Now that you have got angry, please hold on and get ready to read the news (via il blog censurato).

Google's management is encouraging their stockholders to vote against two motions being raised at the annual stockholders' meeting - a motion against internet censorship, and another in favor of the creation of an internal Human Rights Commission, aimed at legally fighting violation of human rights in the countries where Google operates.

Stockholders' hearts might be bad for their pockets, apparently.

Also via il blog censurato, I found this very cool tool comparing English search results for China, the USA, Germany and France. Check out this screen shot, looking at the difference in results when we compare France and China in relations to the search "human rights".


This is a tool developed by Mark Meiss and Filippo Menczer at the Indiana University School of Informatics - you can find more information on the Censearchip website about how the tool works. Notice how, in the image, some of the terms most frequently arising from the French search about human rights are "China" and "Beijing". Not surprisingly, these terms do not emerge in the Chinese search.

But my favorite has got to be the image search, comparing US and Chinese search, using the term "Tienanmen". Here comes the screenshot.


I hope you are not surprised by what's missing on the left side...and no, I was not referring to the lesbian kiss.

Censorship on the net is everybody's business. I encourage you to cover, no matter what the main subject of your blog is, as much news about censorship as you can.


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I do not understand why most of the science research news that can be found in some major mainstream broadcasters' websites are absolute crap. In a world where people are working on endogenous retroviruses, artificial life, stem cell research, and trying to assess and conserve biodiversity...all they are able to come up with in their breaking news is something related to the magical properties of tomato paste.

Maybe I am exaggerating, and I am sure that the study done on the...effects of 5 spoonful of tomato paste and olive oil given out to participants might be groundbreaking. Maybe, regardless of the fact that I am quite skeptical about whether testing tomato paste is a good use for research money (which is hard to come by these days), the science behind the study presented at the annual meeting of the British Society for Investigative Dermatology is sound and valid. But I still cannot see how this deserves a prime spot in the BBC Health section. Here is the summary of the report.

Pizza and spaghetti bolognese could become new tools in the fight against sunburn and wrinkles, a study suggests. A team found adding five tablespoons of tomato paste to the daily diet of 10 volunteers improved the skin's ability to protect against harmful UV rays. Damage from these rays can lead to premature ageing and even skin cancer. The study, presented at the British Society for Investigative Dermatology, suggested the antioxidant lycopene was behind the apparent benefit.
This component of tomatoes - found at its highest concentration when the fruit has been cooked - has already been linked to a reduction in the risk of prostate cancer.
Now researchers at the universities of Manchester and Newcastle have suggested it may also help ward off skin damage by providing some protection against the effects of UV rays.

That's right. Forget the considerable amount of cholesterol that you can possibly find in pizza and spaghetti alla bolognese - go ahead and chug it down, because it might even make your skin look better!

Anti-ageing paste?

They gave 10 volunteers around 55g of standard tomato paste - which contains high levels of cooked tomatoes - and 10g of olive oil daily. A further 10 participants received just the olive oil.

After three months, skin samples from the tomato group showed they had 33% more protection against sunburn - the equivalent of a very low factor sun cream - and much higher levels of procollagen, a molecule which gives the skin its structure and keeps its firm.

"The tomato diet boosted the level of procollagen in the skin significantly. These increasing levels suggest potential reversal of the skin ageing process," said Professor Lesley Rhodes, a dermatologist at the University of Manchester.

Nice. I think I just got a new business idea - injecting tomato paste extracts, you know, for cosmetic purposes. I will call it the ForeverRipe(c) treatment, all rights reserved. Not joking, I am dead serious.

I am tired of Nisbet and Mooney and the other SciBlings arguing. Can somebody please do us a favor, and start writing a few decent articles for main broadcasters, send them out, and get hired part-time? Somebody who possibly knows better than to write about tomato paste, when we are in a time of fabulous advances in system biology, proteomics, synthetic biology, genomics, stem cell and regenerative research?

Please?


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Once in a while i like going around the web looking for cool tools that can be used in research, but also just to visualize scientific knowledge. With the amount of our knowledge, and the size of our databases increasing daily, I find it quite useful to be able to put things in a picture - or to have a tool at hand that would be able to gather recent scientific information and do that for me.

