Cannabis has a long history of use as medicine, with historical evidence dating back more than 4000 years. The potential therapeutic benefits of cannabinoid compounds are huge, but this substance can also have negative effects. A recent paper by Andrés Ozaita and colleagues at the Neurophar laboratory of Rafael Maldonado (CEXS-UPF) has given new insights into the molecular mechanisms that underlie cannabinoid-mediated effects.
Using mice as a model system, the authors had previously shown that blocking the mTOR pathway prevented the amnesic-like effects of THC (a synthetic form of cannabinoid). In the present study, published in the journal Neuropsychopharmacology, they have gone further, proving that the inhibition of the mTOR pathway by the rapamycin derivative temsirolimus, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC, but has no effect on THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception (lack of pain perception).
Therefore, treatment with temsirolimus could segregate the potentially beneficial effects of cannabinoid agonists, such as the decrease of pain and anxiety, from the negative effects, such as amnesia and an increase of anxiety. As the authors say, these results could help targeting the endocannabinoid system in order to prevent possible side effects.
Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the Pharmacological Effects of THC by mTOR Blockade. Neuropsychopharmacology. 2013 Jan 28;
Several studies have suggested that daily caffeine administration can protect against brain injury in some cases, for example in animal models of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, as well as in ischemic and traumatic brain injury, or allergic encephalitis. Olga Valverde’s group at the CEXS-UPF decided to check if it could also have a positive effect on MDMA-induced neuroinflammation.
The recreational drug MDMA, or ecstasy, induces astrocytic and microglial activation in mice striatum, which leads to inflammation and neurotoxicity. They injected caffeine (10, 20, or 30 mg/kg, i.p) for 21 consecutive days into mice, and then on day 22, mice pretreated with caffeine or saline (controls) received a neurotoxic regimen of MDMA (3 × 20 mg/kg, i.p., 2-h interval) or saline. Changes in body temperature were evaluated. Forty-eight hours after the last MDMA or saline injection, behavioral parameters such as locomotor activity, sensorimotor reflexes, and anxiety were investigated and microglia and astroglia activation to MDMA treatment was examined in the mouse striatum.
The results, published in the journal Psychopharmacology, show that consuming regularly low doses of caffeine (10 mg/kg) completely prevented MDMA-induced glial activation without inducing physiological or behavioral alterations in any of the assays performed. Therefore, caffeine can have anti-inflammatory effects on ecstasy-induced neuroinflammation in mice.
Ruiz-Medina J, Pinto-Xavier A, Rodríguez-Arias M, Miñarro J, Valverde O. Influence of chronic caffeine on MDMA-induced behavioral and neuroinflammatory response in mice. Psychopharmacology (Berl). 2012 Nov 29;
The “8th European Zebrafish Meeting“ will be held at the Palau de Congressos de Catalunya, 9-13 July 2013. Organisers include Berta Alsina, from the CEXS-UPF, as well as Angela Nieto (CSIC-Alicante), Paola Bovolenta (CSIC-Madrid), Jose Luis Gómez-Skarmeta (CSIC-Sevilla), Enrique Martin Blanco (CSIC,Barcelona) and Miguel Angel Pardo (Azti-Tecnalia, Derio).
The meeting is intended to serve as a platform of communication for researchers working in zebrafish, a community that has expanded exponentially over the last decade. The European biannual meeting.
Among many others, topics will cover new advances in life imaging, patterning, disease models, gene regulation and genomics, circuits and behaviour, drug screening and cancer.
Prof Sydney Brenner and Prof Denis Duboule, as keynote speakers working with other model organisms, will highlight their discoveries in C.elegans and mouse genetics.
For more information, please see http://www.zebrafish2013.org.
Remember to register early!
Deadline Abstract Submission: 24 March 2013
Deadline Early Registration: 30 May 2013
Stress causes a general down-regulation of gene expression in cells, together with the induction of a set of stress-responsive genes. How do cells know which specific genes to activate when they are silencing most of the others? The (yeast) answer is called Hog1, as shown in a recent paper published in Genome Biology by the Cell Signalling research group at the UPF.
The authors, led by Francesc Posas, used yeast as a model organism to study the response to osmostress, and they focused on Hog1, a stress-activated protein kinase which is related to p38. Using chromatin immunoprecipitation (ChIP) followed by sequencing (ChIP-Seq) they did genome-wide localization studies of RNA polymerase II (RNA Pol II) and Hog1. The results show that upon stress, RNA Pol II localization shifts toward stress-responsive genes relative to housekeeping genes, and that this relocalization required Hog1, which also localized to stress-responsive loci.
Posas and colleagues also looked at the re-organization of nucleosomes by micrococcal nuclease followed by sequencing (MNase-Seq). The analysis showed that, even though chromatin structure was not significantly altered at a genome-wide level in response to stress, there was pronounced chromatin remodeling at stress-responsive loci, which displayed Hog1 association.
