The world is great. We are all happy. Well, that is all true until we write code with a slightly older, but still commonly used version of the .NET framework.
How can we leverage current and future CPU architectures, while still targeting the .NET 2.0 framework? We can manually manage threads in our code. Yuck! There's no way we want to do that! When recently confronted with this problem I decided to take a slightly different approach. I cloned a minimal subset of the Task Parallel Library, and I'd like to share the fruits of my labours here. With you. No ties.
An underlying requirement of the following code is to support .NET 2.0, and above, and Mono 2.2 and above (and it almost certainly works with earlier versions of Mono but that is just a pleasant coincidence).
Background
The normal key to improving software performance on modern computing architectures is to run on multiple processors, or processing cores, in parallel. Microsoft's Task Parallel Library (TPL) is designed to make it easy to develop managed code that automatically uses multiple processors. TPL does not require any particular language extensions and works with the .NET Framework version 3.5 and later.
Unfortunately, the TPL requires the .NET Framework version 3.5, or later.
Solution
I won't describe how the code works in any great detail, as you can read that from the source code itself. A Visual Studio solution is provided, and this should work on Visual Studio 2005 and later versions. It probably also works with Novell's MonoDevelop.
If you wish to run the included unit tests, you'll need the NUnit unit testing framework. I've tested with NUnit 2.4.5, but other version will probably be equally as good. If you don't have NUnit, just exclude the ParallelTests project from the solution in Visual Studio. Apart from that optional dependency, this code is completely standalone, just requiring a C# 2.0 compiler, whether from Microsoft, Mono, or anywhere else.
I have only implemented equivalents of the Parallel.For and Parallel.ForEach looping constructs, but these are typically sufficient for parallelising code in the most obvious way. In both cases, my versions are drop-in replacements for the delegate forms of the constructs in the TPL. Therefore, it should be trivial to "upgrade" to the official TPL at a later date.
To use this within your own code, you can simply duplicate the main Parallel.cs file in your project and then use the Parallel class directly, or you can use my Uk.Org.Adcock.Parallel assembly, as is, and reference the Parallel class from within that.
The included unit tests can act as full examples, if you need then, but it is quite simple...
Stealing an example from the MSDN article linked above, suppose you wanted to square the elements in an array, a, e.g.:
for (int i = 0; i < 100; i++)
{
a[i] = a[i] * a[i];
}
The individual iterations are independent of each other, i.e., subsequent iterations do not depend on prior iterations, you can utilise parallelism with a call to the Parallel.For method, e.g.:
The Parallel.ForEach method is implemented similarly, but I won't insult your intelligence by providing an example. Look at the unit tests if you really need one.
I also allow simple configuration of the maximum number of threads to utilise. By default, however, one thread per CPU core reported by the operating system will be used. Simply set the value of the Parallel.ThreadCount property, where a value of zero indicates that one thread per available CPU core should be used.
Availability and License
I am making this code available freely, under the terms of the 2-clause BSD license.
In roughly 24 hours time, the new Football League 2009/2010 season begins for Norwich City...
...and again, just like last season, and the season before, and the season before, I am quietly confident that Norwich will do well.
Realistically, Norwich really do have a better chance of producing less embarrassing results, because this season they play in the lower trenches of the football league.
Some people seem to be quite delirious at the prospect of supporting a "big club" at this level, like whoever it was that created this:
Buyer beware for Canon Ultra-Compact digital cameras...
My wife and I, plus a good friend had three cameras between us. In America, these are known as the " 7.1MP Digital Elph Camera with 3x Optical Zoom"
They were fantastic "point-and-shoot" ultra compact digital cameras. They produced really good photographs, had plenty of settings to play with, and were really simple to use. The battery life was amazing (I had more than 350 photos on one charge) and, I am told, they looked good. Now, all three have died with a fatal "Lens Error, please restart camera" error!
This is clearly a common fault, as proven by a simple web search. Canon deny a faulty design and always seem to avoid free repairs under their warranty, at least in the UK, by claiming that the camera contains dust or sand particles. In the UK, repairs cost £109+VAT+postage. There is no certainty that the problem won't occur again within a few months, so that price is too high to justify the repair over a new replacement. Effectively, a Canon warranty is a worthless warranty.