PANTHER is just that kind of tool. If you have a favorite protein, and you want to see what pathways this protein is involved in, and what other protein it interacts with, PANTHER can give you a nice picture, and help you extricate yourself from the web of interactions that your favorite protein has drawn all around it.

If your protein happens to be, say, p53, then you might really find this useful. All you need is the name of a pathway and/or protein, an up-to-date Java applet, and a decent internet connection. And then, you are ready to explore.

Say we pick p53 and the pathways for Huntington disease. Then PANTHER would give you this kind of network as a result:


Now you want to keep everything as it is, but then concentrate on the downstream targets of, say, MLK-2 at the top. You right-click, choose to select the downstream players, and you get all the downstream players highlighted in yellow:


I have never personally used PANTHER for my actual work. But I do find it to be quite an interesting tool, if you are working with very well-known (and therefore, well connected) proteins, such as p53. But if you are working with something more obscure, I doubt that PANTHER could help you much.

Off topic, but important news to cap it off: the Skeptics' Circle is up, and yours truly has been kindly invited. Come join the skeptic meeting - we'll be checking out what you can find under a rock.


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I have already discussed one of the newest papers on miRNA-mediated control of oncogenes and cell pluripotency in the field a few days ago. Given the interest, also in the science blogosphere, for studies and news related to miRNAs, I thought I might write here about a few more papers focusing on how miRNAs are able to modulate the protein levels of several genes important for the regulation of major signal transduction pathways, as well as cell growth and differentiation.

Today I am going to be looking at the one that must be the first paper in the field to report the discovery that at least a family of miRNAs, the let-7 family - which you have encountered before on this blog - is able to regulate a major oncogene, RAS. For short review on what miRNAs are, you can check this out. Now, if you are ready...there's more, right below the fold.

This paper starts by looking at the role of the let-7 of miRNAs in vulva development in C. elegans, the nematode. As I have explained in a previous post, C.elegans come in two sexes: a few rare males, and the most common hermaphrodites. The hermaphrodites are able to produce eggs and self-fertilize them, therefore being able to generate progeny on their own. However, from time to time hermaphrodites will mate with males, and the male sperm will fertilize the hermaphrodite's eggs and generate both male and hermaphrodite progeny. The two sexes have distinct primary sexual characteristics identifiable in their genital apparatus, and the hermaphrodite has a vulva, while the male has a fan-like structure at the posterior end.

Vulval development is an excellent model for studying development at the cellular level (how cell lineages are defined), but also to dissect a major signal transduction pathway, the RAS/MAPK pathway, which is involved not only in development, but also in tumorigenesis.

In the course of the analysis of the effect of let-7 miRNAs on vulval development, Johnson et al. realized that these miRNAs can bind to a section of the 3' untranslated region of the C. elegans RNA equivalent of RAS, let-60 (lethal-60). In fact, this gene has let-7 complementary sites (LCSs) that allow the miRNAs to bind and inhibit its translation. Moreover, let-7-mutant animals will burst through the vulva, while they will not burst if let-60 protein expression is also inhibited by RNAi. This is shown in the following figure.



This finding prompted the authors to look for LCSs in the sequence of the human RAS genes (there are multiple versions of RAS). The human RAS genes also show the presence of LCSs, and are regulated by the human version of let-7 family miRNAs. Injecting let-7 in RAS-expressing cells reduces the levels of expressed RAS protein, and conversely inhibiting let-7 in let-7-expressing cells causes a rise in the levels of intracellular RAS (see figure below).



RAS overexpression or unregulated activity is known to be oncogenic, and many tumors show abnormal regulation of RAS. The authors then looked at human tissue samples derived from patients suffering from breast, colon and lung cancer, and compared levels of let-7 expression, and RAS protein in this samples, to those in adjacent normal tissue from the same patients. The experiments showed that let-7 expression was severely altered in lung cancer samples, and that when let-7 was not expressed at normal levels, this resulted in an increased load of RAS.



