<font size="3">Dear Youri, Dear Pedro, and All,</font><div><font size="3"><br></font></div><div><font size="3">The same to you in spades, as we used to say in school in the U.S.!</font></div><div><font size="3"><br></font></div><div><span style="font-size: medium;">I see again in your work, Youri, how good science can be enjoyable as well as thought-provoking. The lines which particularly struck me were the following:</span></div><div><span style="font-family: Times; font-size: 10pt;"><br></span></div><div><span style="font-family: Times; font-size: 10pt;">This r-protein had a kind of subversive and unique behaviour in deciding
to crystallize in both a folded and an unfolded form within the same
crystal </span><sup style="font-family: Times;">20</sup><span style="font-family: Times; font-size: 10pt;">.</span></div><div><br></div><div><font size="3">I see here the underlying "dynamic dualism" of the universe for whose expressions I have tried to find the logic, my Logic in Reality. Although touching on the essence of mind, Youri avoids any anti-scien</font><span style="font-size: medium;">tific panpsychism. I look forward to learning more about this "brain" and its informational dynamics.</span></div><div><span style="font-size: medium;"><br></span></div><div><span style="font-size: medium;">Best,</span></div><div><span style="font-size: medium;"><br></span></div><div><span style="font-size: medium;">Joseph</span></div><div><blockquote style="margin-right: 0px; margin-left:15px;">----Message d'origine----<br>De : pcmarijuan.iacs@aragon.es<br>Date : 08/01/2022 - 20:49 (E)<br>À : fis@listas.unizar.es<br>Objet : [Fis] NEW YEAR LECTURE (Youri Timsit)<br><br><div class="moz-forward-container">
<table class="moz-email-headers-table" cellspacing="0" cellpadding="0" border="0">
<tbody>
<tr>
<th valign="BASELINE" nowrap="" align="RIGHT">Asunto: </th>
<td> NEW YEAR LECTURE<br></td>
</tr>
<tr>
<th valign="BASELINE" nowrap="" align="RIGHT">Fecha: </th>
<td>Thu, 06 Jan 2022 15:09:26 +0100</td>
</tr>
<tr>
<th valign="BASELINE" nowrap="" align="RIGHT">De: </th>
<td>Youri Timsit <a class="moz-txt-link-rfc2396E" style="cursor:pointer; text-decoration:underline; color:blue" onclick="javascript:handleMailto('mailto:youri.timsit@mio.osupytheas.fr');"><youri.timsit@mio.osupytheas.fr></a></td>
</tr>
<tr>
<th valign="BASELINE" nowrap="" align="RIGHT">Para: </th>
<td>Pedro C. Marijuán <a class="moz-txt-link-rfc2396E" style="cursor:pointer; text-decoration:underline; color:blue" onclick="javascript:handleMailto('mailto:pedroc.marijuan@gmail.com');"><pedroc.marijuan@gmail.com></a></td>
</tr>
</tbody>
</table>
<br>
<br>
<style>p.MsoNormal, li.MsoNormal, div.MsoNormal {
mso-style-unhide: no;
mso-style-qformat: yes;
mso-style-parent: ;
margin: 0.0cm;
margin-bottom: 1.0E-4pt;
mso-pagination: widow-orphan;
font-size: 12.0pt;
font-family: Cambria;
mso-ascii-font-family: Cambria;
mso-ascii-theme-font: minor-latin;
mso-fareast-font-family: "ＭＳ 明朝";
mso-fareast-theme-font: minor-fareast;
mso-hansi-font-family: Cambria;
mso-hansi-theme-font: minor-latin;
mso-bidi-font-family: "Times New Roman";
mso-bidi-theme-font: minor-bidi;
}
*.MsoChpDefault {
mso-style-type: export-only;
mso-default-props: yes;
font-family: Cambria;
mso-ascii-font-family: Cambria;
mso-ascii-theme-font: minor-latin;
mso-fareast-font-family: "ＭＳ 明朝";
mso-fareast-theme-font: minor-fareast;
mso-hansi-font-family: Cambria;
mso-hansi-theme-font: minor-latin;
mso-bidi-font-family: "Times New Roman";
mso-bidi-theme-font: minor-bidi;
}
div.WordSection1 {
page: WordSection1;
}
</style>
<div>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">Happy New Year to all! <br></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><br><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">First of all I would like to warmly thank Pedro Marijuán for having offered me to contribute to this New Year lecture. It is a great pleasure to exchange ideas in a context where “informational choreography” </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">1</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> allows for imaginary encounters between Isadora Duncan and José Ortega y Gasset, to explore new ways of thinking about “what is life”. The topic of this new year lecture is “molecular brains”, a theme that has recently been developed on the basis of recent work on the ribosome </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">2</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">, D. Bray's seminal paper