Structural Computational Analysis of the Natural History of Class I aminoacyl-tRNA Synthetases Suggests their Role in Establishing the Genetic Code.

The evolutionary history of Class I aminoacyl-tRNA synthetases (aaRS) through the reconstruction of ancestral sequences is presented. From structural molecular modeling, we sought to understand its relationship with the acceptor arms and the tRNA anticodon loop, how this relationship was established, and the possible implications in determining the genetic code and the translation system. The results of the molecular docking showed that in 7 out 9 aaRS, the acceptor arm and the anticodon loop bond practically in the same region. Domain accretion process in aaRS and repositioning of interactions between tRNAs and aaRS are illustrated. Based on these results, we propose that the operational code and the anticodon code coexisted, competing for the aaRS catalytic region, while consequently contributed to the stabilization of these proteins.

Origin of the 16S Ribosomal Molecule from Ancestor tRNAs.

We tested the hypothesis that concatemers of ancestral tRNAs gave rise to the 16S ribosomal RNA. We built an ancestral sequence of proto-tRNAs that showed a significant identity of 51.69% and a percentage of structural identity of 0.941 with the 3' upper domain of 16S ribosomal molecule. We also propose a hypothesis in which the small ribosomal subunit emerged by proto-tRNA fusion and worked as a point to bind RNAs in an open structure configuration. In this context, the two ribosomal subunits initially worked independently, and that the subunit junction, with consequent primitive ribosome formation, was mediated by interactions with tRNA molecules during the primordial genetic code formation.

The Theory of Chemical Symbiosis: A Margulian View for the Emergence of Biological Systems (Origin of Life).

The theory of chemical symbiosis (TCS) suggests that biological systems started with the collaboration of two polymeric molecules existing in early Earth: nucleic acids and peptides. Chemical symbiosis emerged when RNA-like nucleic acid polymers happened to fold into 3D structures capable to bind amino acids together, forming a proto peptidyl-transferase center. This folding catalyzed the formation of quasi-random small peptides, some of them capable to bind this ribozyme structure back and starting to form an initial layer that would produce the larger subunit of the ribosome by accretion. TCS suggests that there is no chicken-and-egg problem into the emergence of biological systems as RNAs and peptides were of equal importance to the origin of life. Life has initially emerged when these two macromolecules started to interact in molecular symbiosis. Further, we suggest that life evolved into progenotes and cells due to the emergence of new layers of symbiosis. Mutualism is the strongest force in biology, capable to create novelties by emergent principles; on which the whole is bigger than the sum of the parts. TCS aims to apply the Margulian view of biology into the origins of life field.

A neutral evolution test derived from a theoretical amino acid substitution model.

A neutral evolution model that explicitly considers codons, amino acids, and the degeneracy of the genetic code is developed. The model is built from nucleotides up to amino acids, and it represents a refinement of the neutral theory of molecular evolution. The model is based on a stochastic process that leads to a stationary probability distribution of amino acids. The latter is used as a neutral test of evolution. We provide some examples for assessing the neutrality test for a small set of protein sequences. The Jukes-Cantor model is generalized to deal with amino acids and it is compared with our neutral model, along with the empirical BLOSUM62 substitution model. The neutral test provides a baseline to which the evolution of any protein can be analyzed, and it clearly helps in discerning putative amino acids with unexpected frequencies that might be under positive or negative selection. Our model and neutral test are as universal as the standard genetic code.

How to eliminate taeniasis/cysticercosis: porcine vaccination and human chemotherapy (Part 2).

BACKGROUND: The application of effective vaccines against pig cysticercosis and mass chemotherapy against pig cysticercosis and human taeniasis have shown the feasibility of interrupting the parasite's life cycle in endemic areas. METHODS: A mathematical model that divides the population into susceptible, infected, and vaccinated individuals is formulated. The model is based upon the life cycle of the parasite. Computer numerical simulation experiments to evaluate the impact of pig vaccination under different vaccination schedules, and combined intervention strategies including pig vaccination and anthelmintic treatment against human taeniasis are carried out. RESULTS: Vaccination against either pig cysticercosis or against human taeniasis will influence the transmission dynamics not only among vaccinees but also the dynamics of the other hosts as well. When the protective efficacy and/or the coverage rate is less than 100%, different mass interventions like vaccinating the pig population twice in combination with chemotherapeutic treatment against human taeniasis, the elimination of the infection in both pigs and humans can also be achieved. CONCLUSIONS: Our mathematical model has the potential for planning, and designing effective intervention strategies including both mass vaccination and/or chemotherapeutic treatment to eliminate pig cysticercosis, human taeniasis and human neurocysticercosis. The model can be adapted to any given community with mild, moderate endemicity, or even in hyperendemic regions.

