Faculty of 1000

Post-publication peer review

Archive for March, 2010

We will rock you

Posted by rpg on 31 March, 2010

Three’s a crowd

Who would have thought that plants could teach us about deafness? Or single-celled yeast about blood vessel development? Orthologous genes in different species can have totally different effects, and a statistical data-mining technique has thrown up not a few surprising models for human disease. The paper is free at PNAS and reviewed at Faculty of 1000. You can read more at The Scientist and Nature.

In another bizarre turn of events, it turns out that dilute biochemistry is all it’s cracked up to be. People have, over the years, ragged on biochemistry for dealing with dilute proteins and ignoring the ‘crowding’ effects of the cytoplasm (despite biochemical predictions often being borne out by in vivo work, but anyway). An outstanding computational paper looks at models of crowding in the bacterial cytoplasm, successfully simulating the relative thermodynamic stabilities of individual proteins:

But the overall take-home message seems to be that the effect of crowding by steric exclusion is largely cancelled by hydrophobic interactions with the crowders. Protein biochemistry in dilute solution has gained new respect.

The full paper, Diffusion, Crowding & Protein Stability in a Dynamic Molecular Model of the Bacterial Cytoplasm, is available from PLoS Computational Biology.

Got rhythm?

Another strange one, lurking in PNAS (Social Sciences/Psychological and Cognitive Sciences), suggests that humans are born to rock and roll:

One of the most curious effects of music is that it compels us to move in synchrony with its beat. This behavior, also referred to as entrainment, includes spontaneous or deliberate finger and foot tapping, head nodding, and body swaying.

Children under the age of two (and pre-verbal) spontaneously to music, but not speech.As Katrin Schulze, down the road at UCL says,

This suggests a predisposition in humans towards engaging rhythmically to a musical beat.

Yeah.

And finally

It’s competition time!

Faculty of 1000 is approaching the publication of 90,000 evaluations. This morning we had 89210 on the two sites, Biology and Medicine. We’ll be running a little internal compo for the people in the office, but we’d like to throw this open to all our Twitter followers and readers too. Use the hashtag #F90K to tell us the day you think we’ll make the 90 thousand. For a tie-breaker, feel free to put in the time, too (best use UTC. And here’s a clue: our editors work London office hours). Visit http://f1000biology.com/ and http://f1000medicine.com/ to help you with your guesswork.

As usual, a bag of F1000 swag for the winner. Good luck!

Posted in Competition, Weekly roundup | 1 Comment »

Migraines, magnets and a vocabulary straight from science fiction

Posted by Callum Anderson on 30 March, 2010

Whenever Richard Lipton releases a new migraine study I always receive it with interest. Partly because his work is pretty cutting edge and and he leads an excellent team, but partly because migraine science can sometimes sound like an encounter of the third kind in a science fiction novel.

Migraines are typically defined as one sided, throbbing headaches, typically accompanied by other symptoms, ranging from a non-specific ‘aura’ to zigzagging or flashing lights, a specific smell, nausea or sensitivity to light or sound.

According to some research , migraines affect close to 12% of the world’s population.

Well, Professor Lipton and his team at Albert Einstein College of Medicine have certainly not let us science fiction fans down this time either, publishing a randomised, double-blind, parallel-group, sham-controlled trial in which a hand-held transcranial magnetic stimulation device is used to treat the migraine.

Image by Andy Field (Hubmedia) via Flickr

Image by Andy Field (Hubmedia) via Flickr

The interesting thing about this study is that it tests a “handheld device” capable of alleviating migraine aura. So in theory, the study could lead to development of a product that allows sufferers to treat themselves at home rather than rely on a clinician. This is especially useful for something like a migraine which tends todevelop and subside rapidly.

The study randomized participants by computer, handing approximately half (99) a sham stimulation and the others (102) were given the sTMS device.
Those who used the real device had less pain and recurring headaches and were less likely to need medication. Of 164 patients who treated at least one attack with the real or fake stimulation devices, 39 percent of those who used the real device reported no pain after two hours compared to 22 percent of those who used the fake device.

