Cada año, un comité de expertos debe acometer una ardua tarea: de entre todas las publicaciones de ICREA, debe escoger unas cuantas que destaquen del resto. Es todo un reto: a veces los debates se acaloran, y siempre son difíciles, pero acaba saliendo una lista con las mejors publicaciones del año. No se concede ningún premio, y el único reconocimiento adicional es el honor de ser resaltado en la web de ICREA. Cada publicación tiene algo especial, ya sea una solución especialmente elegante, un éxito espectacular en los medios de comunicación o la simple fascinación por una idea del todo nueva. Independientemente de la razón, se trata de los mejores de los mejores y, como tales, nos complace compartirlos aquí.


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  • Controlling brain states with a ray of light (2021)

    Gorostiza Langa, Pau (IBEC)
    Sánchez-Vives, María Victoria (FRCB-IDIBAPS)

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    Controlling brain states with a ray of light

    The brain presents different states depending on the communication between billions of neurons, and this network is the basis of all our perceptions, memories, and behaviours. It is often considered a “black box”, with difficult access for clinicians and researchers, as few tools are available to measure and manipulate brain neuronal networks with spatiotemporal accuracy. Now, a collaboration between the laboratories of Sanchez-Vives (IDIBAPS) and Gorostiza (IBEC) has allowed for the first time to control brain states using a molecule responsive to light, a method called photopharmacology. Results show that the compound PAI (for Phthalimide-Azobenzene-Iperoxo) developed at IBEC can specifically and locally activate muscarinic cholinergic receptors present in the cerebral cortex. They are a specific type of protein that binds acetylcholine, a neuromodulator involved in processes like learning, attention, and memory.

    Transitions between brain states, such as going from being asleep to awake, recovering from anaesthesia, or waking up from a coma, are based on the transmission of chemical and electrical signals between groups of neurons that are activated synchronously, as in waves. Their oscillatory activity is often described as "brain waves" and is an emerging property of the brain cortex. When applying PAI to the intact brain, white light allowed modulating the spontaneous emerging slow oscillations in neuronal circuits and reversibly manipulating the oscillatory frequency. Thus, this molecular tool enables inducing and investigating in a controlled and non-invasive way, the transitions of brain from sleep- to awake-like states using light.

    These results are a breakthrough for neuromodulation technologies to manipulate brain activity patterns, to understand their connections to cognition and behaviour, and could also lead to novel treatments for brain lesions and diseases. Since the method works in intact brain tissue and does not require genetic manipulation, these results open the door to non invasive spatiotemporal control of drug action in the human brain.


  • How do plants and animals use alternative splicing? (2021)

    Irimia, Manuel (CRG)

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    How do plants and animals use alternative splicing?

    Alternative splicing is a pre-translational process by which eukaryotic cells can generate multiple transcripts from a single gene, often in response to specific developmental and/or environmental cues. This can lead to the generation of either multiple protein isoforms, expanding proteome diversity, or of a subset of non-functional transcripts, effectively contributing to downregulate gene expression.

    Alternative splicing exists since the last common ancestor of eukaryotes and it is particularly prevalent in animals and plants, the two major multicellular domains of life. However, a major question remained: how do these two lineages make use of this mechanism? What differences and commonalities do they have?

    To answer this question, we profiled alternative splicing patterns across tissues and environmental conditions in the model plant Arabidopsis thaliana and compared them with those of animal models. We observed that Arabidopsis display high levels of alternative splicing, similar to those of fruit flies, which have complex organs and behaviors. Remarkably, however, we found that Arabidopsis often uses this mechanism to adapt its transcriptome in response to environmental stress, modulating gene expression levels, whereas animals employ it mainly to shape and sculpt their proteomes in a tissue-specific manner (Fig. 1). These divergent patterns are consistent with the different lifestyles of each lineage: whereas plants are sessile and need to respond to any unfavorable condition in situ, animals can run away from those conditions. In turn, animals need highly specialized tissues to accomplish and coordinate these responses, particularly muscle and nervous systems, which show the highest levels of tissue-specific splicing in animals.


  • Strengthening evidence for four-top-quark production at the LHC (2021)

    Juste, Aurelio (IFAE)

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    Strengthening evidence for four-top-quark production at the LHC

    One of the main goals of the ATLAS experiment at CERN’s Large Hadron Collider (LHC) is to challenge the predictions of the Standard Model (SM), our most successful theory of elementary particles. To this end, a promising direction is the study of the production of four top quarks at once, a very rare process that happens only once every 1012 proton-proton collisions. Once produced, each top quark decays into a W boson and a bottom quark, with the W boson decaying into a charged lepton (electron, muon, or tau) and a neutrino, or a quark-antiquark pair. This results in some of the most spectacular signatures ever produced at the LHC.

    In 2020, the ATLAS Collaboration reported strong evidence for this process [1]. To confirm it, ATLAS physicists performed a new study focused on events with one charged lepton or two leptons with opposite electric charge [2, 3]. Despite accounting for the lion’s share of four-top-quark events, these signatures are easily overshadowed by other, much more-common SM processes with similar decay products, requiring the use of sophisticated multivariate techniques to discriminate them. The measured four-top-quark rate is compatible with the previous result [1] and their combination is a factor of two larger than the SM prediction, although still consistent with it within 2.0 standard deviations (s.d.). The existence of the four-top-quark process is therefore favoured with an observed significance of 4.7 s.d. This provides stronger evidence for this process than expected (2.6 s.d.), and is just shy of the conventional requirement of 5 s.d. to claim an observation.

