Archive | October 2011

The Genographic Project confirms that humans emigrated from Africa through Arabia

Modern humans emigrated from Africa along a southerly route, via Arabia, rather than a northerly path through Egypt, as had been thought up to now. This is the main result of a study coordinated by David Comas, Francesc Calafell and Jaume Bertranpetit, from the Institute of Evolutionary 
Biology (UPF-CSIC) and published in the October online edition of Molecular Biology and Evolution. The paper, in which geneticists from the USA, the Netherlands, India, Russia and China participated, also reveals that our ancestors spread into Eurasia along a route located between Iran and India, and not through the Middle East as scholars had thought.

This study is part of the Genographic Project, funded by the National Geographic and IBM and the most extensive project to date to use genetic data from human populations. It utilised a new analytical method that infers the recombinations of the past from human DNA. The study confirmed that African populations are the most diverse on Earth and enabled calculation of the possible size of ancient human communities, which seem to have comprised a few thousand individuals each.

Reference work:

Marta Melé, Asif Javed, Marc Pybus, Pierre Zalloua, Marc Haber, David Comas, Mihai G. Netea, Oleg Balanovsky, Elena Balanovska, Li Jin, Yajun Yang, RM. Pitchappan, G. Arunkumar, Laxmi Parida, Francesc Calafell, Jaume Bertranpetit, and The Genogràfic Consortium (2011), ” Recombination gives a new insight in the effective population size and the history of the Old World human populations“, Mol Biol Evol (2011), doi:10.1093/molbev/msr213.

Postdoctoral Position in Signaling and Gene Expression in Immune Cells

The immunology group of the Department of Experimental and Health Sciences of the UPF seeks for a candidate to apply to the next Juan de la Cierva Programme call (Ministerio de Ciencia e Innovación). This competitive call of three-year contracts will open for applications around February 2012 and is expected to resolve around June 2012.

Details: Postdoctoral Position in  Immunology

Muscle or mosaic?

Muscle or mosaic?

This image by Francesc Sànchez Corredera, from Esther Barreiro’s lab on Molecular mechanisms of lung cancer predisposition (IMIM-Hospital del Mar), is a 3m thick sample of a Guinea pig diaphragm muscle, dyed with an Anti-Myosin Type II antibody and amplified 20 times. The protein myosin II is expressed in fast muscle fibres, but not in slow ones. This is why in this image we can see the fast muscle fibres in which myosin II is present dyed in brown, while the slow muscle fibres are negative (not dyed and therefore white).

This way, researchers can count the number of fibres of each type and establish a fibrilar percentage of each muscle.

Open Day 2011 at the PRBB

Video of the PRBB Open Day 2011 on October 1.  Around 4.000 visitors came to visit the building, do experiments, assist to a science show and listen to the explanations of 200 volunteers doing science at PRBB.

For more information please check here: http://openday.prbb.org/es/index

“Millions of our cells die through apoptosis every day” – Apoptotic signalling research group at the IMIM

Gabriel Gil has directed the Apoptotic Signalling research group of the IMIM since 2000. Apoptosis, or programmed cell death, is a physiological process with an essential role both during development and in the adult organism. “The epithelium of our body renews each day, in such a way that millions of cells die through apoptosis daily. Self-reactive lymphocytes, which recognise the body’s own antigens and which can attack it, are also eliminated by apoptosis”, explains the researcher. The absence of apoptosis, on the other hand, is a trait characteristic of the majority of tumours. “Apoptosis is, in fact, a safeguard mechanism existing in all cells and which ensures that if the DNA becomes damaged and impossible or very difficult to repair, the cell will die, meaning this genetic error will not be passed on. If this mechanism does not work, the errors are perpetuated, as happens in cancer.”

A new Cyclin

Soon after he set up his group, Gil identified a new protein, Cyclin O, which appears to be implicated in the detection of DNA lesions. They believe that it could be the link between the detection of these lesions and the initiation of the apoptotic mechanism. Since then, this protein has been the focus of their research and they have discovered that it is overexpressed in various cancers, especially of the colon and bladder. “We work with pathologists, oncologists, dermatologists, and urologists from the Hospital del Mar in order to study, in patient samples, why Cyclin O is not regulated in these cases and what advantages this offers the tumour”, says Gil.