Complex electronics like this will often have small problems, but Canon's attitude on this matter is a disgrace. So, after buying only ever Canon digital cameras, I can't recommend that anyone buys one now despite good usability and brilliant picture quality.
My wife and I also have, between us, two Canon photo printers. These work well, but are now too expensive to run. It is cheaper to get the photos professionally printed (for 5"x8" or similar sizes), or to use my dead-cheap but solid Lexmark printer instead (for A4 or similar sizes).
I guess Canon's customer care have just lost them a formerly loyal customer.
Technorati is one of the more established blog indexing sites. These are my continuing adventures in the blogosphere...
According to themselves:
Technorati was founded to help bloggers succeed by collecting, highlighting, and distributing the global online conversation. Founded as the first blog search engine, Technorati has expanded to a full service media company providing services to the blogs and social media sites and connecting them with advertisers who want to join the conversation, and whose online properties introduce blog content to millions of consumers.
The leading blog search engine, Technorati.com indexes millions of blog posts in real time and surfaces them in seconds. The site has become the definitive source for the top stories, opinions, photos and videos emerging across news, entertainment, technology, lifestyle, sports, politics and business. Technorati.com tracks not only the authority and influence of blogs, but also the most comprehensive and current index of who and what is most popular in the Blogosphere.
Inhibition of the mitotic spindle formation could be an interesting target for cancer therapeutics. Scientists at MEDIT recently published results of a exploratory computational fragment-based approach on an allosteric binding pocket of the Eg5 mitotic kinesin...
During cellular metaphase, a stage in eukaryotic cell mitosis, the mitotic spindle maintains a constant shape and size as their principal constituent, microtubules, are continuously polymerized, depolymerized and transported towards the two spindle poles. Kinesin motor proteins are involved in the mitotic spindle assembly, in addition to other cellular processes such as intracellular vesicle transport, chromosome segregation, cell division and motility. The role of Kinesin is discussed in this wikipedia article.
Inhibition of mitotic spindle formation is an interesting target in cancer therapeutics. The anti-mitotic agents to date cause serious side-effects, such as neurotoxicity, and the development of drug resistance restricts their application.
A different approach to inhibit the mitotic spindle formation is to inhibit the mitotic motors that interact with microtubules. Eg5 is exclusively involved in the formation and function of the mitotic spindle, driving a relative sliding of microtubules in the mitotic spindle. Inhibition of this results in cell cycle arrest and apoptosis, without interfering with other microtubule-dependent processes. Several small molecules are known to inhibit human Eg5 by binding to the catalytic motor domain. These observations imply the utility of Eg5 as an anticancer drug target.
The Eg5 allosteric binding site surface (Grey: hydrophobic, Blue: hydrophilic) showing co-crystallized monastrol (green) and mon-97 (blue) ligands, as superimposed with MED-SuMo.
My colleagues and I at MEDIT, recently developed a fragment-based drug design protocol. Based on that protocol, the aim of the work presented here was to populate the hydrophobic pocket of the Eg5 allosteric binding site, hopefully to design potential inhibitor molecules.
In the earlier work, we defined a new structural entity known as the MED-Portion. This represents ligand molecules, or substituent fragments, annotated with fragmentation anchors and interaction sites from the protein environment.
MED-Portions retrieved from known protein structures with MED-SuMo were hybridised using the MED-Hybridise and 3D substructure filtering rules to discover novel molecules having similar binding mode to the known inhibitors. Of these potential ligands, we found those that are present in publicly available chemical libraries, such as the PubChem database. We also validated the protocols through a process of recreating the structures of known inhibitors.
For more information see:
Ksenia Oguievetskaia, Laetitia Martin-Chanas, Artem Vorotyntsev, Olivia Doppelt-Azeroual, Xavier Brotel, Stewart A. Adcock, Alexandre G. de Brevern, Francois Delfaud and Fabrice Moriaud, "Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site", Journal of Computer-Aided Molecular Design, 2009 June 17. Epub ahead of print (I'll update this as soon as the paper is in print)
cameras between us. In America, these are known as the "
7.1MP Digital Elph Camera with 3x Optical Zoom"