    Since 2015, researchers at IFAE, under A. Juste’s leadership, are playing a major role in the search for four-top-quark production in ATLAS. The team has not only contributed to the recent results [1-3], but is also leading dedicated searches for beyond-the-SM four-top-quark production via a new heavy Higgs boson, which could potentially explain the measured excess. Additional data from the next LHC run, to start in 2022, along with further analysis improvements, will hopefully allow drawing definite conclusions on whether the breakdown of the SM is finally in sight.

  • Life history evolution of insular dwarf elephants. (2021)

    Köhler, Meike (ICP)
    Moyà Solà, Salvador (ICP)

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    Life history evolution of insular dwarf elephants.

    Human activity is driving the ongoing 6th mass extinction of species in Earth’s history. Insular taxa are particularly vulnerable; though endemic species typically persisted for millions of years on their islands, they now disappear in only a few decades. Therefore, understanding how life history strategies evolve to keep species in the ecological game has become a major concern in ecology.

    Life history strategies evolve in response to ecological conditions; however, they also depend on the size of the animal: small animals live faster than large animals, mature earlier, and have a shorter lifespan, which is usually depicted as the “mouse-elephant curve”.

    Insular endemics undergo changes in body size, with taxa derived from small ancestors growing large and those derived from large ancestors evolving small (the “Island Rule), leading to giant mice and dwarf elephants. These size trends led to the widespread hypothesis that insular dwarfs live fast lives.

    Using bone, molar, and tusk histology of the smallest-ever elephant Palaeoloxodon falconeri from the Pleistocene of Sicily, we disprove this hypothesis. The spectacular size decrease in P. falconeri was instead associated with a shift towards the slow end of the slow-fast life history continuum: the dwarf insular elephant grew at a much slower rate than expected from body mass, extended the time to maturity (first reproduction), and increased the lifespan beyond that of its large continental cousins.

    We interpret this life history strategy as an adaptation to low resource levels (an ecological key-condition on islands). The slow growth, possible under absence of terrestrial predation (the other key condition on islands), allows increased investment in maintenance at the expense of early reproduction, thereby increasing the reproductive success of young mothers through improved calf survival.

    Associated with these advantages, however, is an extended generation time (the mean age of mothers at offspring birth). This implies that the time it takes for a "slow-living" species to recover from disturbance increases importantly, which explains the extreme vulnerability of island endemics.

  • Optical Schrodinger’s cat states in High Harmonic Generation (2021)

    Lewenstein, Maciej Andrzej (ICFO)

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    Optical Schrodinger’s cat states in High Harmonic Generation

    Over the past decades, astounding advances have been made in the laser technologies and the understanding of light-matter interactions. Thanks to this, scientists have been able to carry out complex experiments related, for example, to ultra-fast light-pulses in the visible and infrared range, and accomplish crucial milestones such as using a molecule’s own electrons to image its structure, to see how it rearranges and vibrates or breaks apart during a chemical reaction.

    The development of high-power lasers allowed scientists to study the physics of ultra-intense laser–matter interactions which almost always  treats ultra-strong ultra-short driving laser pulses only from a classical point of view. The famous theory coined as the “three-step model”, which had its 25th anniversary in 2019, dealt with the interaction of an electron with its parent nucleus  in a strong laser field, and elegantly described it according to classical and quantum processes. However, since the laser pulses are highly coherent and contain huge numbers of photons, this description so far has been incomplete, treating the atomic system in a quantum way but the EM field classically.

    So far, in the description of the most relevant processes of ultra-intense laser–matter physics, the quantum-fluctuation effects of the laser electric field, not even to mention the magnetic fields, were negligible. However, the quantum nature of the entire EM fields is always present in these processes, so a natural question arises: does this quantum nature exhibit itself?

    In the recent study published in Nature Physics, ICFO researchers, led by ICREA Prof. Maciej Lewenstein and Javier Rivera, with colleagues from Technion-China, Max Born Institute in Berlin, the experimental group of  Paraskevas Tzallas, from FORTH, have reported on the demonstration that intense laser–atom interactions may lead to the generation of highly non-classical states of light, the so called photonic Schrödinger cat states. This work opens the path toward fascinating applications in quantum information and quantum technologies.

  • Overweight-related fatty liver impacts immune response to therapies in liver cancer (2021)

    Llovet Bayer, Josep M (FRCB-IDIBAPS)

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    Overweight-related fatty liver impacts immune response to therapies in liver cancer

    Liver cancer is the fourth leading cause of cancer-related deaths and its incidence is on the rise, with one million new cases projected annually in 2025. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. For the treatment of patients with advanced HCC, sorafenib was approved in 2007, but recently immune checkpoint inhibitors (atezolizumab + bevacizumab), which promote the ability of the immune system to fight cancer, have become the standard systemic therapies.

    Our article published in Nature shows that checkpoint inhibitors are significantly less effective in patients with non-viral compared to viral-related HCC. We explored the most common non-viral etiology, non-alcoholic steatohepatitis (NASH), associated to overweight and diabetes. We identified a specific population of dysfunctional resident T cells (activated CD8+PD1+CxCR6 T cells) which drive NASH progression and are the primary mechanism of resistance to immunotherapies in murine models of NASH-HCC and in human NASH (Fig 1). In addition, through a meta-analysis of three randomized phase III clinical trials testing inhibitors immunotherapies in 1,600 patients with advanced HCC, we identified that these therapies are significantly more effective in viral-related HCC compared to non-viral etiologies.