Archive for the ‘Articles’ 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.

Divinity II: Dragon Knight Saga – Review

Jan 30th, 2011

Note

This review was originally written for the forums of Rock, paper, Shotgun, it has been modified here to make it more suitable for a blog entry. Unfortunately, as it was somewhat spontaneous, and was written after I had finished, and uninstalled the game, I unfortunately don’t have any screenshots to illustrate the review. The review is for the PC version of the game.

I picked up Divinity II: Dragon Knight Saga with some slight trepidation; while I had been first attracted to the game prior to its initial release in the form of Divinity II: Ego Draconis, poor reviews for the first release dissuaded me from taking the plunge. With the release of the expansion pack, Flames of Vengeance, Larian Studios remastered the first game, incorporating an improved graphics engine and a number of other improvements. The Dragon Knight Saga release includes this remastered version of the first game, and the Flames of Vengeance expansion, which extends and concludes the story. With reports that these improvements had addressed some of the main issues that had marred the original release, I picked up Dragon Knight Saga in the Steam sale, and was pleasantly surprised. In many ways it is a B-list game, lacking spit and polish of your AAA games, while at the same time avoiding the true levels of innovation which would help it truly step above the competition. However, if your looking for an enjoyable RPG romp, with a few neat ideas, then it manages to deliver solidly.

The most obvious of these neat ideas is the central conceit, the ability to turn into a dragon, something which ensured that the game jumped on to my radar. However, while the idea isn’t exactly squandered, it certainly isn’t used to its full potential, barely making an appearance until halfway through the game, and remaining almost entirely unused in the “Flames of Vengence” expansion. For the most part, dragon sections feel like a separate mini-game, albeit one which is remarkably useful for making a rapid escape from danger. They are competent enough, but for the most part lack the depth and variety of the human portions of the game. Instead, the draconic nature of the main character plays a far more interesting role in the development of the plot, although again, this scenario is not explored to its full potential. In practice, neither of these decisions should be seen as a major failing on the part of the game; instead the reflect on clear design decision, in terms of gameplay and exposition respectively. However, if your primary reasons for looking at the game were to take part in epic in air combat, or to experience a detailed consideration of the nature of the self and the nature of humanity (or draconity) then you’d best look elsewhere.

While the central conceit may fail to deliver anything more than a distraction, the rest of the game provides more than enough satisfaction. The mind-reading skill provides a neat mechanic, providing a few rewards or alternative quest solutions along the way. In many ways it acts in a similar manner to speech checks in other RPGs, but the experience cost for mind reading means that its use becomes considered, rather than the ‘speech check option’ magic button seen in games like Mass Effect.

The game is classless, allowing you to easily develop your character as you wish. I was easily able to create a battle mage, giving myself a nice selection of DPS spells, summons, healing and crowd control, while still ensuring I was durable in melee combat and could deal out considerable damage with my dual wield weapons. The ability to upgrade skills ensures that spells do not become underpowered as the game progresses, and it is easy to respec your skill tree later should you have a change of heart.

Other nice mechanics are the weapon and armour enchantment, which can make significant differences to the performance of your kit. However, one criticism is that the weapon damaged modifications are ridiculously overpowered at the higher levels, making them no-brainer choices when compared to the other possibilities. The problem is further compounded for dual wield characters, as damage modifiers on your main hand, also effect your off hand, and vice versa. By the end of the game I was dealing more damage due to my enchantments than due to the base damage of the weapons themselves.

Necromancy provides a ‘creature,’ which acts as a summon for all character builds. The choice of different limb sets allows the creature to be customised to perform different roles, loosely falling into mage, ranger and tank. While in the early game your creature can be a valuable ally, by the end game a maxed out creature will be only a minor distraction for your enemies. It would have been nice to see a bit more tactical depth introduced at this point, allowing the player to issue basic commands to the creature, although it is possible that the developers wished to avoid the feeling that you need to micromanage your summons.

While combat provides enough depth to allow the player to customise their approach, and to ensure they aren’t reduced to continually spamming the same skill, it is slightly lacking in variety. While enemies show slight differences in damage sensitivities, it isn’t sufficient to discourage a one size fits all approach, especially in the later stages. Additionally, power games are likely to find themselves becoming overpowered towards the end of the expansion, although I can be partly blamed here as I entirely forgot I could turn up the difficulty.

The game isn’t going to win any awards for writing, and the plot, while entertaining, is lacking in depth, or any striking originality. However, it is entirely serviceable, and has enough twists and variations to prevent it from becoming overly predictable. ‘Dark’ fantasy this is not, and the game never takes itself too seriously; it is perfectly willing to mock itself when it needs to, voice acting is often served with a large side order of ham, and most conversations have a few witty retorts.

