Archive for the ‘Ponderings’ Category

Technical Issues

Mar 16th, 2011

My blog is currently causing peaks of CPU usage, which are causing problems for my web-host. However, traffic levels are at their usual low. In an attempt to diagnose the problem, I am in the process of disabling plugins. As a result, some features of the site may not be working as intended.

I apologise for any inconvenience.

The Diverse Power of Love

Jan 3rd, 2011

You know how it is, a family discussion leads to debate over who was best known for a particular song, followed by a brief poll over twitter and facebook, which only serves to split the debate further.

The subject of this particular debate “The Power of Love.”

Now, I can’t remember what actually triggered this discussion, but as a Child of the 80’s I immediately plumped for Huey Lewis and the News, which formed the sound track to the 1985 film, Back to the Future. Meanwhile, after a quick and misleading Spotify search my Mum went for the great Jimmy Hendrix, whereas Dad was running for Celien Dion. My slightly illphrased questioning on twitter and facebook turned up Jesus, more Huey Lewis, someone’s auntie and Frankie Goes to Hollywood.

But clearly one of these had to be the original, didn’t they. Well, no. It appears that we were all looking at different songs:

Power of Love 1

Well, going with my choice first we have the Huey Lewis and the News version. The most popular option in my informal poll, this formed the soundtrack of 1985 time travel comedy Back to the Future. It also sits at the top of the ambiguity page on wikipedia, and is the first suggestion in Spotify and Youtube.

Spotify Link

But, naturally, this has been covered, including a slightly disapointing 8-bit inspired mix which infused the back to the future theme by I Fight Dragons (Spotify).

Power of Love 2

I was actualy familiar with this song, even though the Huey Lewis and the News version would come to mind first. Originally done by Frankie Goes To Hollywood, Spotify would suggest that this is one of the most covered songs with this name. Dated from 1984, this predates the Huey Lewis and the News song.

Then a few of the covers.
Free4 (DALA), Dune, Omph! (Quite different), Anneke Van Giersbergen, LOndon Symphony Orchestra

The Power of Love 3

Clearly the mid 1980s were all about the Power of Love, as 1984 also saw the release of the Jennifer Rush song of the Same name. Subsequently covered by Celine Dion, who picked up my Dads vote.

Jennifer Rush (Spotify)
Celine Dion
Gregorian Chants

The Power of Love 3+x

Of course, this being the second decade of the 21st century, we are no longer limited by who manages to find a record label. These enterprising folk clearly decided that they’d release a song under a title that people were doubtlessly fed up of even during 1985. Still, if they had called it something else I wouldn’t be linking it here, so a win on one level I suppose.
DJ Stephanie, Lunatica

Pre-dating all of these we have the Everly Brothers with [You Got] The Power of Love, 1966. Makes you wonder why they they bothered with the brackets. If you want to be strict though, first example of a Power of Love without the brackets appears to be Joe Simon, 1972, shortly followed by Gary Wright, from 1975.

So…

More songs called ‘Power of Love’ than you can shake a stick at. Seems that my mum was completely off with her suggestion of Hendrix, but I blame the erroneous prompting of Spotify on my Android for that. Seems she was actually thinking of Power to Love.

Very A-typical blog post, and I guess plenty of folk will have known all this already, but bah, I can bore you all with science, politics or gaming again at some other point.

Mitochondrial proteins at the proteasome, are you MAD?

Dec 16th, 2010

About this post

This post was originally written for a job application, however I was never able to use it. It covers a growing field closely related to the subject of my PhD. As the article was originally intended to be written for a blog of a biology journal it is primarily written for those with training in the biological sciences, although I also tried to make it accessible to an informed lay audience. Unfortunately I think this attempt at pitching the article at a wide audience hasn’t been entirely successful, at times seeming too simplistic fro the primary audience, and at others too inaccessible to a lay audience. I also feel the article could do with being less formal, however given the original purpose of the article I felt it was better to lean towards too formal, than risk being perceived as too informal.

I should clarify that I don’t discuss any of my work in this article.

When proteins become damaged or are no longer required by the cell, they can be broken down into their component peptides, allowing these resources to be reclaimed. Much of this recycling occurs at proteasomes, hollow barrel like structures located in the cytoplasm and nucleus of the cell. Breakdown of proteins occurs in a catalytic chamber at the centre of the structure, and entry of potential substrates is tightly regulated by caps at either end of the chamber.