This study was of great importance at it showed a direct relationship between let-7 and RAS levels, as well as suggesting that miRNA regulation can be important in tumor biology, and possibly oncogenesis.

Citation

JOHNSON, S., GROSSHANS, H., SHINGARA, J., BYROM, M., JARVIS, R., CHENG, A., LABOURIER, E., REINERT, K., BROWN, D., SLACK, F. (2005). Is Regulated by the MicroRNA Family. Cell, 120(5), 635-647. DOI: 10.1016/j.cell.2005.01.014

Blogroll Additions

Dispatches from the Culture Wars - how did I miss adding this link to my blogroll for so long? Well, here it is.

Dodo's Photoblog and Allen Capoferri: some art, be it sketching or photography, never harmed anybody. So when you feel like you really need a break, check out these two blogs.


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This meta-analysis was published online only yesterday, and it is already going all around the net and the press. Why? Because the authors of the analysis found that

Vitamin A, beta-carotene, and vitamin E may increase mortality.

Moreover, the results for vitamin C were inconclusive. Does it mean that taking vitamins is not only useless, but can even increase your chance to die? I cannot seem to access the full text of this review. However, I thought it would be interesting to go over the methods, the main findings, and the authors' recommendations.

But first of all, some of us out there might be wondering....what is the Cochrane Collaboration? Is this organization reliable or does it call for a hefty dose of skepticism a priori?

More below the fold.

What is the Cochrane Collaboration

The Cochrane Collaboration is a non-for-profit organization founded in 1993. It has little staff, and it is run mainly by a huge number of volunteers, most of whom are medical professionals and/or researchers at universities around the world, and whose main effort is the production of the Cochrane Reviews. The main aim of the Reviews is to try and make sense out of thousand of studies, mainly clinical studies and trials, and to come out with a "state of the union" report which can give medical professional and consumers an idea about what the evidence is, at the moment, pro or contra the use of certain medicines and/or treatments. The video gives you a short introduction to the Cochrane Collaboration.



In case you still have no idea about who these people are...I am sure you have heard of them before. Do you remember the not-so-groundbreaking news that vitamin C really does not help with curing or preventing colds? Well, that was also a result from one of their meta-analyses.

Can we trust data coming out from the Cochrane Reviews? I would suggest that the problem is not with the effort itself, but more with the fact that meta-analyses always come with huge caveats: the data were not collected coherently, probably different parameters were measured in different studies, most probably different statistical methods were used, and it is also quite hard to identify all possible confounding variables. When you look at people affected by a disease, and decide that the vitamins were increasing their risk of death...are you sure that disease progression was not the main confounding variable behind that figure?

Let's find out.

Aim of the study and data collection

The main aim of the study, as stated by the reviewers, was

To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials.

The authors then searched for studies using their own database, MEDLINE, EMBASE,
the Science Citation Index Expanded, and even wrote to pharmaceutical companies for additional information. I do not know how significant this "additional information" was, but it is interesting that they decided to do this, as I wonder how they then assessed the quality of such information.

All studies reporting on the results of primary and secondary prevention randomized clinical trials on beta-carotene, vitamin A, vitamin C, vitamin E, and selenium (versus placebo or no intervention) were included in the review. Participants in these studies were either healthy (primary prevention trials) or not (secondary prevention trials). The authors then tried to assess "bias" for each study, analyzing each of the studies considered for blinding, randomization and follow-up:

Trials with adequate randomisation, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.

Main findings

Here is the quotation, from the review's abstract, describing the results (emphasis and links mine):

Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.91, 95% CI 0.76 to 1.09).

Although I did not have the privilege to look at the full study, this does mean that bias inherent to each study was considered, and that a statistical model controlling for certain time-fixed heterogeneity (think ethnicity, location, and so on) was used. Their results all seemed to be within the 95% confidence interval.

So, what does it mean?

Again, in the words of the authors:

We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.

The results suggest that certain vitamins studied, and known to be antioxidants, have no effect used in a preventative manner on healthy or unhealthy patients, and actually all of them, with the exclusion of vitamin C and selenium, seemed to increase mortality. It must also be said that the authors did not consider cases when individuals were given vitamins because they were vitamin-deprived (that would have confounded the results).