Quest design is pleasantly varied, and often enough allows for a couple of different solutions; although in many cases the repercussions of these decisions are decidedly limited. A few quests even involve jumping puzzles, unusual for an RPG; for the most part the third person perspective, and decent platform placement, ensures that these are pleasant change of pace, rather than a source of hair pulling frustration. Especially nice are the unmarked quests, such as small puzzles in dungeons that may lead to a chest of loot. These latter puzzles couple well with the games rewarding of exploration. With the tutorial out the way, it is theoretically possible to run through the world that will host most of the original campaign. In practice you’ll soon be killed by enemies outside your level; the game features no level scaling, and until the expansion pack, pretty much no respawning.

One of the nicest features of the game is the great art design, and there are some fantastic areas and enemies. While it would have been nice had the designers gone completely overboard with some of these designs, there are still obvious efforts to ensure that some of the more cookie cutter sections, such as the flying fortresses, are still given their own flavour.

I realise that this review might sound a bit 70%, however the game holds together remarkably well; it is better than this. It is, for the large part enjoyably competent, but with a few touches of something much better. Like a cheap summer blockbuster, that somehow manages to get all the elements in the right place, and shines through because the people who made it were genuinely enjoying what they were doing. Divinity II knows that it is not AAA material, and it gloriously recognises this fact and revels in it. It reminds me of games from the 90s, before they were ‘serious business,’ and never worries about being a bit silly if that means things will be more fun. Finally, although you shouldn’t buy it solely because of this fact, you can play a bloody dragon.

In the UK, Divinity II: Dragon Knight Saga is currently available on PC by digital distrubution only.

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.

Shedding light on astrological nonsense

Dec 17th, 2010

Last night I was directed towards an article claiming that scientists had inadvertently found evidence to support astrology:

Principle of astrology proven to be scientific: planetary position imprints biological clocks of mammals

(NaturalNews) Mention the word “astrology” and skeptics go into an epileptic fit. The idea that someone’s personality could be imprinted at birth according to the position of the sun, moon and planets has long been derided as “quackery” by the so-called “scientific” community which resists any notion based on holistic connections between individuals and the cosmos.

Skeptics must be further bewildered by the new research published in Nature Neuroscience and conducted at Vanderbilt University which unintentionally provides scientific support for the fundamental principle of astrology — namely, that the position of the planets at your time of birth influences your personality.

As a member of the “so-called “scientific” community” I admit that I immediately suspected quackery, or woeful misinterpretation on the part of the astrologers writing the article. However, were I to write off their claims entirely based on this suspicion, then I would be guilty of the close mindedness that they accuse me of. So, in order to dissect their claims, I had to go back to the primary source, the paper they were referencing1 .

What do the astrologers claim?

Before we take a look at the original paper, lets have a look at what the astrologers claim. I’ll only concern myself with the claims directly relevant to the paper they are discussing; their claims regarding scientific arrogance, their straw-man scientists, and cold fusion can be left for someone else to tackle.

The first claim is that “according to the conventional view, your genes and your parenting determine your personality, and the position of planet Earth at the time of your birth has nothing to do with it.” This attempt to set out the conventional scientific viewpoint ignores the large number of other environmental effects that scientists accept can influence development. These environmental effects can be influenced indirectly by the position of the earth, as it is the movement of the earth that is responsible for influencing the seasons.

The astrologers then make the following claims regarding the findings of Ciarleglio et al.:

  1. That the position of the planets at the time of your birth influences your personality.
  2. That mice born in the winter show a “consistent slowing of their daytime activity”
  3. That mice born in the winter are more susceptible to Seasonal Affective Disorder (SAD).

They then summarise by claiming that “one of the core principles of astrology [is] that the position of the planets at the time of your birth (which might be called the “season” of your birth) can actually result in changes in your brain physiology which impact lifelong behavior.”

So, does the paper actually support the claims they make of it?

The Paper

Unfortunately the writers of the article don’t actually provide a link to the original paper, something which is sadly all too common . However, they do provide enough information to let us find the paper:

Perinatal photoperiod imprints the circadian clock


Christopher M Ciarleglio, John C Axley, Benjamin R Strauss, Karen L Gamble & Douglas G McMahon
Nature Neuroscience (2010) doi:10.1038/nn.2699
Received 24 August 2010 Accepted 21 October 2010 Published online 05 December 2010

Using real-time gene expression imaging and behavioral analysis, we found that the perinatal photoperiod has lasting effects on the circadian rhythms expressed by clock neurons as well as on mouse behavior, and sets the responsiveness of the biological clock to subsequent changes in photoperiod. These developmental gene × environment interactions tune circadian clock responses to subsequent seasonal photoperiods and may contribute to the influence of season on neurobehavioral disorders in humans.

As far as I can tell, the paper is open access, which means that anyone should be able to read it. I’m afraid the same can’t be said for all the papers I’ve referenced here.

What do they do?

The Circadian Rhythm

That nature responds to the cycle of day and night is easily observable, flowers track the sun, people and other animals sleep and awake, and other behaviour seems to correlate with the time of day. What is perhaps more surprising, is many of these behaviours continue to show a daily cycle, even if the sun is removed from the equation. For example, flowers will continue to track the position of the sun for several days after being placed in a dark room. Typically the cycles shown during these ‘free-running periods’ (either of constant light, or constant dark) are either slightly longer or slightly shorter than twenty-four hours, and the regular light-dark cycle is necessary to maintain calibration.