In most cases, a protein’s fate at the centre of the proteasome is determined by the attachment of a chain of ubiquitin: a small protein, which can be covalently attached to lysine residues on other proteins. This chain is recognised by components of the proteasome, as well as by shuttle factors, which help recruit substrates to the proteasome.

Proteins within the cytoplasm or nucleus have easy access to the proteasome, however those within membrane bound organelles must first be translocated into the cytosol. The first evidence for such processes occurring was found in association with the endoplasmic reticulum.

Endoplasmic reticulum associated degradation, or ERAD, describes the process by which unwanted proteins within the endoplasmic reticulum are retro-translocated to the cytosol. Here they are tagged with ubiquitin, and delivered to the proteasome. ERAD relies on the co-operation of a large number of factors. A series of chaperones identify proteins which are undergoing difficulty folding and in turn they deliver them to complexes in the ER membrane. From here, proteins are transferred to the cytosolic face of the organelle, and chains of ubiquitin are attached, marking them for proteasome mediated degradation. The hydrolysis of ATP by the hexameric Cdc48/p97 provides the energy to extract ubiquitinated proteins from the membrane, and co-factor proteins ensure efficient delivery to the proteasome or its shuttle factors.

For a long time it was assumed that no such system existed in mitochondria, the respiratory centres of the cell, as they have their own complement of proteases. However, increasing evidence is suggesting that the proteasome may play an important role in the degradation of some mitochondrial proteins, leading to the proposition of mitochondria associated degradation, or MAD.

Traditionally, the degradation of mitochondrial proteins has been seen to be the domain of the mitochondrially localised ATP dependent proteases. The inner mitochondrial membrane contains multi-subunit proteases with their catalytic activity orientated to face either the inter-membrane space, or the mitochondrial matrix. Additional proteases, such as Lon/PIM and ClpXP, are found within the mitochondrial matrix. This collection of proteases is sufficient to provide protein degradation in the mitochondrial matrix, inner mitochondrial membrane and the inter-membrane space, however analysis of the products of proteolysis indicate that inter-membrane space proteins are under-represented.

Some of the earliest evidence of proteasome dependent degradation of mitochondrial proteins came in 1985, when Rapoport et al.1discovered that some mitochondrial proteins were ubiquitinated, and degraded in an ATP dependent manner. Subsequent to this, other ubiquitinated proteins have been found to localise to the mitochondria, and appear to undergo proteasome mediated degradation.

More direct evidence arose when Margineantu et al.2 found that the heat-shock protein Hsp90 appeared to promote ubiquitination of OSCP, a matrix localised subunit of the mitochondiral F1F0-ATPase. Further investigation revealed that disruption of Hsp90 resulted in reduced turnover of OSCP and other mitochondrial proteins, resulting in accumulation on the outer mitochondrial membrane; similar changes were observed on proteasome inhibition. This accumulated protein appeared to be a result of retro-translocation of mature mitochondrial proteins, indicating that mitochondria possessed a pathway of retro-translocation and proteasome mediated degradation, analogous to the ERAD pathway.

Dissection of the mitochondria associated degradation pathway is still in its early stages, and as yet many of the required components remain speculative. Comparison with the better characterised ERAD pathway is inevitable, and it remains to be seen if any elements will be shared between the two pathways. Recent work by Heo et al.3 discovered that Cdc48/p97 was recruited to mitochondria in a stress responsive manner by a protein they called Vms1 (VCP/Cdc48-associated mitochondrial stress-responsive). Disruption of this process resulted in a reduction in ubiquitin-dependent degradation of mitochondrial proteins, leading the authors to propose that Cdc48/p97 may perform a key role in MAD, as well as in ERAD.

The highly oxidative environment of the mitochondria means that its proteins are particularly prone to damage. Mitochondrial proteases have long been known to provide one line of protein quality control, and it is increasingly apparent that the proteasome dependent degradation of the MAD pathway may provide another. Dissection of the MAD pathway will be essential for forming a complete picture of the mitochondrial protection against damaged proteins, and may provide insights into diseases such as amyotrophic lateral sclerosis, which are associated with an accumulation of misfolded proteins in the mitochondria.