Here are the results

37 patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with sTMS (n=82) or sham stimulation (n=82; modified intention-to-treat analysis set). Pain-free response rates after 2 h were significantly higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95% CI 3-31%; p=0.0179). Sustained pain-free response rates significantly favoured sTMS at 24 h and 48 h post-treatment. Non-inferiority was shown for nausea, photophobia, and phonophobia. No device-related serious adverse events were recorded, and incidence and severity of adverse events were similar between sTMS and sham groups.

When (and even if) this treatment comes onto the market, it remains unclear, how much it will cost, and Neuralieve don’t have any pricing details on their website.

I am tentatively guessing that a technology in infancy like this won’t be particularly affordable for a good few years, but with more trials comes more corporate interest and it is important to consider that the potential market for something like this could be as high as the aforementioned 12% of population, which globally, represents a huge number.

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Cells and drugs and roll-on/roll-off

Posted by rpg on 24 March, 2010

Everybody loves a good structure. Here’s one of the prototype foamy virus (PFV) integrase in complex with DNA ends. The integrase is the complex that binds the termini of viral DNA and catalyses its insertion into the host genome. Nasty piece of work, and incidentally one that has ‘nasty biophysical properties‘—at least the one from HIV and related retroviruses. Fortunately for the future development of retroviral drugs, Stephen Hare from Imperial College and his colleagues managed to persuade the integrase from PFV to not only bind to DNA, but form a complex that was active in solution and amenable to crystallization. Fred Dyda of the NIH says

This outstanding achievement also speaks volumes about the value of high resolution experimental structures of assembled complexes, as it appears that previous models of intasomes based on fragmentary structural information and a lot of imagination have not been reliable.

C’est n’est pas un stem cell

Elsewhere this week, surprising news from the world of plant biology. A favourite tool of plant biologists is the callus, a mass of seemingly totipotent cells. Callus can be induced starting from virtually any differentiated plant tissue and is the basis for the remarkable ability of plants to regenerate the whole zucchini from just about any tissue, as any gardener is well aware when it comes to rooting out dandelions. The surprise is that the callus resembles the growing tip of roots, and is not the result of a simple reprogramming process to an undifferentiated state.

Vorsprung duck technik

In an amazing piece of German engineering scholarship, the itineraries of 16,363 cargo ships in 2007 were used to construct a network map. And if I could get access to the paper, I’d post a pretty picture here. Sorry. Anyway, the point is that this map could tell us lots about the movement of bioinvasive marine species, seeing as bulk dry carriers and oil tankers are the primary vectors for such beasties, as they hitch rides in the ballast. Jonathan Belmaker and Lewi Stone of Tel Aviv University add,

the network is almost scale-free since there are several large highly connected ports through which all smaller ports transact their trade. This property makes the ship network more prone to the spreading and persistence of bioinvasive organisms.

L’amour est comme un papillon

This is rather sweet, as well as pretty mind-blowing from an evolutionary point of view. A duplicated opsin—a visual pigment—in the Heliconius spp of butterfly evolved by positive selection, giving the insect the ability to discriminate between pigments. Wing pigments in the same butterfly underwent coincident evolution, which might help explain why the yellow wing pigments of Heliconius are so varied in the UV range, compared, with its less colourful relatives.

This is a beautiful example of how evolutionary and functional information together can provide strong evidence on the nature of an evolutionary adaptation.

And finally, a quick cytoskeleton fix. We’ve known for a while that short actin oligomers can anneal in vitro to form fibres. Turns out that this also happens in yeast cells at least; which means that if you sequester all the monomers, you can still build filaments close to the plasma membrane at endocytic sites. Could be important if you’re a budding yeast faced with a shed load of latrunculin A.

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Placebo experimentation and LUTS

Posted by Callum Anderson on 23 March, 2010

A couple of interesting evaluations have made their way past my desk this week, both from Faculty of 1000 Medicine. The first evaluation is of a very interesting paper, originally published in German, which reports results of a questionnaire. The title of the paper is Uncontrolled placebo experimentation in a university hospital, and the results certainly shocked me (I wonder if they would have the same effect on a practicing physician?)