The authors conclude that Hog1 serves to bypass the general down-regulation of gene expression that occurs in response to osmostress, and does so both by targeting RNA Pol II machinery and by inducing chromatin remodeling at stress-responsive loci.
Nadal-Ribelles M, Conde N, Flores O, Gonzalez-Vallinas J, Eyras E, Orozco M, de Nadal E, Posas F. Hog1 bypasses stress-mediated down-regulation of transcription by RNA polymerase II redistribution and chromatin remodeling. Genome Biol. 2012 Nov 18;13(11):R106
Complex genetic disorders often involve multiple proteins interacting with each other, and pinpointing which of them are actually important for the disease is still challenging. Many computational approaches exploiting interaction network topology have been successfully applied to prioritize which individual genes may be involved in diseases, based on their proximity to known disease genes in the network.
In a paper published in PLoS One, Baldo Oliva, head of the Structural bioinformatics group at the GRIB (UPF-IMIM) and Emre Guney, have presented GUILD (Genes Underlying Inheritance Linked Disorders), a new genome-wide network-based prioritization framework. GUILD includes four novel algorithms that use protein-protein interaction data to predict gene-phenotype associations at genome-wide scale, and the authors have proved that they are comparable, or outperform, several known state-of-the-art similar approaches.
As a proof of principle, the authors have used GUILD to investigate top-ranking genes in Alzheimer’s disease (AD), diabetes and AIDS using disease-gene associations from various sources.
GUILD is freely available for download at http://sbi.imim.es/GUILD.php
Guney E, Oliva B. Exploiting Protein-Protein Interaction Networks for Genome-Wide Disease-Gene Prioritization. PLoS One. 2012;7(9):e43557
An interview recently published in Ellipse, the monthly magazine of the PRBB.
Born in Argentina 59 years ago to a Galician father and a mother from Madrid, Fernando Giráldez grew up between Buenos Aires, Santander, Madrid and Valladolid, where he studied medicine. Ten years ago he joined the CEXS-UPF, where he became director from 2003 until 2006. His hobbies are cooking, history and marathon-running.
Did you always want to be a scientist?
I chose medicine because it straddles the sciences and humanities. In the seventies, research was still a dream, only done by a few professors in universities. One of them, Carlos Belmonte, from the University of Valladolid, got me hooked.
Was it hard to choose between the lab and the clinic?
During my military service I was in a neurosurgery unit and I practised clinical medicine. I admire doctors a lot, but I like basic research and the academic life more. Looking back, maybe I would have liked to do research that was closer to medicine.
What was your first research about?
I did my thesis on the electrophysiological properties of corneal pain receptors. At Cambridge, I continued to study cell membranes and I got even more into the tradition of biophysics.
From Cambridge you came back to Valladolid.
In 1983 I joined the world of development. Firstly, doing electrophysiology on the otic vesicle (the precursor of the ear). From there I moved into studying growth and cell proliferation and, later on, the molecular biology of development. Quite a change!
You saw the great transformation of biology…
In the nineties great changes in molecular biology reached vertebrate embryology: the capacity to see and manipulate genes. We changed from only being able to see things, to beginning to understand the mechanisms. It was really interesting to live through this not only technical but also intellectual transformation.
What has your greatest contribution to the field been?
We incorporated in vitro techniques and this led to the identification of growth factors essential for the development of hearing. After this, we contributed to the knowledge of the first stages of sensory cell and auditory neurone development.
As well as doing research, you also teach.
I love teaching. In the second year of my degree I started giving classes to other students and I haven’t stopped since. Explaining something that took me a lot of effort to understand and seeing that in a couple of days the students are able to talk about it confidently is very gratifying.
What does being located in the PRBB offer?
There is magnificent infrastructure here and lots of informal help between the scientists, exchanges of ideas and techniques. In a less tangible way, the PRBB collectively imposes high standards. The better the people around you are, the better you are yourself.
What do you need to do research?
A modicum of ability, a certain level of ambition and the will to excel, a good dose of work and perseverance. But you learn research by doing it and there’s nothing better than doing it alongside good people, who set the standard.
The Molecular physiology and channelopaties research group from the CEXS-UPF is formed by several PhD students, postdocs, a technician and a couple of principal researchers with teaching duties. Miguel Angel Valverde leads the group since 1999, when he came to Barcelona from King’s College in London.
The aim of the group is two-fold. On the one hand, they try to understand how the ionic channels are activated, how they sense the physical or chemical signals that tell them to open or close. The second goal is to understand what happens when these channels don’t work correctly.