To understand how Cyclin O works on a molecular level, the group uses different biochemical and molecular biology techniques. They also work with animal models and have generated the first mouse knockout (KO) for Cyclin O, i.e. a mouse which does not express this protein.

Cyclin O is expressed only when the cell becomes damaged. Over the past years the group has discovered some of the external stimuli which provoke apoptosis via Cyclin O, such as DNA damage or endoplasmic reticulum stress through the accumulation of badly folded proteins. In the case of lymphocytes, glucocorticoids also induce apoptosis, which makes them useful against inflammation, explains the head of the group.

Alongside the patients 

Recently the group has discovered that Cyclin O can regulate ATM, a protein essential for the detection of DNA damage. ATM mutations are the cause of ataxia telangiectasia, a very rare but very serious disease which causes immunodeficiency, neurological problems and a greater risk of developing tumours. Gil received a grant from the Marató de TV3 to study the role of Cyclin O in this disease. Recently, the Spanish association for families with ataxia telangiectasia (AEFAT) invited the scientist together with Oskar Fernández-Capetillo, a researcher from the CNIO and an expert in the field of ATM, to present their research to the families of those affected. The researchers were then asked to help in preparing a simple and standardised molecular diagnostic method for the disease.

“The problem is that there is no established molecular diagnostic procedure, and the complexity of the gene and the low frequency of the disease make it commercially unattractive to develop one. But being able to diagnose it within the first year of life may greatly improve the results of the palliative treatments which these children currently receive”, emphasises the head of the group. “In addition, it would be very useful to identify the carriers of the mutated gene, who, even though they do not suffer the disease, also have a higher probability of developing tumours”.

This article was published in the El·lipse publication of the PRBB

Divide and conquer

Divide and conquer

In this image by Cristina Morera from the CMRB, taken with a SP5 Leica confocal microscope, a mouse stem cell can be seen dividing. The DNA is highlighted in blue, the pluripotency marker Oct4 in red, and α-tubulin, one of the main components of cell cytoskeleton microtubules, in green. The α-tubulin enables the observation of the cell in metaphase, the stage of cell division where the pairs of chromosomes (blue) are aligned in the centre of the cell. Later, the chromosomes will be separated and divided between the two daughter cells by the mitotic spindle formed of microtubules (green).

“Habitual competitors are now working together to get better toxicity predictions”

Ferran Sanz (IMIM-UPF) tells us about the eTOX project in a recent interview published in El·lipse, the monthly PRBB publication.


The electronic toxicology project (eTOX) started in January 2010 as one of the projects funded in the first call of the IMI (Innovative Medicines Initiative), a unique public-private partnership between the European Community and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Ferran Sanz, director of the Research Programme on Biomedical Informatics (GRIB, IMIM-UPF) and academic coordinator of eTOX, evaluates the project’s achievements so far as very positive.

What exactly is eTOX about?
All IMI projects, including eTOX, bring together European pharmaceutical companies and academic groups to address scientific challenges that are a priority for the pharmaceutical industry. In the case of eTOX, the aim is to facilitate the early prediction of drug toxicity through computational models. It will last a total of five years.

How is that done?
The first step is an intensive data collection exercise in which structural and toxicological information on tested compounds is gathered from the archives of the participating pharmaceutical companies. This is the first time they have agreed to share such sensitive information, originating from animal experiments. On the basis of this shared information, computer models can be created to allow better in silico prediction of toxicology for newly designed drugs. The future perspective is to be able to develop new drugs more efficiently, with less toxicity and in a shorter time period. This procedure will not only reduce the costs of drug development, but also the amount of animal experimentation.

Who are the participating partners?
Out of the 25 partners from different European countries, 13 are pharmaceutical companies, five small and medium-sized enterprises, and seven academic institutions. Originally there were 11 pharmaceutical companies, but two more asked to collaborate and contribute after the project had started. The fact that the participation of the companies implies a substantial financial and manpower contribution from their part without receiving any public funding, indicates their interest in the topic.

What were the achievements in this first one and a half year of the project?
In the first year the highlight has been the positive attitudes of all of the partners, which result in the consolidation of a very productive teamwork. Even though some partners are usually competitors searching for new pharmacological targets and drugs, within the eTOX project they collaborate enthusiastically to achieve a common goal: to find a solution to avoid toxicity and develop safer new drugs.