published in 1995 </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">3</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> and the recent papers about consciousness in non-neural organisms </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">4</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">Are “molecular brains” a “vision of the mind” or a real property of matter and universe, born from the first forms of life? And as a corollary, did LUCA have a brain (molecular) and was he “intelligent”? And to go even further, is having systems capable of developing complex behaviours and cognitive faculties a fundamental property of living beings across scales? I hope that future works will shed light on these questions, but in the meantime, I present here briefly, the elements that led to the conclusion that systems equivalent of “neural networks” on a molecular scale could exist in the ribosome and that these systems most probably existed before the radiation of the three kingdoms.
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">The ribosome is indeed considered as window towards the earliest forms of life that predate the three kingdoms. While in astrophysics looking far away gives the opportunity to glimpse the fossil radiation of the universe, looking into the heart of the ribosome may tell us of what the first forms of life might have looked like. The ribosome evolved by accretion around a core that predates the radiation of the three kingdoms and were probably present in LUCA </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">5–9</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. The ribosomes are thus considered as a relic of ancient translation systems that co-evolved with the genetic code have evolved by the accretion of rRNA and ribosomal (r)-proteins around a universal core </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">8,10–14</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. They then followed distinct evolutionary pathways to form the bacterial, archaeal and eukaryotic ribosomes whose overall structures are well conserved within kingdoms </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">15–18</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. The complexity of ribosome assemblies, structures, efficiencies and translation fidelity concomitantly increased in course of the evolution.
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">The molecular brain’s story started with an attempt to understand the surprising electrostatic properties of the bL20 ribosomal protein (r-protein), a protein essential for the assembly of the large subunit of the bacterial ribosome </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">19</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. This r-protein had a kind of subversive and unique behaviour in deciding to crystallize in both a folded and an unfolded form within the same crystal </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">20</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. In trying to better understand its properties, we compared it to the other r-proteins located in the first high-resolution ribosome structures that had just been published </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">21</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">... and that's when something strange was noticed: we realized that uL13 and uL3, two r-proteins of the large subunit, were touching each other by a tenuous interaction between their two extensions, long filaments that weave between the phosphate groups of the rRNA. At that time, these famous r-protein extensions were a real enigma. It was thought that they could play a role in ribosome assembly by neutralising RNA phosphates with their positively charged amino acids </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">22</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. But gradually it became apparent that all extensions of r-proteins systematically wove a gigantic network based on tiny interactions between them. In general, when proteins interact with partners, they form large interfaces (> 2000 Å<sup>2</sup>) sufficient to stabilise their interactions. In this case, the vast majority of the interfaces did not exceed 200 Å<sup>2</sup>, which is all the more surprising given that they were extremely conserved phylogenetically </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">23</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">.