  1. Rapoport, S., Dubiel, W., & Müller, M. (1985). Proteolysis of mitochondria in reticulocytes during maturation is ubiquitin-dependent and is accompanied by a high rate of ATP hydrolysis. FEBS letters, 180(2), 249-52. Pubmed. []
  2. Margineantu, D. H., Emerson, C. B., Diaz, D., & Hockenbery, D. M. (2007). Hsp90 inhibition decreases mitochondrial protein turnover. PloS one, 2(10), e1066. doi: 10.1371/journal.pone.0001066. []
  3. Heo, J.-M., Livnat-Levanon, N., Taylor, E. B., Jones, K. T., Dephoure, N., Ring, J., et al. (2010). A stress-responsive system for mitochondrial protein degradation. Molecular cell, 40(3), 465-80. doi: 10.1016/j.molcel.2010.10.021. []

Where now for a liberal-leftie?

May 11th, 2010

So, the bird has gone to roost in the tree; it remains to be seen whether it will prune back the branches to make a nest, while proudly displaying its plumage, or if it will soon give leaf itself, and become indistinguishable from its new home. While the former situation may make me feel happier in the vote, it also increases the chance that tree and bird will fall out, possibly bringing the whole metaphor down with them.

When the prospects of a Liberal Democrat – Conservative coalition first began to become a practical possibility, rather than a theoretical one, I was initially horrified that the paint may have been flaking of my yellow vote to reveal the blue underneath. It was a popular sentiment. When I tweeted “If the Lib-Dems do team up with the Tories, it will be like a twist in a film when you realise one of the heroes is the bad-guy.” It was rapidly picked up and re-tweeted (forwarded) around the Twittersphere by over 160 people. Clearly many like me felt betrayed, and worried that all the talk of “A vote for the Lib Dems is a vote for the Tories” would turn out far more literally than they may have expected.

However, as time passed it became clear that options were few. While many of the left looked on at a prospect of a grand liberal coalition, the numbers would have been tight, and an already aggressive right wing press would have been attempting to destroy the coalition before parliament was even seated. It was also clear that several senior members of the Labour party were opposed to the proposition, raising the prospect that internal rebellion would seriously threaten the stability of an already precarious position.

The battle was enough to secure a key concession from the Conservatives though, matching Labours offer of AV. With that my most major opposition to the Lib-Con pact was abolished, although I hope the Liberals keep the pressure on to ensure that the changes go through. The situation wasn’t ideal, and I wasn’t about to pretend I was happy with it, but when the cards are dealt you have little choice but to play.

I still worry though. The Conservative party holds vastly more seats than its little pet bird, and I fear that they may get dragged into the fold. Sacrificing ideals for stability, for want of being heard, or for want of power. Furthermore, it is hard to deny the rightward drift of economic policy in the party over the past few years, and it seems possible that the shelter of the leafy boughs of the Conservatives will catalyse this further. Which leaves a problem, if yellow and blue become indistinguishable, either through incompetence or power-grabbing, where next?

Labour may seem an obvious choice, however their dubious record on civil liberties leaves me concerned. While a few back bench rebels still buck the authoritarian trend, the ability to vote for one of them will largely depend on which consistency I end up voting in.

The Greens are considerably to the left of most the mainstream parties, both socially and economically. However, the party occasionally allows its policies to be driven more by ideology than evidence, leaving a few dubious decisions in their science policy. Fortunately they do appear to be attempting to address these in response to criticism in response to their European Election manifesto. Additionally I can’t help but feel that some of their policies seem impractically naive, however this may just be a side effect of their considerable contrast from the mainstream parties. That said, after the election I discovered that my local Green candidate was following Ben Goldacre on twitter, something that had I realised before-hand would have likely persuaded to switch my vote to her.

So where does that leave me? If the AV vote system does get introduced, at least I will be able to vote for who I want, even if they are a minority party. I must admit I am unfamiliar with many of the other minority parties, although know I rejected the Scottish Socialist Party on the basis of their belief in an independent Scotland. (I rejected the SNP on similar principals) It also doesn’t help that most discussion of neo-liberal economics, Keynsian economics etc. just causes my brain to melt. To actually try and work out if it a) is ‘morally’ acceptable and b) will work, is sadly a bit beyond me.

And that’s that, an entry that tails of into navel gazing hand-wringing. How fucking Lib Dem of me. If you want to preach your party, you are welcome to do so in the comments. I’m genuinely interested.