Mathematical model of the life cycle of taenia-cysticercosis: transmission dynamics and chemotherapy (Part 1).

BACKGROUND: Taenia solium is the aetiological agent of human taeniasis, pig cysticercosis and human neurocysticercosis, which are serious public health problems, especially in developing countries. METHODS: A mathematical model of the transmission dynamics of taeniasis-cysticercosis is formulated. The model consists of a coupled system of differential equations, which are density-dependent equations for describing the flow of the parasite through the life cycle. The model is hybrid since it comprises deterministic equations with stochastic elements which describe changes in the mean parasite burden and incorporates the overall pattern of the parasites' distribution. RESULTS: Sensitivity and bifurcation analyses were carried out to determine the range of values of the model. The model can reproduce the observed epidemiological patterns of human taeniasis, pig and human cysticercosis. For example, for a wide range of parameter values, the mean intensity of adult worms tends to rapidly stabilize in one parasite per individual host. From this model, we also derived a Susceptible-Infected model to describe the prevalence of infection in humans and pigs. Chemotherapeutic interventions against pig cysticercosis or human taeniasis may reduce rapidly and effectively the mean intensity of human taeniasis, pig cysticercosis and human cysticercosis. This effect can be achieved even if the protective efficacy of the drug is of the order of 90% and the coverage rate is 90%. This means that health in humans infected either with adult worms or cysticerci may be achieved by the application of anthelmintic drugs against pig cysticercosis. However, treatment against human cysticercosis alone, does not influence neither human teniasis nor pig cysticercosis. This is because human cysticercosis infection does not influence the value of the basic reproductive number (Ro). CONCLUSIONS: Even coverage of 100% in the administration of anthelmintics did not eliminate the infection. Then elimination of the infection in all hosts does not seem a feasible goal to achieve by administering only chemotherapeutic interventions. Throughout the manuscript a discussion of our model in the context of other models of taeniasis-cysticercosis is presented.

Phenotypic Graphs and Evolution Unfold the Standard Genetic Code as the Optimal.

In this work, we explicitly consider the evolution of the Standard Genetic Code (SGC) by assuming two evolutionary stages, to wit, the primeval RNY code and two intermediate codes in between. We used network theory and graph theory to measure the connectivity of each phenotypic graph. The connectivity values are compared to the values of the codes under different randomization scenarios. An error-correcting optimal code is one in which the algebraic connectivity is minimized. We show that the SGC is optimal in regard to its robustness and error-tolerance when compared to all random codes under different assumptions.

Identity Elements of tRNA as Derived from Information Analysis.

The decipherment of the tRNA's operational code, known as the identity problem, requires the location of the sites in the tRNA structure that are involved in their correct recognition by the corresponding aminoacyl-tRNA synthetase. In this work, we determine the identity elements of each tRNA isoacceptor by means of the variation of information measure from information theory. We show that all isoacceptors exhibit sites associated with some bases of the anticodon. These sites form clusters that are scattered along the tRNA structure. The clusters determine the identity elements of each tRNA. We derive a catalogue of clustered sites for each tRNA that expands previously reported elements.

A Proposal of the Ur-proteome.

Herein we outline a plausible proteome, encoded by assuming a primeval RNY genetic code. We unveil the primeval phenotype by using only the RNA genotype; it means that we recovered the most ancestral proteome, mostly made of the 8 amino acids encoded by RNY triplets. By looking at those fragments, it is noticeable that they are positioned, not at catalytic sites, but in the cofactor binding sites. It implies that the stabilization of a molecule appeared long before its catalytic activity, and therefore the Ur-proteome comprised a set of proteins modules that corresponded to Cofactor Stabilizing Binding Sites (CSBSs), which we call the primitive bindome. With our method, we reconstructed the structures of the "first protein modules" that Sobolevsky and Trifonov (2006) found by using only RMSD. We also examine the probable cofactors that bound to them. We discuss the notion of CSBSs as the first proteins modules in progenotes in the context of several proposals about the primitive forms of life.