We have already created the database for the shared information and procedures for semiautomatic data extraction from the toxicology reports. We have also defined the computational architecture of the predictive system and we have already developed the first modules of such system.

What steps will be taken in the future?
Once the database infrastructure has been set up, it is being fed with the information extracted by the archives of the pharmaceutical companies. On the basis of the data accumulated in the database in each moment, the predictive system is being progressively trained. Then, it will be tested within each company with internal data not included in the eTOX database. According to the incremental experience and emerging problems, the system will be improved and further developed.

3D embryos

3D embryo

The image, by Laura Quintana (CRG) shows a mouse embryo with double antibody staining for Neurofilament (blue) and E-cadherin (green) proteins, labelling the nervous system and the internal organs respectively. It was captured using OPT (Optical Projection Tomography), a microscopy technique for 3D imaging of specimens of between 1mm-1cm.
The OPT scanner projects light through the cleared specimen (a specimen made transparent using a clearing solution), taking 400 images as it rotates 360º. Those images are reconstructed using computer software to create a 3D image of the whole specimen. Since it uses diverse UV-filters and white light, multiple labelling can be simultaneously captured, as it shows in the image.

“Alzheimer’s is the price we pay for a life of thinking” – Ageing brain research group of the CEXS-UPF

All four of the PhD students in the ageing brain research group of the CEXS-UPF studied biology at the UPF. “It is our direct source of students!”, says Paco Muñoz López, head of the group and professor at that university. A postdoctoral researcher completes the group, which focuses on nitro-oxidative stress and its link to Alzheimer’s disease.

“The most important risk factor in Alzheimer’s disease is age –says Muñoz–. About 10% of the population over 65 suffer Alzheimer’s, but the percentage goes up to 50% in over 80 year-olds. I think it’s just the price to pay for a life of thinking, a consequence of the overuse of our neurones”. There are also genetic factors, but less than 3% of the cases are familial, mostly due to mutations in APP (amyloid precursor protein) and presenilins.

An aggregation problem

At a molecular level, Alzheimer’s is triggered by the accumulation of amyloid ß-peptide (Aß) aggregates in the brain, in particular in the hippocampus and the cortex. The Aß is a subproduct of the processing of APP, a ubiquitous protein of unknown function. Muñoz’s group suggests that it is a key protein in memory and learning processes.

In other parts of the body, the soluble Aß is eliminated through the liver, but in the case of the brain it cannot pass the bloodbrain barrier and therefore it accumulates. “Once it aggregates the problem starts”, says Muñoz. The group tries to understand how and when APP is processed by BACE1, the enzyme that generates Aß from APP, as well as the role of nitroxidative stress in BACE1 activation and Aß neurotoxicity. When the Aß aggregates it produces free radicals which react with the neuronal nitric oxide, generating peroxynitrite, a very reactive anion that harms proteins.

On the other hand, Aß oligomers bind different membrane proteins, in particular NMDA, a huge receptor for glutamate that, when opened, lets Ca2+ into the cell. When Aß amyloid binds NMDA, it forces the receptor to be half open all the time. This allows a constant flux of Ca2+ into the neurone which, slowly, kills it. The inhibition of the NMDA receptor has been proposed as a specific treatment to slow down Alzheimer’s. But there are other proteins that could pave the way to new therapeutic targets.

One of these was pinpointed by Muñoz’s group in a study that took them four years. “We added Aß to cell cultures and then did some proteomic analyses to determine which proteins had been nitrated. One of them was TPI, a key glycolytic enzyme. Interestingly, glucose consumption in the neurones of people with Alzheimer’s is lower than normal, and it wasn’t known why”, explains the biologist. They looked in APP and presenilin transgenic mice and in brains of Alzheimer’s patients. In both cases they saw that TPI was nitrated. The biochemical studies that followed and some computational studies done by colleagues at the GRIB (UPF-IMIM) confirmed that, when nitrated, TPI was less active. A three-month stay in Japan followed, where Muñoz cloned the TPI enzyme. Finally, they were able to show by electron microscopy that the nitrated TPI aggregated within the cell.

“So far we have focused on the pathological role of APP. But in the near future I want to understand the physiological role of APP in memory, something that remains a mystery”, concludes Muñoz.

This article was published in the El·lipse publication

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