(Note: First time comments will need to be approved manually. I’m not blocking, I’m just being slow.)

Responding to spam comments

Jan 17th, 2010

One of the problems with running a blog is the spam. In addition to the junk I receive through E-mail, I also get plenty of comments spam, from people hoping to get their little spammy plug onto my blog. They don’t succeed. Not only are comments to the blog moderated, but the automatic spam filters catch many of them before they even reach me, but they do still allow me to read them.

Of course, almost every blog in existence has some form of spam prevention, without it they’d soon be overrun. To avoid this they try and not look like spam, either by using generically applicable comments, or else by playing Consequences with key words. This can lead to some peculiar results.

I thought I’d reply to some of this spam. All comments have been cut and pasted, and usernames remain unchanged. Where appropriate URLs have been nullified to prevent the spammer getting any links, or benefit to their Google rank.

Re: On art and games [Part 3]
Matthew C. Kriner
If you’re still on the fence: grab your favorite earphones, head down to a Best Buy and ask to plug them into a Zune then an iPod and see which one sounds better to you, and which interface makes you smile more. Then you’ll know which is right for you.

Thanks Matthew! I’m not sure how you knew I was in the market for a new MP3 player, as I’m pretty sure I never mentioned it in this post. What is interesting however is that you should make you comments on a post which is considering regional differences in gaming market and culture. You may be interested to know that for example, Best Buy doesn’t exist in the United Kingdom, and, for that matter, neither does the Zune. Did it occur to you that perhaps the reason I hadn’t done the bloody obvious thing of physically comparing the Zune and the iPod was because A) The Zune isn’t availible in this country and I am not interested in the support hassles importing would cause b) Because popping down the nearest Best Buy is considerably more hassle when a plane journey was involved. Y’know, for someone with the psychic ability to know I was going to buy a new music player, you should really brush up on your ability to work out that I don’t live in the US and aren’t a total mind-numbing idiot.

Oh, and for future reference, I went for the Sony Walkman X-Series.

Re:Tim Berners-Lee Has a Blog
Plasma TV kopen
This will get some interresting comments haha :P

Well Plasma, you certainly had some interesting parents. Mr and Ms Kopen must have thought themselves highly original with then name Plasma. However, I’m afraid I must disagree with you sentiments. It is not often that a four year old article about a fairly non-controversial topic picks up many interesting comments. For the record, if it does, your certainly wasn’t part of that trend.

Re: This Week’s Tweets
James T.
Considerably, the article is really the greatest on this notable topic. I fit in with your conclusions and will eagerly look forward to your future updates. Just saying thanks will not just be sufficient, for the extraordinary lucidity in your writing. I will right away grab your rss feed to stay privy of any updates. Solid work and much success in your business dealings!

It is a page of fucking tweets! I’m not one to knock twitter, but 140 characters can hardly be called ‘extraordinary lucidity!’ What have you been reading prior to now, YouTube comments?

Re:Merry Christmas
Mireille Clinebell

Sorry? You found this page on a dishwasher?

Re:This Week’s Tweets
Wonda Lynds
Do you know if there are any natural remedies for this?

For twitter? Perhaps you are confusing it with thrush? If so, I recommend steering clear of most ‘natural remedies’ and consulting your GP.

Re:This Week’s Tweets
Elda Amstutz
How fast can someone start to see the results from using it?

Twitter? Well assuming it is not overloaded its pretty much instant? Wait… is this Wonda again?

Re:Homophobic Censorship?
New Proxy
Why would you want to wait till you are out of school to unblock mysace? You can do it easily with a myspace proxy. Its pretty handy to have around if you need to do some unmonitored surfing.

Wait. People who are out of school use Myspace?

Re:This Week’s Tweets
Georgeanna Bisges
the blanket was Kos’s nickname for so long

And you told me that because?

Re: Political Compass
Regine Siverson
Great fight! Lovely to see Penn headkick Sanchez’s forehead open

Remind me never to be alone with you Regine.

Re:This Week’s Tweets
Marcos Shinault
Sorry, I really hate to ask this but do you have any advice on stopping spam? My sites have been getting hammered lately and i’m not quite sure how to stop it.

It’s called karma. Stop spamming other blogs and you may stop receiving it.