August 25, 2010

Since there are several traffic meters running here at DM on Scientopia, I was curious as to how the GoogleAnalytics, Sitemeter and WordPress in house statistics compare. Read the rest of this entry »

A fascinating vignette into the glorious future of online commenting on papers was passed along to me by a reader.

Laurén and colleagues published a paper in Nature in February 2009 describing a phenomenon related to understanding the process of Alzheimer’s disease and a possible role for prion. From the Abstract we can glean the essentials.

Here we identify the cellular prion protein (PrPC) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPC is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

This is grand stuff. Treatment for AD continues to be a holding/rearguard action to slow progression and maintain cognitive function as long as possible. Our treatments are not so great, even at that limited role. So any new therapeutic targets, particularly ones that interfere with the pathological processes (as opposed to treating the symptoms of such unrelenting processes), are a BigDeal (or BFD as the US Vice President would have it).

However, a “brief communication arising” which has just been published in Nature says “uh-uh, not so fast”. Kessel et al (2010) conclude the following from their results:

Laurén et al. suggested that binding between oligomeric amyloid-β … and the cellular prion protein (PrPC)8 is necessary for synaptic perturbations. Here we show that PrPC is not required for amyloid-β-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-β-mediated synaptic defects do not require PrPc.

Laurén et al provided a response, in Nature, to possibly explain the different outcomes.

Great, right? Big new idea/finding, some people jump on it and either confirm or question the results. These get published, and a dialog results. Happy, happy, amirite?

Well, somebody isn’t too thrilled and has offered a comment on the Kessels et al paper. A. Aguzzi congratulated the group on their study and then points out that they scooped him. Not by getting their first in offering a counterpoint to Laurén et al

on May 19th, 2009, I have reported my lab’s finding indicating that the Prnp genotype (Prnp+/+ vs +/-, /, and overexpressors) exerts no influence on LTP degradation in APPPS1 transgenic mice at the CDD conference in Rome.

but by being the first to be able to publish a counterpoint in Nature.

Marie-Therese Heemels, Nature editor, attended the talk and asked me (during the lunch break) to send her my findings to be considered for publication as ?brief matters arising? in Nature. (3) Following Dr. Heemels? request, we rapidly submitted our paper (Calella et al.). The paper was rejected on August 21, 2009 despite largely positive referees? comments (which I shall be happy to post separately if the blog editor allows for sufficient space). (4) because of the favorable, encouraging comments we opted to perform additional experimentation and to resubmit a further version of our paper, which was again rejected on May 5th, 2010 despite additional commendatory comments by the referees.

Our manuscript was then submitted to EMBO Molecular Medicine, where it received a rather enthusiastic reception and was finally published on July 21st, 2010

Yowsa! Now, I will admit right up front that I am unable to reasonably judge the quality of the papers of Kessels et al and of A. Aguzzi (Calella et al, 2010; EMBO Mol Med) so as to be able to determine why the one was worthy of Nature publication (as correspondence arising) and the other was not. Nor am I able to determine if one is a “better” criticism, counterpoint or elucidation of Laurén et al. But one thing does seem obvious to me. If the publication of Kessels et al in Nature was driven mostly by the mere fact it questioned or pared back the claims of Laurén et al then it would seem that Aguzzi’s work was similarly meritorious on this criterion.

I will be fascinated to see if Nature responds to this in any way, including deleting the comment. Clearly they are going to have to take the view that Aguzzi’s description of the reviews as largely positive and commendatory is a bit inaccurate. Right? Because beyond the scientific view of the reviewers, the only possible role for nonscientific professional editors is to judge hotness, relevance, impact and all that. And clearly since they published Kessels et al (which Nature received 22 Feb 2010 and accepted 01 Apr 2010), they think critique of Laurén et al is sufficient justification. If Aguzzi’s contention that Nature rejected his second submission 05 May 2010 is valid, obviously the journal had both of these criticisms of Laurén et al in hand at the same time and chose to publish one but not the other.

I’d be interested to hear their thinking on that one.

I have a trainee running a study in which she is examining the effects of methamphetamine on Bunny Hopping using the established open field to hedgerow assay. The primary dependent variable is escape latency from stimulus onset to crossing the plane of the hedge.

She is examining the effects of a locomotor stimulant dose of methamphetamine derived from her pilot dose-response study versus vehicle in groups of Bunnies which have been trained for six weeks in our BunnyConditioning Model and age matched sedentary Bunnies. (The conditioning training consists of various sprint, long run, horizonal hop and vertical leap modules.)

So we have four groups of Bunnies as follows:
1. Conditioned, Vehicle
2. Conditioned, Meth
3. Sedentary, Vehicle
4. Sedentry, Meth

The trainee is actually a collaborating trainee and so these data involve the analytic input of multiple PIs in addition to the trainee’s opinio. We are having a slight disagreement over the proper analysis technique so I thought I would turn to the brilliant DM readers.