So what percentage of practitioners do you think would admit to regularly treating with placebos in a ‘university hospital’?

The paper reported that 72% of participants admitted to regularly using placebos.

And this despite only 62% of the same group believing that placebos worked “often” (as opposed to 3% – “forever”; 35% – “Sometimes”.)

All those with medical knowledge are aware that placebos do work, and often work better than drugs with active compounds. This paper had me digging through a 2008 copy of the BMJ and the paper [subscription required] entitled What is the placebo worth? in which David Spiegel put forward the case that the most significant part of the placebo is the doctor-patient interaction.

He says

Perhaps the ratcheting down of the time that doctors spend with patients and our modern overemphasis on procedures is “penny wise and pound foolish.” Patients might respond better to real as well as placebo interventions if they were associated with a good doctor-patient relationship.

So perhaps placebo treatment has a place in medicine for some conditions. Spiegel specifically notes that a patient with a condition such as irritable bowel syndrome might be best treated by a doctor with an empathetic ear and time to listen to their story.

I think we still have a tremendous amount to learn about placebos, and studies such as the one conducted by Bernateck et al. imply that despite this obvious lack of understanding their use in clinical situations is relatively commonplace. With more research, and a better understanding of placebos, they could represent a very useful alternative treatment. Perhaps in a case where the clinician has reason to reduce the daily dose of certain pharmacological treatments for some reason or another; or simply in a case where psychophysiological treatment is a more sensible option.

However, a hospital setting is not the right place for experimentation, especially when the results of this survey suggest an assumption amongst medical practitioners that patients typically exaggerate symptoms.

Keeping on the same track – well sticking to medicine at least – another important paper, evaluated in Faculty of 1000 by Julian Wan, concerns an interesting and ubiquitous clinical situation: women presenting with lower urinary tract symptoms (LUTS). This randomized-controlled-trial seeks to establish if any improvements to current diagnostic procedures can be made.

A recent trend in general practice has been for patients to present to their doctor much earlier than has been typical previously. This makes it very difficult for the doctor to diagnose the condition without sending off for formal testing or culture, and as a result, antibiotics are typically prescribed by symptom alone.

This paper looked at  309 non-pregnant women aged 18-70 all presenting with LUTS (dysuria, nocturia, cloudy/foul smelling urine etc.) The women were randomized into five management approaches: empirical antibiotics, delayed empirical antibiotics, targeted antibiotics, dipstick result or midstream urine analysis. It certainly covers an appealing research topic, especially as LUTS represent a very common clinical situation.

As Faculty of 1000 member Julian Wan says

For many practitioners, it is common practice to simply prescribe by symptom without formal testing or culture. There is surprisingly little published about this very common approach, and no large scale randomized trial based on symptom relief and ‘delayed’ antibiotic prescribing.

In a nutshell, the conclusion is that there is no advantage from the perspective of alleviating symptoms in sending out routine midstream urine samples. The approach put forward is empirical delayed prescription to reduce antibiotic use, and targeting with a dipstick test rather than sending the samples off to a lab.

What I really like about this paper is that it makes surprising conclusions, but uses a significant evidence based study to make them. A study like this certainly makes me think that there is still plenty of research to be made into other common conditions. Medicine can sometimes be prone to treat according to status quo, and perhaps with more evidence based research, we could learn to treat more effectively?

Posted in f1000, Medicine | Tagged: , , , | 1 Comment »

Scifubar-the winner

Posted by rpg on 22 March, 2010

Ever blown up the lab with dry ice? Run protein into blotting buffer or DNA into TBE? Have no fear, just about every practicing scientist in the world has done something equally daft.

But for a mistake that possibly, just possibly, says more about the supervisor than the victim, here’s a tweet from Alejandro Montenegro:

Undergrad said he couldn’t “paint” the black lines on the autoclave tape as good as his supervisor (he even bought a black marker)

For making me guffaw on a Monday morning, and bringing back a slightly uncomfortable memory of being new in a lab and wondering just what the hell was going on, Alejandro wins #scifubar! (And if you don’t know it already, check out his blog, ‘Molbio Research Highlights‘.)