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">Strikingly, it was found that the r-protein network also interacted with or “innervate” the ribosome functional centres such as tRNA sites, the Peptidyl Transfer Centre (PTC), and the peptide tunnel </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">23,24</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. Due to its functional analogy with a sensor-motor network, the r-protein network has been compared to a neural network, at the molecular level. Thus, it has been concluded that these tiny but highly conserved interfaces have been selected during evolution to play a specific role in inter-protein communication and they possess interacting residues to ensure information transfer from a protein to another. Thus, these tiny “molecular synapses" display a “necessary minimum” for allosteric transmission: a few conserved aromatic/charged amino acid motifs (fig. 1). Moreover, it is possible that these minimalist “molecular synapses” reveal much more general principles in molecular communication. Indeed, these tiny interfaces, which appear in their simplest expression in the ribosome thanks to the spatial constraints of ribosomal RNA (rRNA), could be ubiquitous in macromolecular complexes, but drowned out by a 'structural' background involving other amino acids for their stabilisation. <br></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><br><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-family: Times;mso-bidi-font-family: Times;mso-no-proof: yes;"></span><span style="font-family: Times;mso-bidi-font-family: Times;"><img src="cid:part1.308119B2.35B6ED9C@aragon.es" alt="">
<o:p></o:p></span></p>
<p class="MsoNormal" style="margin-bottom: 12.0pt;mso-pagination: none;mso-layout-grid-align: none;text-autospace: none;"><span style="font-size: 8.0pt;font-family: Times;mso-bidi-font-family: Times;mso-bidi-font-weight: bold;">Figure 1. Molecular synapses and wires in the bacterial large subunit r-protein network. The tiny interfaces (the molecular synapses) between r-proteins are represented by surfaces </span><span style="font-size: 8.0pt;font-family: Times;mso-bidi-font-family: Times;">
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">Data from the literature support our “vision of mind” that r-protein networks could contribute in both the ribosomal assembly and in the “sensorimotor control” during protein synthesis. Many experimental studies have indeed shown indeed that ribosome functional sites continually exchange and integrate information during the various steps of translation. As the numerous studies of the Dinman group have shown: “<i>an extensive network of information flow through the ribosome</i>” during protein biosynthesis </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">25–32</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. For example, several studies have also demonstrated long-range signalling between the decoding centre that monitors the correct geometry of the codon-anticodon and other distant sites such as the Sarcin Ricin Loop (SRL) or the E-tRNA site </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">15,33</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. R-proteins of the ribosomal tunnel also play an active role in the regulation of protein synthesis and co-translational folding </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">34,35</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. Ribosomes also perceive each other through quality sensor of collided ribosomes in eukaryotes </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">36</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. In addition, the ribosomes synchronize many complex movements during the translation cycles </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">37–39</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. The recent discoveries of “ribosome heterogeneity” </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">40</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> also significantly expands the complexity of the possible ribosome’s network topologies </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">41</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> and open new perspective on “network plasticity” that could also play a role its behavioural richness.
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">A recent interdisciplinary study with my mathematician colleagues Daniel Bennequin and Grégoire Segeant-Perthuis has shown how r-protein networks have evolved toward a growing complexity through the coevolution of the r-protein extensions and the increasing number of connexions </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">42</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. This study revealed that network expansion is produced by the collective (co)-evolution of r-proteins leading to an asymmetrical evolution of the two subunits. Furthermore, graph theory showed that the network evolution did not occur at random: each new occurring extensions and connections gradually relates functional modules and places the functional centres in central positions of the network. The strong selective pressure that is also expressed at the amino acid acquisition links the network architectures and the r-protein phylogeny thus suggesting that the networks have gradually evolved to sophisticated allosteric pathways. The congruence between independent evolutionary traits indicates that the network architectures evolved to relate and optimize the information spread between functional modules (fig. 2). In summary, graph theory, without knowing the function of the ribosome, can blindly detect the central functional centres of the ribosome. Conversely, ribosomes have learned graph theory during evolution, by placing the PTC and important functional centres at nodes corresponding to the maximum centrality of the network.</span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><br><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-family: Times;mso-bidi-font-family: Times;"><img src="cid:part2.EAF6D293.A8E4653E@aragon.es" alt=""></span><br><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-no-proof: yes;"></span><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></p>
<p class="MsoNormal" style="margin-bottom: 12.0pt;mso-pagination: none;mso-layout-grid-align: none;text-autospace: none;"><b><span style="font-size: 8.0pt;font-family: Times;mso-bidi-font-family: Times;">Figure 2. r-protein and functional centres networks in the large subunit of the eukaryotic ribosome. </span></b><span style="font-size: 8.0pt;font-family: Times;mso-bidi-font-family: Times;">The r-proteins and their extensions are represented according to their evolutionary status. Universal (common to bacteria, archaea and eukarya): red; Archaea: cyan; Eukarya: yellow. Lines between two circles symbolize an interaction between two globular domains. The colours of the lines follow the code for the evolutionary status described above, except for eukarya specific connection that are represented with black lines, for clarity. “N” or “C” indicate if the seg or mix are N-terminal or C-terminal extensions. NC indicates proteins without a globular domain (uS14, eL29, eS30, eL37 and eL39). Functional sites (PTC, Tunnel, tRNAs and mRNA) are represented in light blue. The names of bacterial proteins which, by convergence, occupy a position similar to that of Eukaryotic or Archaeal r-proteins, are shown in blue below the circles.
