Negative CG dinucleotide bias: An explanation based on feedback loops between Arginine codon assignments and theoretical minimal RNA rings.

Theoretical minimal RNA rings are candidate primordial genes evolved for non-redundant coding of the genetic code's 22 coding signals (one codon per biogenic amino acid, a start and a stop codon) over the shortest possible length: 29520 22-nucleotide-long RNA rings solve this min-max constraint. Numerous RNA ring properties are reminiscent of natural genes. Here we present analyses showing that all RNA rings lack dinucleotide CG (a mutable, chemically instable dinucleotide coding for Arginine), bearing a resemblance to known CG-depleted genomes. CG in "incomplete" RNA rings (not coding for all coding signals, with only 3-12 nucleotides) gradually decreases towards CG absence in complete, 22-nucleotide-long RNA rings. Presumably, feedback loops during RNA ring growth during evolution (when amino acid assignment fixed the genetic code) assigned Arg to codons lacking CG (AGR) to avoid CG. Hence, as a chemical property of base pairs, CG mutability restructured the genetic code, thereby establishing itself as genetically encoded biological information.

Primitive Oligomeric RNAs at the Origins of Life on Earth.

There are several theories on the origin of life, which differ by choosing the preponderant factor of emergence: main function (autocatalysis versus replication), initial location (black smokers versus ponds) or first molecule (RNA versus DNA). Among the two last ones, the first assumes that an RNA world involving a collaboration of small RNAs with amino-acids pre-existed and the second that DNA-enzyme-lipid complexes existed first. The debate between these classic theories is not closed and the arguments for one or the other of these theories have recently fueled a debate in which the two have a high degree of likelihood. It therefore seems interesting to propose a third intermediate way, based on the existence of an RNA that may have existed before the latter stages postulated by these theories, and therefore may be the missing link towards a common origin of them. To search for a possible ancestral structure, we propose as candidate a small RNA existing in ring or hairpin form in the early stages of life, which could have acted as a "proto-ribosome" by favoring the synthesis of the first peptides. Remnants of this putative candidate RNA exist in molecules nowadays involved in the ribosomal factory, the concentrations of these relics depending on the seniority of these molecules within the translation process.

An Unsupervised Classifier for Whole-Genome Phylogenies, the Maxwell© Tool.

The development of phylogenetic trees based on RNA or DNA sequences generally requires a precise and limited choice of important RNAs, e.g., messenger RNAs of essential proteins or ribosomal RNAs (like 16S), but rarely complete genomes, making it possible to explain evolution and speciation. In this article, we propose revisiting a classic phylogeny of archaea from only the information on the succession of nucleotides of their entire genome. For this purpose, we use a new tool, the unsupervised classifier Maxwell, whose principle lies in the Burrows-Wheeler compression transform, and we show its efficiency in clustering whole archaeal genomes.

Why Is AUG the Start Codon?: Theoretical Minimal RNA Rings: Maximizing Coded Information Biases 1st Codon for the Universal Initiation Codon AUG.

The rational design of theoretical minimal RNA rings predetermines AUG as the universal start codon. This design maximizes coded amino acid diversity over minimal sequence length, defining in silico theoretical minimal RNA rings, candidate ancestral genes. RNA rings code for 21 amino acids and a stop codon after three consecutive translation rounds, and form a degradation-delaying stem-loop hairpin. Twenty-five RNA rings match these constraints, ten start with the universal initiation codon AUG. No first codon bias exists among remaining RNA rings. RNA ring design predetermines AUG as initiation codon. This is the only explanation yet for AUG as start codon. RNA ring design determines additional RNA ring gene- and tRNA-like properties described previously, because it presumably mimics constraints on life's primordial RNAs.

The Ring World: Eversion of Small Double-Stranded Polynucleotide Circlets at the Origin of DNA Double Helix, RNA Polymerization, Triplet Code, Twenty Amino Acids, and Strand Asymmetry.

It is not entirely clear why, at some stage in its evolution, terrestrial life adopted double-stranded DNA as the hereditary material. To explain this, we propose that small, double-stranded, polynucleotide circlets have special catalytic properties. We then use this proposal as the basis for a 'view from here' that we term the Circlet hypothesis as part of a broader Ring World. To maximize the potential explanatory value of this hypothesis, we speculate boldly about the origins of several of the fundamental characteristics and briefly describe the main methods or treatments applied. The principal prediction of the paper is that the highly constrained, conformational changes will occur preferentially in dsDNA, dsRNA and hybrid RNA-DNA circlets that are below a critical size (e.g., 306 bp) and that these will favor the polymerization of precursors into RNA and DNA. We conclude that the Circlet hypothesis and the Ring World therefore have the attraction of offering the same solution to the fundamental problems probably confronting both the earliest cells and the most recent ones.