Alejandro, drop me a line with your address and I’ll make sure a coveted bag of F1000 swag very shortly wings its way to Chile.

Posted in Competition | 5 Comments »

Every picture tells a story

Posted by rpg on 19 March, 2010

Lord Lichfield

One of the great things about doing science, especially if you’re lucky enough to be a cell or structural biologist, is just how gosh-darned pretty it can be. Sometimes, crouched over a microscope or synchrotron hutch late at night (or very early in the morning, with the latter), the sheer prettiness of what I was doing was all that kept me going.

Mercedes BenzStructure of MFP2

The images above are but two of probably hundreds I’ve captured or rendered in my career. Whether they can be called ‘art’ is possibly a matter for the philosophers* but I like ’em. But there is definitely an overlap between science and (visual) art, where pure information becomes something more than that, where the representation acquires meaning or emotional impact of its own. You might know in your heart that this is the first time anyone has ever seen this protein’s structure, or that particular cellular effect, and you will get an emotional as well as intellectual kick out of it; but even someone with no scientific training can look at some of these images and be just as moved.

What we do as scientists has some mechanistic meaning, but it is also inherently pretty. And if you’re not convinced, you should take a look at Creaturecast.

CreatureCast – Footage From The Deep from Casey Dunn on Vimeo.

Creaturecast is produced by the Dunn Lab at Brown University, and showcases particularly interesting and/or beautiful scenes of zoology. It’s a site well worth looking around, especially on a damp Friday afternoon or for a morale boost on a Monday. It’s educational, too: did you know that Emperor Hirohito was a poet and a marine biologist too? Apparently he published (after the Second World War) he published 32 books of plates, that described 23 new species of ascidians, 7 new species of crabs, 8 new species of starfish and 6 new species of pycnogonids. He surveyed the biodiversity of Sagami Bay, and had a special interest in the tiny tentacled sea floor polyps called hydrozoans. He published under the name ‘Hirohito Emperor of Japan’.

And don’t think Creaturecast is simply observation, there’s also original art:

In a similar vein, the website from which I pulled the ‘Snake oil supplement‘ graphic last week has a Facebook group. As, in fact, does the Wellcome Trust, or at least their image collection. Very pretty, go and take a look.
Ingredients for a medical career

Ingredients for a medical career

We’ve been doing a bit of art ourselves. Here’s the Wordle of Callum’s blog post the other day (Callumwordle?):

Wordle: f1000 blog

No prizes for guessing what he was talking about.

Heath Robinson

In these times of budget cuts and recession and financial uncertainty, it helps if you can make the grant money go further. What better way, then, to build your own equipment? A Google software engineer by the name of Neil Fraser wanted to know if a Lava Lamp would work in a high-gravity environment such as Jupiter.

Would the wax still rise to the surface? Would the blobs be smaller and faster?

How to find out? With NASA cutting back on manned spaceflight, the answer wasn’t likely to be forthcoming any time soon, so Neil built a centrifuge to find out. From Meccano. A lava lamp at the end of one arm and a counterweight at the other. Genius.
Lava lamp centrifuge

In his own words, the device is genuinely terrifying: he ran the centrifuge from the (alleged) safety of the next door room. But the experiment worked:

Despite the technical hurdles, the centrifuge performed its job well … the lava lamp continues to operate well at three times the force of gravity. That’s slightly higher than Jupiter’s gravity (2.3 G) and it is equivalent to launching in the Space Shuttle.

Have a great weekend, and remember; be careful out there. You never know when you might come across a scientist building their own equipment, and taking photographs of it.

HeLa Cells from Jenny

Image credit: Jennifer Rohn, UCL

Read the rest of this entry »

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Last drinks

Posted by stevepog on 19 March, 2010

Richard has previously mentioned my imminent departure from f1000 and it’s come to the day where I pack up my desk, hand back the security pass and read my last free copy of The Scientist.

It’s been a great experience being involved in a forward-thinking project like f1000 and getting stuck into the social media side of PR (like it or loathe it, PR has a place amongst the Twitter, Youtube, Facebook generation)

But aside from meeting some brilliant people through Twitter (@scicheer, @tallscientist, @boraz, @sciencegoddess, @ritarubin to name a few), this humble blog is where most of the action has happened.