Multivariate Entropy Characterizes the Gene Expression and Protein-Protein Networks in Four Types of Cancer.

There is an important urgency to detect cancer at early stages to treat it, to improve the patients' lifespans, and even to cure it. In this work, we determined the entropic contributions of genes in cancer networks. We detected sudden changes in entropy values in melanoma, hepatocellular carcinoma, pancreatic cancer, and squamous lung cell carcinoma associated to transitions from healthy controls to cancer. We also identified the most relevant genes involved in carcinogenic process of the four types of cancer with the help of entropic changes in local networks. Their corresponding proteins could be used as potential targets for treatments and as biomarkers of cancer.

Effects of Orthostatism and Hemodialysis on Mean Heart Period and Fractal Heart Rate Properties of Chronic Renal Failure Patients.

The aim of this work was to evaluate the short-term fractal index (α1 ) of heart rate variability (HRV) in chronic renal failure (CRF) patients by identifying the effects of orthostatism and hemodialysis (HD), and by evaluating the correlation between α1 and the mean RR interval from sinus beats (meanNN). HRV time series were derived from ECG data of 19 CRF patients and 20 age-matched healthy subjects obtained at supine and orthostatic positions (lasting 5 min each). Data from CRF patients were collected before and after HD. α1 was calculated from each time series and compared by analysis of variance. Pearson's correlations between meanNN and α1 were calculated using the data from both positions by considering three groups: healthy subjects, CRF before HD and CRF after HD. At supine position, α1 of CRF patients after HD (1.17 ± 0.30) was larger (P < 0.05) than in healthy subjects (0.89 ± 0.28) but not before HD (1.10 ± 0.34). α1 increased (P < 0.05) in response to orthostatism in healthy subjects (1.29 ± 0.26) and CRF patients after HD (1.34 ± 0.31), but not before HD (1.25 ± 0.37). Whereas α1 was correlated (P < 0.05) with the meanNN of healthy subjects (r = -0.562) and CRF patients after HD (r = -0.388), no significance in CRF patients before HD was identified (r = 0.003). Multiple regression analysis confirmed that α1 was mainly predicted by the orthostatic position (in all groups) and meanNN (healthy subjects and patients after HD), showing no association with the renal disease condition in itself. In conclusion, as in healthy subjects, α1 of CRF patients correlates with meanNN after HD (indicating a more irregular-like HRV behavior at slower heart rates). This suggests that CRF patients with stable blood pressure preserve a regulatory adaptability despite a shifted setting point of the heart period (i.e., higher heart rate) in comparison with healthy subjects.

Genomic signatures in viral sequences by in-frame and out-frame mutual information.

In order to understand the unique biology of viruses, we use the Mutual Information Function (MIF) to characterize 792 viral sequences comprising 458 viral whole genomes. A 3-base periodicity (3-bp) was observed only in DNA-viruses whereas RNA-viruses showed irregular patterns. The correlation of MIF values at frequencies of 3-bp (in-frame) with frequencies of 4 and 5bps (out-frame), turned out to be useful to distinguish viruses according to their respective taxonomic order, and whether they pertain to any of the three different kingdoms, Eubacteria, Archaea and Eukarya. The clustering of viruses was carried out by the use of a new statistics, namely, the pair of in- and out-frame values of the MIF. The clustering thus obtained turned out to be entirely consistent with the current viral taxonomy. As a result we were able to compare in a single plot both viral and cellular genomes unlike any given phylogenetic reconstruction.

Preserved autonomic heart rate modulation in chronic renal failure patients in response to hemodialysis and orthostatism.