Also, the results were obtained in the fixed-effect analysis, but not in the random-effect analysis. What does it mean? First of all, we need to understand what the difference between the two models is:

A fixed effects ANOVA refers to assumptions about the independent variable and the error distribution for the variable. An experimental design is the easiest example for illustrating the principal. Usually, the researcher is interested in only generalizing the results to experimental values used in the study. For instance, a drug study using 0 mg, 5 mg, or 10 mg of an experimental drug. This is when a fixed effects ANOVA would be appropriate. In this case, the extrapolation is to other studies or treatments that might use the same values of the drug (i.e., 0 mg, 5 mg, and 10 mg). However, if the researcher wants to make inferences beyond the particular values of the independent variable used in the study, a random effects model is used. A common example would be the use of public art works representing low, moderate, and high abstractness (e.g., statue of a war hero vs. a pivoting geometric design). The researcher would like to make inferences beyond the three pieces used, so the art pieces are conceptualized as pieces randomly drawn from a larger universe of possible pieces and the inferences are made to a larger universe of art work and range of abstractness values. Such a generalization is more of an inferential leap, and, consequently, the random effects model is less powerful.

It would be nice to see how, in this review, they actually analyzed the data, because I cannot really see that from the abstract. Did the studies they decided to look at use similar, if not the same, methods of administration of supplements? It does seem, from their summary, that only a certain range of values was considered.

Do the results mean that you should stop taking your vitamins otherwise you'll die? As the authors themselves say, these results grant the need for further investigation into harmful effects of certain supplements. This does not necessarily mean you will die because of vitamins - as correlation with higher mortality does not necessarily imply causation. But it does at least suggest that using vitamins is useless, unless you really need them - in which case, you are usually severely food-deprived.

Update: Holford Watch also weighs in, but focuses on some of the responses to the study. Skeptical responses...but not coming out of genuine skepticism. Check it out!

Citation

Bjelakovic, G., Nikolova, D., Gluud, L.L., Simonetti, R.G. (2008). Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.. Cochrane Database of Systematic Reviews, ?(2), ?-?.

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I kind of stumbled into this funny program this morning, while I was loitering around the net, and the first question I asked myself when I found this was: can we even believe it? So, of course, I run a test with myself first, and then I decided to run a couple of experiments, just to see what popped up. I would not really attach huge value to the "experiments", as I did not control for text length much, my sample population was minute - to use a euphemism - and I used Google Translate. But I think I did find something interesting nonetheless. Which is, the program and the algorithm have an inherent language bias. Or at least, seem to have.

More below the fold.

As the program works best with passages that are 500 words long or longer, I decided to first try out with one of my long posts about peer-reviewed research. And of course, the programs decided that I was, by a large advantage margin, writing like a male. So then I decided to try something else - just to see how sure the "program's judgement" was - and I picked something else, also talking about research, but not about a specific paper. Again, I have some serious balls according to the Genie. Here is a snapshot of the results.


The Genie is based on an algorithm which basically counts certain "gender-specific" words in a passage, calculates a score for each of them, and then gives you a cumulative score. I am using inverted comas because these are very basic words, but the authors behind the algorithm have noticed that one gender uses some of these significantly more often than the other gender does, and therefore this special word count could be used to estimate how "male" or "female" the writing is. Now, I want you to look at the numbers - the table right under the score - and notice which words are the most frequent in my article. Here is a list of those words that got a score equal to or higher than 100: "with", "not" - on the feminine side - "are", "as", "is", "the" - on the masculine side. The male score was 1182, and the female score 781, total word count 607. We are cutting it pretty close, but if you look at the table you will see how much more frequent the "male" words seem to be.

Which is all good. I would have to run the program with my writing, say, 100 times, controlling for length and maybe topic, to really get an idea of how consistent this is. I tried in total three times, with articles longer than 500 words, and the Genie showed no doubts whatsoever.