Ca2+ and its role in disease
Different types of ion channels are present in all cells, but they all have a unique, essential function: to modify the electric potential of the cell with the ultimate goal of regulating the intracellular Ca2+ concentration. Indeed, Ca2+ is not only an ion itself, but also a signalling molecule involved in many processes, such as muscle contraction, neurotransmitter release, or even gene transcription. This is why, when its concentration is deregulated, problems as diverse, common and complex as cardiovascular, respiratory or neuronal pathologies can arise. And these are precisely the channelopaties that the group studies.
Hypertension is one of the most important predictors of cardiovascular diseases. And one of the causes of hypertension is the contraction of the arteries, which makes their diameter smaller. This contraction is started by the Ca2+ signalling in the vascular smooth muscle. Ca2+ concentrations are also crucial for the immune system response, which explains why the group is interested in asthma, an inflammatory pathology. Finally, migraine is caused by a hyper excitability of the brain cortex, which in its turn is caused by an increase in the activation of synaptic transmission. Again, we find the usual suspect, an increase in Ca2+ levels, at the beginning of the chain of events that lead to migraine.
A multidisciplinary approach
role of ion channels in these channelopaties is studied at the genetic, molecular, cellular and physiological level. The group collects population samples, either by themselves or in collaboration with clinical or epidemiological groups. They sequence some candidate genes to find any genetic variations (called polymorphisms) that may be linked to the pathology. Once there is a polymorphism that represents a clear risk or beneficial factor, the group studies why this change in the genome is associated with the disease. “We don’t just link a gene to a disease. Instead we want to understand the whole process: how this gene affects the protein structure, and how that change in structure affects the function of the channel and the Ca2+ concentration”, explains Valverde.
They introduce the genetic changes under study in cells in culture and they analyse how the Ca2+ concentration varies by fluorescent microscopy, or do electrophysiology studies to look at the electrical activity of a single channel.
Such a multidisciplinary work requires lots of collaborations, and the laboratory has found many of them within the PRBB. They have worked with researchers at the IMIM and with neurologists and pediatricians at the Hospital del Mar for the cardiovascular and asthma studies; with groups at the CRG and other colleagues at the UPF and the GRIB for some genetic, biochemical and computer modelling aspects of the studies. “We do truly translational research, and are compulsive collaborators”, concludes Valverde with a smile.
This article was published in the El·lipse publication of the PRBB.
An interview published in Ellipse, the monthly magazine of the PRBB.
Mar Albà is a biologist who has moved from the lab to the computer and the analysis of the genome. After five years in England, she joined the UPF with a Ramon y Cajal contract, and since 2005 she is an ICREA Research Professor. Currently she coordinates the group of Evolutionary Genomics at the GRIB (IMIM/UPF) and the subject ‘Principles of Genome Bioinformatics’ at the master of Bioinformatics at the UPF. Since several months she has added motherhood to those tasks.
What memories do you have from your PhD?
It was a good experience, but I did see that I was not made for the laboratory but for a more theoretical research.
How did you decide to do bioinformatics?
It was somewhat by chance. When I arrived at University College London in 1997, I didn’t know where to direct my career. I joined a Master’s degree in bioinformatics and molecular modelling, and it was decisive.
What fascinates you most about your research?
Trying to figure out how organisms evolve using the tracks present in the DNA sequence. Understanding how our genes have originated and how, during evolution, certain sequences happen to have an important role that natural selection is responsible for preserving. We do this indirectly by comparing the genomes of different species and trying to infer what may have happened on the way.
What have been the highlights of your career?
The studies I made in London in the late 90s about the evolution of repetitive sequences in the laboratory of John Hancock, the first one to use data from the complete genome of yeast. Also the research on the origin and evolution of genes that have recently appeared, which I have done in collaboration with José Castresana and Macarena Toll-Riera, indicating that these genes have an evolutionary plasticity that will be lost over time.
What are the differences in the way of doing research in London?
There weren’t big differences in the quality of research, but it was a more open, more American system, where the merits of the person are what counts, and not their origin or who they know. In fact, many group leaders were foreigners. This surprised me a lot because when I did my PhD in Barcelona, there weren’t even any foreign researchers. Things are changing now with centres like the PRBB, the CNIO or the Parc Cientific, which try to adopt a different philosophy in recruiting and which, being new, don’t suffer from certain inertia.
Is informatics a male area?
Yes, but so are other sciences. In fact, I think the working world is designed for people with few family responsibilities, which traditionally have been men. We must also take into account the instability of the research career and the continuity you need in a system where assessment is done through the production of publications and attendance at conferences. Difficult to assume if you have kids.
How can it change?
Perhaps when more women are in positions of decision, since they have a broader vision. And it’s not just a question of children, but also other aspects of a person’s life, such as caring for the elderly.
What advice would you give to junior researchers?
Do not be discouraged. At times when you doubt about your research, remember that it is a privilege to live off what you love.
What would you be if you were not a scientist?
I never thought I would do something else other than research. I never had a plan B.