The impact of circadian rhythms on human behaviours should be apparent to anyone who has ever experienced jet lag, and the depression that can follow the shorter winter days (SAD), has been linked to the circadian cycles. In humans and other mammals, this internal biological clock has been tracked down to a region of the brain known as the suprachiasmatic nuclei (SCN), in which the expression of a number of genes, or associated hormone production, vary on an approximately twenty-four hour cycle. These cycles continue, even when exposed to constant light, or constant dark, thus providing an internal ‘body clock.’

The ‘clock genes’ are those whose expression (the level at which the cell makes protein from a given gene) varies over the cycle. For example, the gene per1 is most active during the day. By genetic manipulation, is is possible to ensure that per1 produces a product with a fluorescent tag, allowing its activity to be measured by monitoring cell florescence.

Mice were exposed to either short-day or long-day light cycles (8 or 16 hours of ‘daylight’ respectively) from before birth until weaning (The perinatal phase). Following weaning, mice were either maintained under the same light cycle, or were stitched to the opposite cycle for a further 28 days (The continuation phase, Figure 1). Experiments were repeated in both winter and summer, to take into account variations that may be induced by the actual season.

Figure 1: Mice were expose to either long or short day light cycles prior to weaning. Subsequently mice were either maintained under the same conditions, or were switched to the opposite cycle.


Following this treatment, the circadian rhythms of the rodents were studied, either by tracking the expression of specific ‘clock genes,’ or by monitoring rodent behavioural activity2.

What do they find?

The authors found that the ‘day length’ at birth continues to have an impact on the circadian rhythms of the mice, even after they have been shifted to a different cycle. In particular, long-day born mice, showed a narrower peak of activity in the SCN, and in addition showed a shorter internal clock cycle, this resulted in more consistency between subsequent exposure to either long or short day cycles. In contrast, short-day born mice generally showed wider peaks of activity, and longer internal clock cycles. They were also subject to more variation in circadian rhythm behaviour between subsequent ‘summer’ or ‘winter’ cycles.

What does this mean?

This indicates that the day length at birth may have long term effect on subsequent circadian rhythms, even when the day length changes. In particular, mice born during a ‘winter’ cycle seem to show more variation in subsequent seasonal changes. The authors indicate that this may have implications with respect to previous findings, which show that mice born during winter-like cycles show increased levels of depression like symptoms, and that winter born humans show increased levels of SAD, bipolar disorder and schizophrenia. However at this stage it is not possible to draw a firm link between the findings.

What are the limitations of the study?

One of the primary limitations of the study is that it only addresses a short time span, and the authors acknowledge that they have no indication as to how long the effects may last. This may be especially relevant when attempting to translate the results to humans: not only a different species, but one with a significantly longer lifespan.

Additionally, I am also concerned that the study only considered two phases, the perinatal phase, and then either a continuation of the initial levels, or a switch to the opposite seasonal cycle. The possibility remains that exposure to a long-day cycle outside the perinatal period is sufficient to, at least partially, imprint the same pattern as seen in the long-day born mice. In support of this possibility is the considerably lower variation between short-day and long-day born mice under long-day conditions. However it should be pointed out that there are still significant differences between shot-day and long-day born mice.

Does the paper support the claims of the original article?

In short no.

Firstly, the only planet whose position has effect on day length is planet earth, where the orientation of its axis relative to the sun determines the season, and hence the day length. The other planets have different orbital periods, which means that Mars won’t be at the same point in the sky on December 17th 2010, as it was on December 17th 2000. Furthermore, while the northern hemisphere is in the grip of winter, the southern hemisphere is in the middle of summer, meaning that any seasonal effects are going to depend on the hemisphere, as much as the location of the earth.

But importantly, the researchers have been careful to isolate day length as the variable, separating other seasonal effects, such as temperature, or indeed the earth’s location. Furthermore, by conducting the experiment in summer AND winter, the effectively prevent any actual seasonal variations from having an effect.

In short, the findings have nothing to do with astrology. Ironically, the ‘tabloid horoscopes’ derided in the article have more to gain; your star sign is correlated with day length when you were born, at least assuming we confine ourselves to a narrow latitude.

Oddly the article also ascribes the findings regarding depression like symptoms in winter-born mice to this study, when in fact they were conducted separately. But again, these findings were purely associated with day length, not planetary position.

So in summary we have either a gross misrepresentation of scientific findings, or a major misunderstanding. We also have a paper which is potentially interesting, although I’d like to see how stable the effects are through multiple changes in day-length. If the effect is isolated to a short period of possible imprinting, then it will be interesting to narrow this period down in different organisms.

  1. Ciarleglio, C. M., Axley, J. C., Strauss, B. R., Gamble, K. L., & McMahon, D. G. (2010). Perinatal photoperiod imprints the circadian clock. Nature neuroscience. doi:10.1038/nn.2699. []
  2. Wheel usage []

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. []