BACKGROUND: The aim of this work was to measure the impact of active orthostatism and hemodialysis (HD) upon heart rate variability (HRV) in chronic renal failure (CRF) patients before and after HD. METHODS: Nineteen healthy subjects (age 27 ± 8 years old, 13 were female) and 19 unmedicated CRF patients with HD thrice per week (average HD vintage = 12 months, age 32 ± 9 years old, 11 were female) were included. Five-minute length HRV time series were obtained during supine position and orthostatism. Recordings from CRF patients were obtained before and after HD. Time domain and frequency domain HRV indexes were compared by analysis of variance. The correlation between each HRV index and change in sympathetic weighting induced by different maneuvers was tested by Kendall's Tau correlation. A p value <0.05 was considered statistically significant. RESULTS: HRV indexes which are associated with sympathetic activity increased in response to orthostatism in the healthy group, e.g., low-frequency to high-frequency (LF/HF) ratio, Ln (LF/HF) = -0.3 ± 0.9 versus 0.9 ± 0.9. CRF patients before HD had higher sympathetic weighting than healthy participants, even in supine position, Ln (LF/HF) = 0.6 ± 1.0, but such a difference was accentuated during orthostatism, Ln (LF/HF) = 1.5 ± 1.0, and after HD: Ln (LF/HF) = 0.8 ± 1.3 (supine position) and 2.5 ± 2.1 (orthostatism). All HRV indexes were associated with increments in sympathetic weighting between maneuvers (Kendall's correlations absolute values ≥ 0.24). CONCLUSION: Unmedicated young CRF patients treated with hemodynamically stable maintenance HD showed preserved capacity of autonomic response (with gradual sympathetic increases) induced by cardiovascular challenges such as orthostatism and HD.

Symmetrical and Thermodynamic Properties of Phenotypic Graphs of Amino Acids Encoded by the Primeval RNY Code.

The 12 different types of graphs of the 8 amino acids encoded by the presumably primeval RNY code are derived. The symmetry groups of these graphs are analyzed and coincide with the corresponding values of polar requirement for each amino acid. The symmetry groups at the codon level are partially carried over as a group or subgroup at the amino acid level. Measures of centrality of the 12 graphs indicate that all amino acids were equally relevant irrespective of its chronological order of its appearance. The elimination of any amino acid would be strongly selected against and therefore the genetic code at this stage was already frozen.

Human repetitive sequence densities are mostly negatively correlated with R/Y-based nucleosome-positioning motifs and positively correlated with W/S-based motifs.

We examined statistical correlations between the frequencies of seven proposed nucleosome positioning motifs and the densities of repetitive sequences in the human genome. For both parametric and non-parametric measures of statistical correlations there is a tendency for repetitive sequence density to be negatively correlated with the density of R/Y-based nucleosome positioning motifs, while being positively correlated with that of W/S-based motifs. These results largely hold even when motifs are examined only within repeat-filtered sequences. The RRRRRYYYYY motif and its 5-base shift YYYYYRRRRR, in particular, is over-represented in the human genome; and its negative correlation is consistently present at different regions and at different length scales. For some other nucleosome positioning motifs, the relationship with repeats can be regional or length scale dependent. Considering the importance of nucleosome formation in epigenetic regulations, these results may provide new insight to the evolution of repetitive sequences.

A Proposal of the Ur-RNAome.

It is widely accepted that the earliest RNA molecules were folded into hairpins or mini-helixes. Herein, we depict the 2D and 3D conformations of those earliest RNA molecules with only RNY triplets, which Eigen proposed as the primeval genetic code. We selected 26 species (13 bacteria and 13 archaea). We found that the free energy of RNY hairpins was consistently lower than that of their corresponding shuffled controls. We found traces of the three ribosomal RNAs (16S, 23S, and 5S), tRNAs, 6S RNA, and the RNA moieties of RNase P and the signal recognition particle. Nevertheless, at this stage of evolution there was no genetic code (as seen in the absence of the peptidyl transferase centre and any vestiges of the anti-Shine-Dalgarno sequence). Interestingly, we detected the anticodons of both glycine (GCC) and threonine (GGU) in the hairpins of proto-tRNA.

Groups of Symmetries of the Two Classes of Synthetases in the Four-Dimensional Hypercubes of the Extended Code Type II.

