Blastocrithidia nonstop is a protist with a highly unusual nuclear genetic code, in which all three standard stop codons are reassigned to encode amino acids, with UAA also serving as a sole termination codon. In this study, we demonstrate that this parasitic flagellate is amenable to genetic manipulation, enabling gene ablation and protein tagging. Using preassembled Cas9 ribonucleoprotein complexes, we successfully disrupted and tagged the non-essential gene encoding catalase. These advances establish this single-celled eukaryote as a model organism for investigating the malleability and evolution of the genetic code in eukaryotes.

• Keywords
• CRISPR‐Cas9, codon reassignment, genetic code, model organism, trypanosomatids,
• MeSH
• Genetic Code * genetics   MeSH
• Catalase genetics   MeSH
• Protozoan Proteins genetics   MeSH
• Codon, Terminator genetics   MeSH
• Trypanosomatina * genetics   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Catalase MeSH
• Protozoan Proteins MeSH
• Codon, Terminator MeSH

Arbitrariness in the genetic code is one of the main reasons for a linguistic approach to molecular biology: the genetic code is usually understood as an arbitrary relation between amino acids and nucleobases. However, from a semiotic point of view, arbitrariness should not be the only condition for definition of a code, consequently it is not completely correct to talk about "code" in this case. Yet we suppose that there exist a code in the process of protein synthesis, but on a higher level than the nucleic bases chains. Semiotically, a code should be always associated with a function and we propose to define the genetic code not only relationally (in basis of relation between nucleobases and amino acids) but also in terms of function (function of a protein as meaning of the code). Even if the functional definition of meaning in the genetic code has been discussed in the field of biosemiotics, its further implications have not been considered. In fact, if the function of a protein represents the meaning of the genetic code (the sign's object), then it is crucial to reconsider the notion of its expression (the sign) as well. In our contribution, we will show that the actual model of the genetic code is not the only possible and we will propose a more appropriate model from a semiotic point of view.

• Keywords
• Arbitrariness, Biosemiotics, Genetic code, Protein function, Semiotics,
• MeSH
• Amino Acids chemistry   MeSH
• Point Mutation MeSH
• DNA chemistry   MeSH
• Genetic Code * MeSH
• Histones chemistry   MeSH
• Models, Genetic MeSH
• Nucleotides genetics   MeSH
• RNA chemistry   MeSH
• Protein Folding MeSH
• Models, Theoretical MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amino Acids MeSH
• DNA MeSH
• Histones MeSH
• Nucleotides MeSH
• RNA MeSH

In the philosophy of science, we can consider debates about the nature of non-causal explanations in general (e.g. Reutlinger, Saatsi 2018; Lange 2017) and then especially those in the life sciences (e.g. Huneman, 2018; Kostić 2020). These debates are accompanied by the development of a new mechanism that is becoming the major response to the nature of scientific explanation in the life sciences (e.g. Craver, Darden 2013; Craver 2006); and also by the development of a design explanation (e.g. Eck, Mennes 2016) that represents a modern variant of a functional explanation. In this paper, we will methodically: 1. evaluate the plurality of explanatory strategies in contemporary science (chapter 2). 2. describe the mechanical philosophy and mechanistic explanation (Glennan 2016; Craver, Darden 2013, etc.) (chapter 3). 3. explicate the role of mechanisms in code biology (Barbieri 2015, 2002, etc.) and its relation to the new mechanism (chapter 4). 4. fulfill the main goal of the paper - to apply mechanistic explanations in code biology (Barbieri 2019, etc.) and to apply their suitability for this scientific domain (chapter 5).

