A lot has been said about the link between calorie restriction and aging -- eat less, live longer. But if that wasn't enough, there seems to be a new reason to do away with snacking: calorie restriction has an anti-depressant effect in mice, which depends on orexin-mediated signaling.

Michael Lutter and his colleagues tested mice in two animal models of depression -- forced swim (a "depressed" animal will stop trying to escape from the water and will therefore cease to swim) and social defeat (a mouse that has been bullied will express its "depression" by reduced social interactions with other mice). The authors found that, if the mice were on calorie restriction, both their latency to stop swimming and their likelihood to engage in social interactions increased. In other words, the restricted mice did not show signs of depression.

But if the mice lacked orexin, calorie restriction had no effect. Orexin's claim to fame is its relationship to narcolepsy -- people (and some dog breeds) without orexin fall asleep without warning. But orexin has also been linked to the regulation of food and drug reward, pointing to a role for orexin in emotional processes. Lutter et al. further strengthen the link of orexin with depression by showing that mice in the social-defeat model have epigenetic modifications in the orexin promoter, which lead to decreased expression of the orexin gene in the "depressed" mice.

Clearly, the mechanistic link between depression, orexin and calorie restriction could do with some additional tightening. Similarly, the existing animal models of depression and their relevance to human depression are consistently criticized by the community. One also wonders about the behavioral (or "psychological", if you will) effects of calorie restriction per se on an animal that is undergoing a stressful situation like the one the mice experience in the forced-swim and social-defeat tests. In other words, is the increased latency to show depression a true anti-depressant effect, or is it that the mouse's hunger causes it to be more anxious in the context of the behavioural testing it is exposed to?

All of that said, other effects of calorie restriction that were originally met with scepticism now enjoy widespread acceptance. Maybe the same will turn out to occur in this fascinating case.

Posted by Juan Carlos Lopez at 04:36 PM | Permalink | Comments (1)

There's a remarkable number of drugs that people use for which the mechanism of action is unknown, and two papers in the Journal of Neuroscience illustrate this point from two different perspectives.

Methylprednisolone is an anti-inflammatory drug that is often used -- with modest success -- in multiple sclerosis and (off label) after spinal cord injury. People think that its effect depends on its ability to dampen inflammation but, as Jin-Moo Lee and colleagues show, the drug seems to act in vitro and in vivo (at least in rats) by preventing oligodendrocyte apoptosis through the indirect activation of glucocorticoid receptors. By contrast, the drug has no such protective effect on neurons, which may start to account for its limited therapeutic effect.

The second paper has to do with a drug that people use with recreational, as opposed to therapeutic, purposes -- ecstasy. Carla Busceti and her colleagues report that giving ecstasy to mice results in a transient increase in the phosphorylation of tau -- the same molecule that is phosphorylated in Alzheimer disease and in a series of conditions known as tauopathies. They further show that the increased phosphorylation, which is primarily seen in the hippocampus, depends on both GSK3β and cdk5, a pair of kinases known to phosphorylate tau. So, ecstasy induces the expression of Dickkopf-1, which inhibits Wnt signalling, thereby increasing GSK3β activity, and it also induces the expression of p25, a known activator of cdk5. It's very hard to know if there is any relationship between these biochemical changes and neurological diseases, but it would be very interesting to see if there is an increased incidence of any tauopathy in frequent users of ecstasy. I guess we'll have to wait for epidemiological studies to know the answer.

Posted by Juan Carlos Lopez at 04:00 PM | Permalink | Comments (0)

Sighs of relief from the whole editorial community were heard this weekend, following a ruling denying Pfizer accces to confidential peer-review documents from the NEJM.

Pfizer is facing a lawsuit over injuries believed to have come from use of their drug Celebrex. So, this January the drug company filed a motion asking for peer-review documents -- including reviewers' names and confidential comments -- that might be relevant to the lawsuit and useful for its defense. (If you want to read all the details about the legal showdown between Pfizer and the NEJM, I would recommend that you read this excellent blog entry in "In the Pipeline".)

This past Friday, the U.S. District Court for the Northern District of Illinois ruled that "it is not unreasonable to believe that compelling production of peer review documents would compromise the process". And as Pfizer didn't explained in sufficient detail what they expected to find in the confidential documents, the court decided that "whatever probative value the subpoenaed documents and information may have is outweighed by the burden and harm that would result" to the journals.

I was also delighted by the news, but I'm somewhat uncomfortable by the fact that the decision in favor the journals was shaped in no small measure by Pfizer's inability to produce convincing-enough arguments. I wonder what would happen if a future motion makes a good case for what a company or any other party expects to find in our confidential information. Would the court then rule in favor of the company, setting a devastating precedent?

I must admit that my understanding of all the legal aspects that surround matters of this sort is very limited. But if journalists are protected from identifying their sources in court (what is often referred to as "privilege"), is that the same kind of protection that our "sources" -- our referees -- get when they share confidential information with us and when we promise to protect their anonymity? If this is not the case, why not? And is there something that we, the editors of scientific journals, could do to make sure that we have "privilege"?