Aminoacyl-tRNA synthetases (aaRSs) originated from an ancestral bidirectional gene (mirror symmetry), and through the evolution of the genetic code, the twenty aaRSs exhibit a symmetrical distribution in a 6-dimensional hypercube of the Standard Genetic Code. In this work, we assume a primeval RNY code and the Extended Genetic RNA code type II, which includes codons of the types YNY, YNR, and RNR. Each of the four subsets of codons can be represented in a 4-dimensional hypercube. Altogether, these 4 subcodes constitute the 6-dimensional representation of the SGC. We identify the aaRSs symmetry groups in each of these hypercubes. We show that each of the four hypercubes contains the following sets of symmetries for the two known Classes of synthetases: RNY: dihedral group of order 4; YNY: binary group; YNR: amplified octahedral group; and RNR: binary group. We demonstrate that for each hypercube, the group of symmetries in Class 1 is the same as the group of symmetries in Class 2. The biological implications of these findings are discussed.

Decoding viruses: An alternative perspective on their history, origins and role in nature.

This article provides an alternative perspective on viruses, exploring their origins, ecology, and evolution. Viruses are recognized as the most prevalent biological entities on Earth, permeating nearly all environments and forming the virosphere-a significant biological layer. They play a crucial role in regulating bacterial populations within ecosystems and holobionts, influencing microbial communities and nutrient recycling. Viruses are also key drivers of molecular evolution, actively participating in the maintenance and regulation of ecosystems and cellular organisms. Many eukaryotic genomes contain genomic elements with viral origins, which contribute to organismal equilibrium and fitness. Viruses are involved in the generation of species-specific orphan genes, facilitating adaptation and the development of unique traits in biological lineages. They have been implicated in the formation of vital structures like the eukaryotic nucleus and the mammalian placenta. The presence of virus-specific genes absent in cellular organisms suggests that viruses may pre-date cellular life. Like progenotes, viruses are ribonucleoprotein entities with simpler capsid architectures compared to proteolipidic membranes. This article presents a comprehensive scenario describing major transitions in prebiotic evolution and proposes that viruses emerged prior to the Last Universal Common Ancestor (LUCA) during the progenote era. However, it is important to note that viruses do not form a monophyletic clade, and many viral taxonomic groups originated more recently as reductions of cellular structures. Thus, viral architecture should be seen as an ancient and evolutionarily stable strategy adopted by biological systems. The goal of this article is to reshape perceptions of viruses, highlighting their multifaceted significance in the complex tapestry of life and fostering a deeper understanding of their origins, ecological impact, and evolutionary dynamics.

Symmetrical distributions of aminoacyl-tRNA synthetases during the evolution of the genetic code.

In this work, we formulate the following question: How the distribution of aminoacyl-tRNA synthetases (aaRSs) went from an ancestral bidirectional gene (mirror symmetry) to the symmetrical distribution of aaRSs in a six-dimensional hypercube of the Standard Genetic Code (SGC)? We assume a primeval RNY code, two Extended Genetic RNA codes type 1 and 2, and the SGC. We outline the types of symmetries of the distribution of aaRSs in each code. The symmetry groups of aaRSs in each code are described, until the symmetries of the SGC display a mirror symmetry. Considering both Extended RNA codes the 20 aaRSs were already present before the Last Universal Ancestor. These findings reveal intricacies in the diversification of aaRSs accompanied by the evolution of the genetic code.

Evolutionary origin of B family DNA-dependent DNA polymerases from retrotranscriptases.

The evolution of DNA and DNA polymerases was a crucial step in the evolution of life on Earth. In the present work, we reconstruct the ancestral sequence and structure for the B family polymerases. Using comparative analyses, we infer the transient state between the ancestor retrotranscriptase and the contemporary B family DNA polymerases. Exonuclease motif was detected in the primary ancestral sequence, as well as an elongation-functioning motif. It is remarkable that the ancestral molecule is more comparable to the retrotranscriptases in terms of structural domains, even though we discovered similarities in the primary sequence with proteins from the B family of DNA polymerases. The present B family proteins differ structurally from retrotranscriptases the most, although the reconstruction of the ancestor protein was able to capture the transitional steps between these two families of polymerases.