• Keywords
• Biological sciences, Causal and non-causal explanation, Code biology, Mechanistic and design explanation, ‘Why’-questions,
• MeSH
• Biological Evolution MeSH
• Models, Biological * MeSH
• Biological Science Disciplines methods   MeSH
• Biology methods   MeSH
• Philosophy * MeSH
• Causality * MeSH
• Humans MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Barbieri's semantic biology (originally Barbieri, 1985) provides an extension of the standard biological ontology, through a new theoretical entity: the code. A specific feature of Barbieri's semantic turn in biology is the use of mechanistic explanations of living systems. This approach allows to work with meaning as the 'new observable' of biology. The relationship between meaning and code is expressed by Barbieri as follows: "[ …] meaning is an entity which is related to another entity by a code." (Barbieri, 2015, 26). Barbieri refers to the mechanistic model of meaning as an 'extended mechanism'. This work is a follow-up to a previously published paper in which we concluded that the von Neumann probe (and thus the Turing machine) can serve as a "minimal sufficient model of Barbieri's extended mechanism" (Jurková and Zámečník, 2023a). We now build on this by connecting the concept of self-reproduction as conceived by Norbert Wiener. Firstly, in order to further explore the 'extended mechanism', but also in an attempt to highlight the importance of self-reproduction as a model of biological processes. We want to highlight the extent to which von Neumann and Wiener collaborated, but also where their understanding and conception of self-reproduction diverge. Wiener, unlike von Neumann, emphasizes that such a machine is "an agency for accomplishing certain definite purposes" (Wiener, 2019/1948, 245) and self-propagation "is the creation of a replica capable of the same functions" (Wiener, 2019/1948, 245). We suggest that when Wiener views the machine in terms of an 'operative procedure' that enables machine self-propagation, he is implicitly referring to the role of code as thematized in Barbieri's extended mechanism (Wiener, 2019/1948, 249). We want to focus not only on classical scientific publications, but also to analyse the personal correspondence between von Neumann and Wiener in which they discussed the issue and how it can change the way we perceive self-reproducing machine.

• Keywords
• Biological meaning, Code biology, Extended mechanism, Self-propagating machine, Self-reproducing machine,
• Publication type
• Journal Article MeSH

Recent years have seen a great expansion in our understandings of how silent mutations can drive a disease and that mRNAs are not only mere messengers between the genome and the encoded proteins but also encompass regulatory activities. This review focuses on how silent mutations within open reading frames can affect the functional properties of the encoded protein. We describe how mRNAs exert control of cell biological processes governed by the encoded proteins via translation kinetics, protein folding, mRNA stability, spatio-temporal protein expression and by direct interactions with cellular factors. These examples illustrate how additional levels of information lie within the coding sequences and that the degenerative genetic code is not redundant and have co-evolved with the encoded proteins. Hence, so called synonymous mutations are not always silent but 'whisper'.

• MeSH
• Genetic Code genetics   MeSH
• Codon genetics   MeSH
• Humans MeSH
• RNA, Messenger chemistry   genetics   MeSH
• Models, Genetic MeSH
• Mutation * MeSH
• Open Reading Frames genetics   MeSH
• Proteins chemistry   genetics   metabolism   MeSH
• Protein Biosynthesis genetics   MeSH
• Protein Folding MeSH
• RNA Folding MeSH
• RNA Stability genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Codon MeSH
• RNA, Messenger MeSH
• Proteins MeSH

Recent advances in protein 3D structure prediction using deep learning have focused on the importance of amino acid residue-residue connections (i.e., pairwise atomic contacts) for accuracy at the expense of mechanistic interpretability. Therefore, we decided to perform a series of analyses based on an alternative framework of residue-residue connections making primary use of the TOP2018 dataset. This framework of residue-residue connections is derived from amino acid residue pairing models both historic and new, all based on genetic principles complemented by relevant biophysical principles. Of these pairing models, three new models (named the GU, Transmuted and Shift pairing models) exhibit the highest observed-over-expected ratios and highest correlations in statistical analyses with various intra- and inter-chain datasets, in comparison to the remaining models. In addition, these new pairing models are universally frequent across different connection ranges, secondary structure connections, and protein sizes. Accordingly, following further statistical and other analyses described herein, we have come to a major conclusion that all three pairing models together could represent the basis of a universal proteomic code (second genetic code) sufficient, in and of itself, to "encode" for both protein folding mechanisms and protein-protein interactions.