The ruling favored us this time, setting some sort of precedent for the protection of confidential information at scientific journals, but the matter is far from closed, and heaven knows what will happen next time.

Posted by Juan Carlos Lopez at 05:44 PM | Permalink | Comments (4)

This week's issue of JAMA struck me as pretty interesting. They normally publish stuff that's too clinical or epidemiological for my taste and in comparison to what we publish, but this time they had a themed issue on genomics with four articles reporting associations between gene variants and diseases of different systems.

Two of the articles are relevant to the cardiovascular system. First, Tamali Bhattacharyya and colleagues established a link between polymorphisms that affect the function of paraoxonase 1 (an HDL-bound enzyme with cardioprotective properties), oxidative stress and cardiovascular disease. As might be expected, forms of the enzyme with higher activity were associated with less oxidative stress and a reduced risk of cardiac events.

The second paper, by Irene Bezemer and her colleagues, disclosed gene polymorphisms linked to deep vein thrombosis. These variants affected several genes (CYP4V2, SERPINC1, GP6, KLKB1 and F11), and some of these were also linked to higher levels of coagulation factor XI, hinting at a possible molecular mechanism.

Next, a study by Joyce van Meurs and colleagues reports polymorphisms in the low-density lipoprotein receptor-related protein LRP5 that are associated with osteoporosis. As mutations in LRP5 had already been linked to bone disorders, it is not entirely surprising that variants of this gene would lead to reduced bone density and increased fracture risk.

Last, but not least, there's a very intriguing contribution by Elisabeth Binder and her colleagues, who found that variants in the FKBP5 gene (which encodes a protein that interacts with the glucocorticoid receptor to modulate its cortisol-binding affinity and has therefore been linked to physiological responses to stress) interact with the occurrence of abuse during childhood, predicting the severity of posttraumatic stress disorder (PTSD) in adulthood. The gene variants themselves were not good predictors of PTSD. So, this is a fine example of gene-environment interactions in the context of mental disease.

Very interesting associations indeed. Hopefully they'll lead to some hardcore molecular work that results in some mechanistic insight into the biological meaning of this gene polymorphisms that goes above and beyond the correlations found in these studies.

Posted by Juan Carlos Lopez at 05:00 PM | Permalink | Comments (0)

Two papers in Nature these past few days reported on some very intriguing biology of cancer cells.

Some tumor cells have the peculiar property of acting like anaerobic cells, producing lactate even in the presence of oxygen -- a property known as aerobic glycolysis or the Warburg phenomenon. The molecular mechanisms behind this phenotype are not clear, but the first of these two papers provides a very solid clue to account for it. Heather Christofk and her colleagues show that a switch between isoforms of the glycolytic enzyme pyruvate kinase is crucial for aerobic glycolysis and tumorigenesis. Tumor cells express the embryonic M2 isoform of pyruvate kinase, but by knocking it down and replacing it with the M1 (adult) isoform, the authors reversed aerobic glycolysis and reduced tumor growth in mice.

The second paper takes a look at the hardcore signaling that takes place inside tumor cells. We know very well that the Ras-PI3K-AKT pathway is crucial for tumor maintenance. The new study, by Kian-Huat Lim and colleagues, shows that blocking the AKT-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) also inhibits tumor maintenance. As eNOS enhances the nitrosylation and activity of Ras proteins, which are required for tumorigenesis, the authors come full circle by proposing a (mutated) Ras-PI3K-AKT-eNOS-(wild-type) Ras pathway for tumor growth.

Posted by Juan Carlos Lopez at 02:04 PM | Permalink | Comments (1)

Ahead of a meeting with a representative from the recently-formed UK Research Integrity Office, I sorted through my file of papers on research misconduct. Amongst them I found a ‘News in Brief’ page from Nature Medicine, 2005 . On it, I found the headline that had caused me to photocopy the page – “Many scientists admit to misconduct”, drawing attention to a paper in its sister publication Nature published a month earlier. The paper described a survey in which it was revealed that one in three scientists has committed some type of scientific misconduct.

The irony was that at the bottom of the same page was a short piece (from the same correspondent, Emily Singer) announcing “South Korean chalks up another stem cell victory”. The article highlighted the work of Woo-Suk Hwang in which he claimed to have cloned human embryonic stem cells in a paper published two months earlier in Science. The disgraced Professor, formerly of Seoul National University, is now used as a case-study for fraud in research (for example, Fraud Advisory Panel Occasional paper 01/07 Fraud in Research: Is it new or just not true?).

Was this incredible prescience on the part of the author, or just a strange coincidence of publishing?

Posted on behalf of Dr. Dave Wilson, Cardiff School of Biosciences, Cardiff University, Wales, UK

Posted by Juan Carlos Lopez at 10:06 AM | Permalink | Comments (1)