But one trend resulted to be clear. All the most frequent words in my articles - and I mean, in absolute terms - are articles, specifically "a" and "the". There also seem to be a lot of descriptive and/or passive sentences, which explain the "are" and "is". These are all very frequently used words in the language of the Country of Jokes. So I decided to be naughty, and run a tiny little experiment.

For my experiment, I picked a male writer and a female writer from the Country of Jokes. I also picked passages longer than 500 words, as advised by the Genie. Then, I run them through Google Translate. You'll think I am crazy, right? Because literal translation with Google Translate, we all know it, makes hardly any sense at all. But what it does, is that it keeps everything pretty much as it is - including the amount of articles and passive sentences. Of course, I do not use literal translation when I write in English, but I do retain certain tendencies from my mother tongue, tendencies I often have to work intently to overcome.

I run the male writer, after translating everything to English. And the Genie, of course, got it right. Now I want you to look at the screen shot.


Let's look at the most frequent words from both sides, above 100 points. On the feminine side, we have "if", "not", "and"; on the masculine side, we have "are", "who", "the" - and interestingly, "as" got 92. Not completely identical, I grant you, but the frequency of "are" and "the" was quite high.

I then switched to the female writer. Here is her screenshot. And, of course....she was male, according to the Genie.


Although the male score was almost certainly not significant, let's look again at the words with more than 100 points. On the feminine side, we find "with", "not", "and"; on the masculine side, "are", "who", "is", "the", "a". The "the" alone gathered 700 points.

Noticed anything by now? Writers from the Country of Jokes seem to use language in a very similar way regardless of gender...or, do they? The most important step in all this is the translation, or the transposition from one language to another. The results do not necessarily imply that there is no gender bias. They simply imply that writers from the Country of Jokes use a lot of articles and passive or descriptive sentences. Which is undoubtedly the case in real life.

This shows, even with all the limitations of this tiny experiment, that the Genie probably has an inherent language bias. Maybe a program one day will be really able to tell male from female from word counts; but it should be adjusted for the different languages, and even so...why would you leave it to a program to tell you something about your gender?

Humans, I swear, are the only things I will never understand.


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Do you remember the time when the discussion on whether it would be ethical to use cognitive enhancers not for medical reasons, but to improve one's mental function?

The buzz was so great that Nature set up a in-house survey, to be voluntarily completed over the Internet, to investigate what the general attitude (in the scientific crowd, that is) to cognitive enhancers is, how much they are used, for what reasons, and so on. The buzz was also big enough that an April Fool's joke centred on these enhancers, and started on a personal blog, ended up reaching up to the pages of Nature News - by the way, not surprising, seeing that some of the "co-conspirators" for the joke are on the Nature Network. The joke was so amazing that it even included a fake website to corroborate the bloggers' report.

Anyway, I am meandering! Let's go back to the results of the Nature cognitive enhancement survey. The survey data includes results collected from about 1400 people from more than 60 countries. The first obvious problem with the data is that it was collected voluntarily - which means, the data might be already skewed and unreliable from the start - but so is life when it comes to surveys. On the good side, 1400 is quite a sizable number. However, do not be fooled by the number of countries: the responses originated overwhelmingly from the United States, followed by Great Britain, Canada and Australia. The other countries were only represented by trace amounts, so to speak.

While one would have expected that the majority of respondents would be involved in science research, a good chunk of the respondent where not, or did not want to reveal their occupation. When asked about their field of work, 35.5% of respondents chose "other". The given options were biology, chemistry, physics, environmental science, engineering, media, education and medicine. For some reason, computer science and maths were completely absent. This question makes me wonder about what population the survey was scouting for - because the phrasing of the question does not allow one to measure, say, what proportion of respondents involved in grant-driven areas resorts to cognitive enhancement. We get a potpourri of responses, but we already cannot answer that simple question, which is really what spurred the initial debate to start with.

The age of the respondents seemed to be skewed towards younger ages, as 57.2% of participants in the survey were 25-35 years old. Again, there are two different ways one can interpret this: either younger people seem to be more receptive to this issue (cognitive enhancement), or it is simply that younger people are those who would feel more comfortable with filling in an online survey. In fact, only 2.2% of the respondents were 66 year old or older.