• Keywords
• Contact map, Protein 3D structure, Protein folding, Protein-protein interactions, Proteomic code, Sense-antisense,
• MeSH
• Amino Acids * chemistry   genetics   MeSH
• Databases, Protein MeSH
• Humans MeSH
• Models, Molecular * MeSH
• Proteins * chemistry   genetics   metabolism   MeSH
• Proteomics * MeSH
• Protein Folding * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amino Acids * MeSH
• Proteins * MeSH

In this paper we investigate the rate coding capabilities of neurons whose input signal are alterations of the base state of balanced inhibitory and excitatory synaptic currents. We consider different regimes of excitation-inhibition relationship and an established conductance-based leaky integrator model with adaptive threshold and parameter sets recreating biologically relevant spiking regimes. We find that given mean post-synaptic firing rate, counter-intuitively, increased ratio of inhibition to excitation generally leads to higher signal to noise ratio (SNR). On the other hand, the inhibitory input significantly reduces the dynamic coding range of the neuron. We quantify the joint effect of SNR and dynamic coding range by computing the metabolic efficiency-the maximal amount of information per one ATP molecule expended (in bits/ATP). Moreover, by calculating the metabolic efficiency we are able to predict the shapes of the post-synaptic firing rate histograms that may be tested on experimental data. Likewise, optimal stimulus input distributions are predicted, however, we show that the optimum can essentially be reached with a broad range of input distributions. Finally, we examine which parameters of the used neuronal model are the most important for the metabolically efficient information transfer.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Action Potentials physiology   MeSH
• Excitatory Postsynaptic Potentials physiology   MeSH
• Membrane Potentials physiology   MeSH
• Models, Neurological * MeSH
• Neural Conduction physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Neural Inhibition physiology   MeSH
• Neurons physiology   MeSH
• Computer Simulation MeSH
• Signal-To-Noise Ratio MeSH
• Computational Biology MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH

This paper presents a rate-code model of binaural interaction inspired by recent neurophysiological findings. The model consists of a peripheral part and a binaural part. The binaural part is composed of models of the medial superior olive (MSO) and the lateral superior olive (LSO), which are parts of the auditory brainstem. The MSO and LSO model outputs are preprocessed in the interaural time difference (ITD) and interaural level difference (ILD) central stages, respectively, which give absolute values of the predicted lateralization at their outputs, allowing a direct comparison with psychophysical data. The predictions obtained with the MSO and LSO models are compared with subjective data on the lateralization of pure tones and narrowband noises, discrimination of the ITD and ILD, and discrimination of the phase warp. The lateralization and discrimination experiments show good agreement with the subjective data. In the case of the phase-warp experiment, the models agree qualitatively with the subjective data. The results demonstrate that rate-code models of MSO and LSO can be used to explain psychophysical data considering lateralization and discrimination based on binaural cues.

• MeSH
• Discrimination, Psychological MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Sound Localization * MeSH
• Models, Neurological * MeSH
• Brain Stem physiology   MeSH
• Evoked Potentials, Auditory, Brain Stem MeSH
• Ear physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of receptacle of living organism evolution. In this article, we propose an analogy between the genetic code and a broader Platonic hypodoché, a concept that Alfred North Whitehead used to explain various aspects of science.

• Keywords
• Platonic receptacle, Whitehead’s argument, evolution changes, genetic code, present day genetics, realization of ideas,
• MeSH
• Models, Biological * MeSH
• Genetic Code * MeSH
• Evolution, Molecular * MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Humans MeSH
• Bone Resorption pathology   MeSH
• Education, Medical, Undergraduate * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Bulgaria MeSH