And so allow me to reflect back on some of the inspiring, thought-provoking or just plain amusing posts from my six months here.

Most recently, Callum’s post stirred up controversy on all sides with the Pubmed and PLoS discussion from a few days back, on a day where our usual daily hit count doubled due to the massive interest from the science community.

Richard’s weekly roundups have been getting a lot of interest as he, obviously, looks over the  week’s happening at f1000 and in the broader world of science.

His post on the Faraday Prize Lecture would have excited anyone with multiple passions into maths, music and science while the new competition on scientific mistakes, while not drawing the same enthusiastic responses as his #sci140 comp, has still been kicking along.

For my own part, the most enjoyable pieces I had the chance to write involved anything from the Great Garbage Patch to periodic table-chanting cheerleaders, how music can make us smarter and scientists with fantastic beards.

I’ll leave you with this shot of my Science Online companions and I at the Chapel Hill campus of the University of North Carolina, which we visited during the SciOnline 2010 conference in January.

There’s some historic significance to this well that we are still unsure of but apparently it’s the place where freshmen kiss each other for luck. We declined to participate in the ritual (owing to being neither freshmen nor single) and instead opted for this memento.

It’s one of the good memories I’ll take away from my time at f1000, along with the all-too-regular Friday afternoon cakes and of course the dedication and enthusiasm of work colleagues towards making f1000 a quality database for post-publication peer-reviewed biology and medicine research.

I’m off to travel Europe for five months and then head home to Australia. Thanks to everyone for the support, keep reading the blog and, in the words of my friend Darlene, GO SCIENCE!

**PS I’m on Twitter at @stevepog for anyone wanting to keep in touch and my sports-focused blog is http://stevepog.blogspot.com

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What’s your worst scientific mistake?

Posted by rpg on 18 March, 2010

Just a reminder that I’ve extended the deadline for our twitter #scifubar competition until Monday. Post your most embarrassing scientific error or egregious lab-based manipulation to Twitter with the #scifubar hashtag.

If you’re too shy to ‘fess up, pretend it was your labmate…

The winner gets a bag of F1000 swag, including the much-coveted laser-stylus-pen-torch thingy.

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Waltzing Mathilda

Posted by rpg on 17 March, 2010

You turn me right round

As an undergraduate, I remember being fascinated by the family of rotary motors that is the proton-translocating ATPase. This is the protein complex, resembling something from the imagination of E. E. ‘Doc’ Smith rather than anything merely biological, that either pumps protons from one side of a membrane to another, or uses a proton gradient to drive its rotation and make ATP. One of the less obvious difficulties with this amazing piece of machinery is that because the thing rotates, you need something to counteract the torque generated. So the ATPase has a additional stator component, the peripheral stalk, that links the nucleotide-binding domain to the membrane-embedded domain, which stops the entire thing waltzing away.

Interestingly, despite its essential role, the peripheral stalk is the least conserved element of the structure, varying in composition and number of subunits across the family. Daniela Stock’s lab at the Victor Chang in Sydney has recently published the structure of the peripheral stalk of the Thermus thermophilus H+-ATPase/synthase, in the process discovering a new protein structural motif—a right-handed hetereodimeric coiled-coil.

peripheral stalk

And that’s fascinating because the central stalk contains a left-handed coiled-coil, and it’s tempting to speculate that the opposite coiling of the two stalks is important, either in stabilizing the whirligig and/or for proton pumping. Read all about it (free link):

This paper reports, for the first time, a crystal structure of the bacterial A/V-ATP synthase peripheral stalk complex, which shows the N-terminal domains of the two peripheral-stalk-forming subunits E and G to be folded in a heterodimeric right-handed coiled coil, a protein fold not seen before.