The large majority of participants (66.3%) reported that they have never used prescription drugs for cognitive enhancement purposes. Among those who do, Ritalin seems to be the drug of choice. While trying to achieve better focusing and concentration seem to be the main motives behind the drug use, users evenly split between those who take the drugs daily, weekly, monthly or even once a year.


This is bizarre. Focusing and achieving better concentration are two things that are almost indistinguishable from each other, and that is probably why the respondents are so evenly split between them - because they are probably considering them to be almost equivalent, and picking the answer almost at random. Now, assuming that that's the case, focusing/concentrating seems to be necessary at different frequencies for different people. And that's where a good wording to question 2(occupation) would have come really handy. Are people in research-driven occupations more likely to take drugs, and more often than other people? Is the different pressures linked to different occupations also reflected in difference in the use of cognitive enhancers?

The Nature article reviewing the results of the survey also reports that

perhaps surprisingly, a high four-fifths thought that healthy adults should be able to take the drugs if they want to. And 69% reported that they would risk mild side effects to take such drugs themselves.

I am not very surprised by the fact that people would risk mild side effects. That's what human beings do every time they open a bottle of beer, or drink coffee to keep themselves awake early in the morning. In my humble opinion, however, the fact that people would not see any problem in healthy adults exposing themselves to the risks of addiction that these drugs can cause...is really alarming. Especially when it comes from a highly-educated sample population (the readers of Nature).

The survey also asked questions about using drugs for cognitive enhancement in children:

When asked whether healthy children under the age of 16 should be restricted from taking these drugs, unsurprisingly, most respondents (86%) said that they should. But one-third of respondents said they would feel pressure to give cognition-enhancing drugs to their children if other children at school were taking them.

Again, the latter data is quite worrying. But this really is the fulcrum of the question: when other people around you, be it at work or school, are taking enhancement drugs that they do not need, but which give them some kind of an advantage (be it based on placebo or not), are you stupid if you refuse to take them - because you know have a higher risk of falling behind? Or are you wise - because you are not exposing yourself to the risk of physical or psychological addiction? That's what the dilemma is, and where the "pressure" is probably coming from.

This issue needs urgent ethical attention from legislators. And better surveys should be run to assess what proportion of researchers is already resorting, or thinking to resort, to potentially addictive medications to try and get an edge.

If our work is so stressing that we need cognitive enhancement, is it not time to start reconsidering our mentality (especially in research-driven academia) and focus on creating a healthier work environment for the body and the mind, just like every other decent company has been doing for years? Given the inherent stress of having to publish and get grants to maintain one's position, wouldn't a stronger emphasis on research workers' wellness be something we urgently need? I shall point my finger to universities that want research faculty to bring in money, but are unwilling to spill any of their own...but also, to the faculty members' themselves, and to the mentality that, if "shit comes down, tough luck, you're gonna have to deal with it somehow" and nobody is going to give a crap about your mental and physical health.

Update: other bloggers are weighing in on the results. Some are concerned, while others aren't. This section might expand with new links coming in the next few hours/days, so stay tuned.

P.S.: The latest meeting of the Skeptics' Circle has been hosted by Archeoporn. Flying piggies included.


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It's long but it's worth it, regardless of whether you completely agree with him or not. Especially as we know that it's a bit hard to always agree with Venter's points of view. But he hits the critical point of scientific literacy here, which is really the main idea behind the lecture. It is arguable whether or not all the solutions he proposes are really part of the problem rather than "part of the solution". But the need for scientific literacy, in a world facing problems of increasing complexity, is not.



If you cannot see the video in your feed, click here.

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I will be away from this blog for a couple of days, and re-appear for the Cancer Research Blog Carnival on April 4th. In the meantime, I will leave you with the chance to get some nice reading done...as well as some writing.

For the reading: the latest Scientiae carnival is up, and it will be followed pronto by Tangled Bank tomorrow. Encephalon is also up over at Of Two Minds, where we apparently realize that Paris (Hilton) has a brain.