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">Moreover, a network archaeology study has also revealed the existence of a universal network, that consists of 49 strictly conserved connections that was probably present before the radiation of the bacteria and archaea </span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">43</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">. This primordial network is much more developed in the small ribosomal subunit suggesting that the large subunit network complexity developed in later evolutionary stages. These findings therefore suggest that LUCA already possessed such type of molecular networks, with long wires and tiny interfaces. Interestingly, these networks also mix the i-systems of rRNA and aromatic amino acids of proteins for forming conserved structural motifs probably involved in a still unknown mechanism of signal transduction (probably involving electron or charge transfer). It is therefore possible that this ancestral mode of communication has then not only evolved in modern ribosomes but in other macromolecular systems for information transfer and processing. These results therefore suggest that the ribosome opens a window on the first information processing networks, which appeared at the origin of life. They probably diverged towards other cell systems that have been compared to brains such as the multiple nano-brains. These works provide the molecular basis to decipher how non-neural unicellular organisms may display complex behaviours such as associative learning and decision-making</span><sup><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;line-height: 150.0%;font-family: Times;">1,2,44</span></sup><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">.</span><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><br></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><font size="-1">Waiting for your comments and opinions,</font></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><font size="-1">Best regards to all!</font></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;text-indent: 35.4pt;line-height: 150.0%;"><font size="-1">Youri<br><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB">
<o:p></o:p></span></font></p>
<font size="-1"></font>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 9.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"><br></span><span style="font-size: 9.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"><br></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">1. Marijuán, P. C., Navarro, J. & del Moral, R. How the living is in the world: An inquiry into the informational choreographies of life. <i>Prog Biophys Mol Biol</i><b>119</b>, 469–480 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">2. Timsit, Y. & Grégoire, S.-P. Towards the Idea of Molecular Brains. <i>International Journal of Molecular Sciences</i><b>22</b>, 11868 (2021).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">3. Bray, D. Protein molecules as computational elements in living cells. <i>Nature</i><b>376</b>, 307–312 (1995).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">4. Baluška, F., Miller, W. B. & Reber, A. S. Biomolecular Basis of Cellular Consciousness via Subcellular Nanobrains. <i>International Journal of Molecular Sciences</i><b>22</b>, 2545 (2021).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">5. Belousoff, M. J. <i>et al.</i> Ancient machinery embedded in the contemporary ribosome. <i>Biochem. Soc. Trans.</i><b>38</b>, 422–427 (2010).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">6. Fox, G. E. Origin and evolution of the ribosome. <i>Cold Spring Harb Perspect Biol</i><b>2</b>, a003483 (2010).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">7. Opron, K. & Burton, Z. F. Ribosome Structure, Function, and Early Evolution. <i>Int J Mol Sci</i><b>20</b>, (2018).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">8. Melnikov, S. <i>et al.</i> One core, two shells: bacterial and eukaryotic ribosomes. <i>Nat. Struct. Mol. Biol.</i><b>19</b>, 560–567 (2012).