Stephan Wilkens

Some shall pass

Peroxisomes can import fully-folded, native proteins across their lipid bilayer. How they achieve this wasn’t known—hypotheses included the transient formation of pores or a process similar to endocytosis (compare with the nucleus, for example, which transports macromolecules in and out via stable pores existing within the double membrane). It turns out that the membrane-associated receptor Pex5p, which recognizes the peroxisome signal motif Ser-Lys-Leu at the C-terminus of potential cargo, forms a highly dynamic, ion-conducting channel in conjunction with its docking partner Pex14p and cargo. These transient pores can be opened to a diameter of about 9 nm, allowing quite large protein complexes to pass. (Meinecke et al., Nat Cell Biol)

Who are you?

Whole genome sequencing is getting a fair bit of press recently. The ‘$1000 genome’ is still a way off; but a case can be made that even the current cost (~$50,000 and dropping) compares favourably with current diagnostic procedures for genetically heterogenous conditions. A paper in NEJM shows the feasibility of using whole genome sequencing to identify clinically relevant variants in the case of a rare, inherited disease, and provide diagnostic information to inform the care of patients:

the patient described is a compound heterozygote for two different missense mutations, which are easily missed in standard sequencing-based strategies for mutation identification.

(Free F1000 evaluation)

And finally, don’t forget to check out the Faculty Faves at The Scientist homepage. These are selected from the previous day’s most interesting papers at F1000, and available for free.

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Is it a cancer drug or not?

Posted by stevepog on 16 March, 2010

The media faces constant criticism from medical specialists and  advocacy groups whenever it trumpets the latest new wonder drug to cure any form of cancer.

Many spurious claims have over the years been splashed across the UK Daily Mail’s front page, prompting backlash from organisations such as the National Health Service, Cancer Research UK and even the appearance of a Facebook group with more than 40,000 members criticising the Mail’s cancer cure/cause agenda.

But the recent news that pharma giant Roche was revising its position on Avastin after the drug failed in a late-stage study, evaluating the blockbuster as a treatment for advanced stomach cancer, was an example of where the stock market, media expectations of a miracle cure and a pharma giant collided.

The Wall Street Journal said the announcement had the effect of:

‘undermining market expectations the drug could reach annual peak sales of more than eight billion Swiss francs ($7.48 billion)’

Roche’s PR team has had the very difficult job of trying to push the share price back up and regain investors confidence. One of their newest stabs at this crisis communications was a release today stating that

‘the eyesight of two patients with a rare condition was saved through the groundbreaking use of the drug Avastin’

At the time of writing, the news is only 20 minutes old so and there is little detail contained on how many people have been involved in trials by Southampton ophthalmologist Dr Andrew Lotery, only to state that his research on treating Sorsby’s Fundus Dystrophy (SFD) has been accepted by US journal Retinal Cases & Brief Reports. The release goes on:

He (Lotery) said it was the first time the drug had been used to treat the rare genetic condition(SFD) which caused the two patients, both in their 30s, to suffer blurred vision and a general deterioration of sight.
Avastin halts the growth of blood vessels and stems bleeding and is commonly injected with good results into the eyes of patients with “wet” age related macular degeneration (AMD) – the leading cause of blindness in the western world in people over 50

Avastin has already been trialled successfully in conjunction with chemotherapy in ovarian cancer sufferers so the prospect of another potential target would be welcomed by the shareholders but more importantly, by sufferers of the targeted conditions. But this is a situation where the media needs to tread carefully and wait for stronger research to appear before latching onto another cure-all drug.

New antibiotic treatments for gastric cancer

On another cancer story, Yoshio Yamaoka, an F1000 Medicine faculty Member from Japan, has looked recently at the use of various drugs to treat Helicobacter pylori infection, which often leads to gastroduodenal ulcers, gastric cancer and associated diseases.

While there are positive signs from a large multicenter trial in Japan of H. pylori antibiotics on patients with gastric cancer, Yamaoka warned that practitioners should exercise caution with regard to widespread antibiotic treatment saying,

‘if all infected persons are to be treated, we should consider the increase in frequency of antibiotic resistance and unexpected consequences such as esophageal adenocarcinoma, asthma, and autoimmune disease’

Posted in Communication, f1000, FMs, Medicine, Random, Science | Tagged: , , | Comments Off on Is it a cancer drug or not?