Highlights

Every year, a committee of experts sits down with a tough job to do: from among all ICREA publications, they must find a handful that stand out from all the others. This is indeed a challenge. The debates are sometimes heated and always difficult but, in the end, a shortlist of  the most outstanding publications of the year is produced. No prize is awarded, and the only additional acknowledge is the honour of being chosen and highlighted by ICREA. Each piece has something unique about it, whether it be a particularly elegant solution, the huge impact it has in the media or the sheer fascination it generates as a truly new idea. For whatever the reason, these are the best of the best and, as such, we are proud to share them here.

LIST OF SCIENTIFIC HIGHLIGHTS

Format: yyyy

  • How does the cell open and close electron taps? (2022)

    Gorostiza Langa, Pau (IBEC)
    Rovira Virgili, Carme (UB)

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    How does the cell open and close electron taps?

    Researchers at the Institute for Bioengineering of Catalonia (IBEC) have achieved a nanoscale view of the electron transport between redox partner proteins of the respiratory chain, allowing for a better understanding of their regulation by phosphorylation.

    Mitochondria play a key role in cellular energy production. They are membrane-bound cell organelles found in almost all eukaryotic cells (animals, plants, and fungi). Their main function in animal cells is to convert nutrients into chemical energy, stored in the form of adenosine triphosphate molecules, through a process called cellular respiration, which includes a tightly regulated electron transport chain. In addition to this function, mitochondria are also responsible for other functions, such as inducing cell death in response to stress events. How does the cell open and close the "taps" that control electron transport through these processes?

    A previous study by IBEC demonstrated that the transfer of electrons between mitochondrial proteins cytochrome c and cytochrome bc1takes place at a distance through the aqueous solution, via a charge conduit established between them. This new study reveals how this process is regulated by phosphorylation (addition of a phosphate group near the redox active site of cytochrome c).

    The researchers combined the analysis of electron transport at the molecular level with the measurement of protein-protein interaction forces, leading to a better understanding of the effects of cytochrome c phosphorylation on the molecular regulation of the mitochondrial respiratory chain. They discovered that phosphorylation impairs electron transport by disrupting the charge conduit and increasing the affinity between cytochrome c and cytochrome bc1, thus leading to the formation of bottlenecks in the process, and slowing the flow of electrons in the chain.

    These results also highlight the biological relevance of long-distance charge transport between redox proteins through the aqueous solution and contribute to the understanding of interprotein electron transfer.

  • Stick around and pass the electron! (2022)

    Gorostiza Langa, Pau (IBEC)
    Pruneri, Valerio (ICFO)

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    Stick around and pass the electron!

    Photosynthesis is a fundamental process that uses light to synthesize molecular fuel, driven by large protein complexes at internal membranes of vegetal cells. The protein plastocyanin (Pc) is responsible for shuttling electrons between two of these protein complexes in the photosynthetic electron transport chain. For an efficient electron flow, Pc must transiently bind its partner complex (Photosystem I) keeping a balance between specificity and binding strength (too weak will bind slowly and too strong will get stuck upon binding). Researchers at the Institute for Bioengineering of Catalonia (IBEC) studied the binding frequency and the unbinding force between suitably oriented plant PSI and Pc under electrochemical control using single molecule force spectroscopy. The observation of individual binding-unbinding events between PSI and Pc depends on their electrochemical states (that is, whether they carry an electron or are ready to receive one). The frequency of PSI-Pc interaction is higher when at least one of the partners is in a state ready for electron transfer, and it is lower once the electron is transferred. This appears to facilitate Pc unbinding and leave PSI ready to bind the next electron-carrying Pc.

  • Does more information lead to better predictions in network inference? (2022)

    Guimerà Manrique, Roger (URV)

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    Does more information lead to better predictions in network inference?

    Predicting whether two drugs have a harmful interaction or whether someone is going to like a certain movie are examples of network inference problems. In these problems, the goal is to predict new interactions (between drugs or between people and movies) based on some previously observed interactions. Having additional information about the network nodes or their metadata (for example, the mechanism of action of the drugs or the age of the individuals) helps to make better predictions, though it is not clear why or how. We explored how that improvement happens.

    We studied a very general network inference problem and showed that node metadata do not affect the inference problem gradually. Rather, even when the importance assigned to the metadata increases smoothly, the inference process crosses over from a data-dominated regime to a metadata-dominated regime. These crossovers show some similarities to transitions driven by temperature, where one finds energy- and entropy-dominated regimes. Importantly, optimal inference is often encountered exactly at this crossover.

    This study opens the door to better understanding the role of metadata in network inference problems and, more broadly, establishes further connections between general inference problems and physical concepts such as phase transitions.

  • An act of self-sabotage modulates DNA damage response in early mammalian development (2022)

    Irimia, Manuel (CRG)

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    An act of self-sabotage modulates DNA damage response in early mammalian development

    Alternative splicing expands transcriptome diversity in eukaryotes. Impacting most human genes, alternative splicing can famously generate multiple protein isoforms from the same gene. However, it can also be used to control the final amounts of functional proteins, by generating non-productive transcripts that effectively downregulate gene expression.