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">9. Lecompte, O., Ripp, R., Thierry, J.-C., Moras, D. & Poch, O. Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. <i>Nucleic Acids Res.</i><b>30</b>, 5382–5390 (2002).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">10. Petrov, A. S. <i>et al.</i> History of the ribosome and the origin of translation. <i>Proc. Natl. Acad. Sci. U.S.A.</i><b>112</b>, 15396–15401 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">11. Grosjean, H. & Westhof, E. An integrated, structure- and energy-based view of the genetic code. <i>Nucleic Acids Res.</i><b>44</b>, 8020–8040 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">12. Root-Bernstein, M. & Root-Bernstein, R. The ribosome as a missing link in the evolution of life. <i>J. Theor. Biol.</i><b>367</b>, 130–158 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">13. Root-Bernstein, R. & Root-Bernstein, M. The ribosome as a missing link in prebiotic evolution II: Ribosomes encode ribosomal proteins that bind to common regions of their own mRNAs and rRNAs. <i>J Theor Biol</i><b>397</b>, 115–127 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">14. Root-Bernstein, R. & Root-Bernstein, M. The Ribosome as a Missing Link in Prebiotic Evolution III: Over-Representation of tRNA- and rRNA-Like Sequences and Plieofunctionality of Ribosome-Related Molecules Argues for the Evolution of Primitive Genomes from Ribosomal RNA Modules. <i>Int J Mol Sci</i><b>20</b>, (2019).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">15. Voorhees, R. M. & Ramakrishnan, V. Structural basis of the translational elongation cycle. <i>Annu. Rev. Biochem.</i><b>82</b>, 203–236 (2013).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">16. Ban, N., Nissen, P., Hansen, J., Moore, P. B. & Steitz, T. A. The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. <i>Science</i><b>289</b>, 905–920 (2000).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">17. Ben-Shem, A. <i>et al.</i> The structure of the eukaryotic ribosome at 3.0 Å resolution. <i>Science</i><b>334</b>, 1524–1529 (2011).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">18. Wilson, D. N. & Doudna Cate, J. H. The structure and function of the eukaryotic ribosome. <i>Cold Spring Harb Perspect Biol</i><b>4</b>, (2012).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">19. Wilson, D. N. & Nierhaus, K. H. Ribosomal proteins in the spotlight. <i>Crit. Rev. Biochem. Mol. Biol.</i><b>40</b>, 243–267 (2005).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">20. Timsit, Y., Allemand, F., Chiaruttini, C. & Springer, M. Coexistence of two protein folding states in the crystal structure of ribosomal protein L20. <i>EMBO Rep.</i><b>7</b>, 1013–1018 (2006).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">21. Selmer, M. <i>et al.</i> Structure of the 70S Ribosome Complexed with mRNA and tRNA. <i>Science</i> (2006) doi:10.1126/science.1131127.
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">22. Timsit, Y., Acosta, Z., Allemand, F., Chiaruttini, C. & Springer, M. The role of disordered ribosomal protein extensions in the early steps of eubacterial 50 S ribosomal subunit assembly. <i>Int J Mol Sci</i><b>10</b>, 817–834 (2009).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">23. Poirot, O. & Timsit, Y. Neuron-Like Networks Between Ribosomal Proteins Within the Ribosome. <i>Sci Rep</i><b>6</b>, 26485 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">24. Timsit, Y. & Bennequin, D. Nervous-Like Circuits in the Ribosome Facts, Hypotheses and Perspectives. <i>Int J Mol Sci</i><b>20</b>, (2019).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">25. Rhodin, M. H. J. & Dinman, J. D. An extensive network of information flow through the B1b/c intersubunit bridge of the yeast ribosome. <i>PLoS ONE</i><b>6</b>, e20048 (2011).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">26. Meskauskas, A. & Dinman, J. D. A molecular clamp ensures allosteric coordination of peptidyltransfer and ligand binding to the ribosomal A-site. <i>Nucleic Acids Res.</i><b>38</b>, 7800–7813 (2010).