Gaining Insights Into the Estimation of the Circadian Rhythms of Social Activity in Older Adults From Their Telephone Call Activity With Statistical Learning: Observational Study.

BACKGROUND: Understanding the social mechanisms of the circadian rhythms of activity represents a major issue in better managing the mechanisms of age-related diseases occurring over time in the elderly population. The automated analysis of call detail records (CDRs) provided by modern phone technologies can help meet such an objective. At this stage, however, whether and how the circadian rhythms of telephone call activity can be automatically and properly modeled in the elderly population remains to be established. OBJECTIVE: Our goal for this study is to address whether and how the circadian rhythms of social activity observed through telephone calls could be automatically modeled in older adults. METHODS: We analyzed a 12-month data set of outgoing telephone CDRs of 26 adults older than 65 years of age. We designed a statistical learning modeling approach adapted for exploratory analysis. First, Gaussian mixture models (GMMs) were calculated to automatically model each participant's circadian rhythm of telephone call activity. Second, k-means clustering was used for grouping participants into distinct groups depending on the characteristics of their personal GMMs. RESULTS: The results showed the existence of specific structures of telephone call activity in the daily social activity of older adults. At the individual level, GMMs allowed the identification of personal habits, such as morningness-eveningness for making calls. At the population level, k-means clustering allowed the structuring of these individual habits into specific morningness or eveningness clusters. CONCLUSIONS: These findings support the potential of phone technologies and statistical learning approaches to automatically provide personalized and precise information on the social rhythms of telephone call activity of older individuals. Futures studies could integrate such digital insights with other sources of data to complete assessments of the circadian rhythms of activity in elderly populations.

RNA Rings Strengthen Hairpin Accretion Hypotheses for tRNA Evolution: A Reply to Commentaries by Z.F. Burton and M. Di Giulio.

Theoretical minimal RNA ring design ensures coding over the shortest length once for each coding signal (start and stop codons, and each amino acid) and their hairpin configuration. These constraints define 25 RNA rings which surprisingly resemble ancestral tRNA loops, suggesting commonalities between RNA ring design and proto-tRNAs. RNA rings share several other properties with tRNAs, suggesting that primordial RNAs were multifunctional peptide coding sequences and structural RNAs. Two hypotheses, respectively, by M. Di Giulio and Z.F. Burton, derived from cloverleaf structural symmetries suggest that two and three, respectively, stem-loop hairpins agglutinated into tRNAs. Their authors commented that their respective structure-based hypotheses reflect better tRNA structure than RNA rings. Unlike these hypotheses, RNA ring design uses no tRNA-derived information, rendering model predictive power comparisons senseless. Some analyses of RNA ring primary and secondary structures stress RNA ring splicing in their predicted anticodon's midst, indicating ancestrality of split tRNAs, as the two-piece model predicts. Advancement of knowledge, rather than of specific hypotheses, gains foremost by examining independent hypotheses for commonalities, and only secondarily for discordances. RNA rings mimick ancestral biomolecules including tRNAs, and their evolution, and constitute an interesting synthetic system for early prebiotic evolution tests/simulations.

Pentamers with Non-redundant Frames: Bias for Natural Circular Code Codons.

The natural circular code consists of 20 codons (X0) overrepresented in the coding frame of protein-coding genes as compared to remaining noncoding frames, and X1 and X2 (N1N2N3 → N3N1N2 and N1N2N3 → N2N3N1 permutations of X0, overrepresented in + 1 and - 1 frames of protein-coding genes, not self-complementary). X0, X1 and X2 detect ribosomal, + 1 and - 1 frames. X0 spontaneously emerges in the 25 theoretical minimal RNA rings, 22-nucleotide-long circular RNAs designed to code once for each of the genetic code's coding signals (a start, a stop and each of the 20 amino acids) by three overlapping frames. RNA rings presumed ancient are biased for X1, and bias for X0 increases in presumed recent RNA rings, indicating an evolutionary X1-to-X0 switch. Here, analyses explore biases for X0, X1 and X2 in non-redundant nucleotide tetra- and pentamers, for different genetic codes. Biases for X0 occur in non-redundant nucleotide pentamers and seem stronger in nuclear than mitochondrial genetic codes; tendencies are opposite for X1. Strand-asymmetric replication presumably causes mitogenomes to escape Chargaff's rule which expects ratios A/T = G/C = 1 in single-stranded sequences. Hence, presumably X1 emerged in ancient genetic codes used in single-stranded protogenomes/coding RNAs; the self-complementary X0 presumably evolved secondarily with double-stranded genomes and strand-symmetric replication. Results indicate that selection for non-redundant overlap coding in short nucleotide sequences produced the natural circular code.