    Here, we investigated how alternative splicing was regulated during the first stages of embryonic development in mammals, when a major molecular event occurs: the awakening of the zygotic genome. Whereas the first steps are fully driven by the mRNAs and proteins deposited by the mother, the zygotic genome starts to be transcribed soon and takes full control of embryogenesis.

    We found that the cells in the embryo undergoing zygotic genome activation (ZGA) exhibit the highest levels of exon skipping of all cell and tissue types (including the brain). However, this striking transcriptomic diversity is temporary, lasting only 1-2 cell cycles (Fig. 1a). Moreover, it mainly leads to the production of unproductive transcripts (Fig. 1b), effectively killing genes enriched for DNA damage responses (DDR) at ZGA, in line with the low reparative response of early embryos.

    Remarkably, this is due to a developmentally programmed splicing failure (Fig. 1d): during oogenesis some core spliceosomal components (Snrpb/d2) are not deposited at sufficient levels and splicing for some genes fails when zygotic transcription starts. However, these core components are themselves strongly transcribed at ZGA, and thus their levels recover after 1-2 stages, giving rise to the peak-like splicing patterns.

    This model makes a simple prediction: if we express Snrpb/d2 earlier, we should be able to "rescue" the failed splicing patterns (Fig. 1d). This is what we saw. Moreover, this also increased DDR in those "rescued" embryos.

    In summary, we uncovered an evolutionarily conserved, developmentally programmed splicing failure during ZGA, which modules DDR. What we have not yet answered is: why would the embryo boycott itself at ZGA? Future research will tell...

  • A novel function of Capicua family proteins (2022)

    Jiménez Cañero, Gerardo (CSIC - IBMB)

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    A novel function of Capicua family proteins

    The Capicua (Cic) protein is an evolutionarily conserved nuclear factor with important roles in human biology. It acts, for example, by restricting the activity of genes involved in cell proliferation and, consequently, the loss of Cic function by mutation can lead to uncontrolled cell division and cancer. Moreover, one key feature of Cic is that it is sensitive and can be turned off by a major cell-to-cell communication system (the so-called Ras-MAPK signaling pathway) which is itself frequently mutated in human tumors.

    Previously, we and others have discovered and characterized Cic function using the fruit fly Drosophila as a model. And further studies in mammals have confirmed a similar activity of Cic in these organisms. However, these analyses had not addressed the fact that Cic actually exists as two variants of different lengths and potentially exerting different activities. In fact, while most of what we know about Cic comes from studies on the shorter form (Cic-S), the function of the longer variant (Cic-L) has been a mystery for years.

    Now, we have studied Cic-L in Drosophila and shown that it performs two different roles: a canonical function equivalent to that of Cic-S, and a novel, non-canonical function controlling the size and behavior of cells required for oocyte maturation. This second function, which affects the activity of conserved regulators of cell growth, is mainly mediated by a protein fragment of Cic-L that is not present in Cic-S, and is therefore very different in nature from the classical function of Cic. Since the structure of Cic-L is so well conserved in evolution, we have proposed that it also has dual roles in human development and disease.

  • One Higgs boson found – could there be more? (2022)

    Juste, Aurelio (IFAE)

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    One Higgs boson found – could there be more?

    The discovery of the Higgs boson in 2012 by the ATLAS and CMS Collaborations at the Large Hadron Collider (LHC) came with pride and prejudice. Pride that a new dynamical principle, envisioned by theorists 60 years ago, found its incarnation in Nature. Prejudice that the Higgs sector may in fact be more complex than predicted by the Standard Model (SM). Many theories (e.g., Supersymmetry) suggest that the Higgs boson is but the first to be observed from a larger Higgs family, whose discovery would signal the breakdown of the SM and trigger a new revolution in particle physics.

    Over the years many searches for extra Higgs bosons have been performed, each time coming out empty handed. However, there is a chance these searches were misguided by theoretical prejudice, such as e.g., that a heavy neutral Higgs boson preferentially couples to a top-antitop-quark pair. If instead it coupled to two particles of different flavour, e.g., a top-anticharm-quark pair, the phenomenology would be totally different, opening new opportunities for discovery [1]. On July 2022, the ATLAS Collaboration reported the results of the first-ever search for such a neutral Higgs boson [2], probing its main production and decay modes, giving two, three, or four top quarks in the final state (Fig. 1). The search targeted events with two same-charge leptons (electrons or muons), three leptons, and at least four leptons. An excess with a significance of up to 2.8 standard deviations (s.d.) was found in events with two positively charged leptons (Fig. 2), compatible with the production of a heavy neutral Higgs boson with a sizable coupling to top and up quarks.

    Since 2015, researchers at IFAE, under A. Juste’s leadership, are playing a major role in the program of searches for an extended Higgs sector in ATLAS. The team has not only performed the search discussed here, but 1.5 years ago completed a search for a flavour violating charged Higgs boson, which found a 3 s.d. excess [3]. Additional data from the LHC Run 3 (2022-2025), along with further analysis improvements, will allow drawing definite conclusions on whether the heavier siblings of the Higgs boson have finally been found.

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