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">27. Sulima, S. O. <i>et al.</i> Eukaryotic rpL10 drives ribosomal rotation. <i>Nucleic Acids Res.</i><b>42</b>, 2049–2063 (2014).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">28. Gulay, S. P. <i>et al.</i> Tracking fluctuation hotspots on the yeast ribosome through the elongation cycle. <i>Nucleic Acids Res.</i><b>45</b>, 4958–4971 (2017).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">29. Rakauskaite, R. & Dinman, J. D. rRNA mutants in the yeast peptidyltransferase center reveal allosteric information networks and mechanisms of drug resistance. <i>Nucleic Acids Res.</i><b>36</b>, 1497–1507 (2008).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">30. Bowen, A. M. <i>et al.</i> Ribosomal protein uS19 mutants reveal its role in coordinating ribosome structure and function. <i>Translation (Austin)</i><b>3</b>, e1117703 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">31. Kisly, I. <i>et al.</i> The Functional Role of eL19 and eB12 Intersubunit Bridge in the Eukaryotic Ribosome. <i>J. Mol. Biol.</i><b>428</b>, 2203–2216 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">32. Meskauskas, A., Russ, J. R. & Dinman, J. D. Structure/function analysis of yeast ribosomal protein L2. <i>Nucleic Acids Res.</i><b>36</b>, 1826–1835 (2008).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">33. Zaher, H. S. & Green, R. Fidelity at the molecular level: lessons from protein synthesis. <i>Cell</i><b>136</b>, 746–762 (2009).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">34. Wilson, D. N., Arenz, S. & Beckmann, R. Translation regulation via nascent polypeptide-mediated ribosome stalling. <i>Curr. Opin. Struct. Biol.</i><b>37</b>, 123–133 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">35. Pechmann, S., Willmund, F. & Frydman, J. The ribosome as a hub for protein quality control. <i>Mol. Cell</i><b>49</b>, 411–421 (2013).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">36. Juszkiewicz, S. <i>et al.</i> ZNF598 Is a Quality Control Sensor of Collided Ribosomes. <i>Mol Cell</i><b>72</b>, 469-481.e7 (2018).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">37. Korostelev, A., Ermolenko, D. N. & Noller, H. F. Structural dynamics of the ribosome. <i>Curr Opin Chem Biol</i><b>12</b>, 674–683 (2008).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">38. Paci, M. & Fox, G. E. Major centers of motion in the large ribosomal RNAs. <i>Nucleic Acids Res</i><b>43</b>, 4640–4649 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">39. Paci, M. & Fox, G. E. Centers of motion associated with EF-Tu binding to the ribosome. <i>RNA Biol</i><b>13</b>, 524–530 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">40. Genuth, N. R. & Barna, M. The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life. <i>Mol. Cell</i><b>71</b>, 364–374 (2018).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">41. Dinman, J. D. Pathways to Specialized Ribosomes: The Brussels Lecture. <i>J. Mol. Biol.</i><b>428</b>, 2186–2194 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">42. Timsit, Y., Sergeant-Perthuis, G. & Bennequin, D. Evolution of ribosomal protein network architectures. <i>Sci Rep</i><b>11</b>, 625 (2021).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">43. Forterre, P. The universal tree of life: an update. <i>Front Microbiol</i><b>6</b>, 717 (2015).
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 10.0pt;mso-bidi-font-size: 12.0pt;font-family: Times;">44. Baluška, F. & Levin, M. On Having No Head: Cognition throughout Biological Systems. <i>Front Psychol</i><b>7</b>, 902 (2016).
<o:p></o:p></span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></p>
<p class="MsoNormal" style="text-align: justify;text-justify: inter-ideograph;line-height: 150.0%;"><font size="+1"><span style="font-size: 10.0pt;line-height: 150.0%;font-family: Times;mso-ansi-language: EN-GB;" lang="EN-GB"> </span></font></p>
<font size="+1"></font>
</div> -----------------------------------------------------------
<span id="OLK_SRC_BODY_SECTION"></span>
</div><br></blockquote><br><p></p></div>