For the writing: there is, of course, the upcoming Cancer Research Carnival (submit posts here), and the brand-new Molecular and Cell Biology Carnival (submit posts here), which will be also hosted here, but in two weeks' time.

Have a blast!


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This is the third and final post on the story of FAPP2. You might want to read part I and part II before diving into this one, unless you are already familiar with secretory transport and the various organelles involved in it.

In this post, I am going to go over a 2006 paper written by Kai Simons and some of his grad students, in collaboration with other researchers from the University of Coimbra (Portugal). In this paper, the authors finally link FAPP2 to membrane polarization and cilium formation in the apical membrane of MDCK cells.

In case you completely forgot how polarized epithelial cells - such as MDCK cells - look like, here is a pictorial reminder from the previous post...


These cells are ciliated - and their cilia help them sense the flow of fluid within the kidney. The cilia themselves, however, are immotile - which means they are not flagella. Here is a schematic explanation of how the cilium can sense flow. For more information on the primary cilium and its many functions in signalling, you can turn to the review this figure belongs to (simply follow the citation link at the end of the post, or click on the figure).


You can imagine that defects in cilia structure would impact the ability of these cells to sense flow, and that they would therefore lead to a serious impairment in kidney function. And this is where the study of FAPP2, that until now might have looked like it was of remote importance for biomedical applications, gives us an insight on the maintenance of a very important cellular organelle.

More on FAPP2 and cilium formation below the fold.

First of all, the authors investigated whether cilium structure was affected in FAPP2 knockdown cells. They used fluorescence microscopy to visualize the cilia (staining acetylated tubulin) and the cell nuclei (using DAPI staining). They looked at cells that were grown in a layer and in a cyst. These cells will normally form cyst-like structures in the kidneys, but growing them in layers can be useful to run experiments in the lab; however, one would always want to check that the results obtained by the two different methods are comparable and consistent with each other.


As you can see, the cells suffering a FAPP2 knockdown (B, E and white bars in graphs) suffer from decreased or abolished ciliogenesis. But it must be noted that these cells' cilia end up growing back to normal over time - which might be due to the fact that the knockdown is 'leaky', or that FAPP2 knockdown alone is not sufficient to stop ciliogenesis. As we already know from previous studies that the knockdown method still leaves about 10% FAPP2 protein expression as compared to untreated cells, probably that 10% was enough, over time, to promote ciliary growth.

These figures alone, however, are already able to show that FAPP2 is somehow involved in the maintenance of the primary cilium.

The authors then check whether the lipid composition of the apical and basolateral membranes of the MDCK cells has been affected by the knockdown. To do this, they use a technique known as Laurdan staining. Laurdan is a dye that intercalates between lipids, and membrane fluidity affects the emission spectrum of Laurdan. This shift can then be normalized and quantified, giving us a measure of whether the membrane in FAPP2-depleted cells is moving toward a more disordered (fluid) or more ordered (lipid rafts) state.

We have already seen in previous papers how FAPP2 was shown to have some involvement with lipid rafts, so this experiment is the next logical step. Through Laurdan staining (I am not going to show the figure here), Simons and colleagues discovered that the lipid composition, and the state of the two different membranes in MDCK cells is affected by the lack of FAPP2 protein. In fact, while the usually raft-rich apical membrane shifts toward a more disordered state, the basolateral membrane seems to be gaining lipid rafts.

From this, one can deduce that the actual chemical composition of the two membranes has been affected, and that FAPP2 might be affecting the targeting of different lipids to the different membranes: this would explain why its lack causes mistargeting of lipids, usually destined to the apical surface, to basolateral surfaces.

Finally, the authors look at the membrane structure at the base of the cilium, using both Laurdan staining and standard fluorescence microscopy, and show that, in wild-type MDCK cells, there is a domain of condensed lipids (rafts?) around the base of the cilium. What is notably lacking in this paper is the corresponding experiment with the knockdown cells - which makes me wonder whether they did try and saw no difference with the wild-type at all.


But in absence of such evidence...one can argue that FAPP2 depletion is affecting lipid targeting, and probably this also has an impact on the stat