The primordial tRNA acceptor stem code from theoretical minimal RNA ring clusters.

BACKGROUND: Theoretical minimal RNA rings code by design over the shortest length once for each of the 20 amino acids, a start and a stop codon, and form stem-loop hairpins. This defines at most 25 RNA rings of 22 nucleotides. As a group, RNA rings mimick numerous prebiotic and early life biomolecular properties: tRNAs, deamination gradients and replication origins, emergence of codon preferences for the natural circular code, and contents of early protein coding genes. These properties result from the RNA ring's in silico design, based mainly on coding nonredundancy among overlapping translation frames, as the genetic code's codon-amino acid assignments determine. RNA rings resemble ancestral tRNAs, defining RNA ring anticodons and corresponding cognate amino acids. Surprisingly, all examined RNA ring properties coevolve with genetic code integration ranks of RNA ring cognates, as if RNA rings mimick prebiotic and early life evolution. METHODS: Distances between RNA rings were calculated using different evolutionary models. Associations between these distances and genetic code evolutionary hypotheses detect evolutionary models best describing RNA ring diversification. RESULTS: Here pseudo-phylogenetic analyses of RNA rings produce clusters corresponding to the primordial code in tRNA acceptor stems, more so when substitution matrices from neutrally evolving pseudogenes are used rather than from functional protein coding genes reflecting selection for conserving amino acid properties. CONCLUSIONS: Results indicate RNA rings with recent cognates evolved from those with early cognates. Hence RNA rings, as designed by the genetic code's structure, simulate tRNA stem evolution and prebiotic history along neutral chemistry-driven mutation regimes.

Codon Directional Asymmetry Suggests Swapped Prebiotic 1st and 2nd Codon Positions.

Background: Codon directional asymmetry (CDA) classifies the 64 codons into palindromes (XYX, CDA = 0), and 5'- and 3'-dominant (YXX and XXY, CDA < 0 and CDA > 0, respectively). Previously, CDA was defined by the purine/pyrimidine divide (A,G/C,T), where X is either a purine or a pyrimidine. For the remaining codons with undefined CDA, CDA was defined by the 5' or 3' nucleotide complementary to Y. This CDA correlates with cognate amino acid tRNA synthetase classes, antiparallel beta sheet conformation index and the evolutionary order defined by the self-referential genetic code evolution model (CDA < 0: class I, high beta sheet index, late genetic code inclusion). Methods: We explore associations of CDAs defined by nucleotide classifications according to complementarity strengths (A:T, weak; C:G, strong) and keto-enol/amino-imino groupings (G,T/A,C), also after swapping 1st and 2nd codon positions with amino acid physicochemical and structural properties. Results: Here, analyses show that for the eight codons whose purine/pyrimidine-based CDA requires using the rule of complementarity with the midposition, using weak interactions to define CDA instead of complementarity increases associations with tRNA synthetase classes, antiparallel beta sheet index and genetic code evolutionary order. CDA defined by keto-enol/amino-imino groups, 1st and 2nd codon positions swapped, correlates with amino acid parallel beta sheet formation indices and Doolittle's hydropathicities. Conclusions: Results suggest (a) prebiotic swaps from N2N1N3 to N1N2N3 codon structures, (b) that tRNA-mediated translation replaced direct codon-amino acid interactions, and (c) links between codon structures and cognate amino acid properties.

System Design for Emergency Alert Triggered by Falls Using Convolutional Neural Networks.

The world population ageing is on the rise, which has led to an increase in the demand for medical care due to diseases and symptoms prevalent in health centers. One of the most prevalent symptoms prevalent in older adults is falls, which affect one-third of patients each year and often result in serious injuries that can lead to death. This paper describes the design of a fall detection system for elderly households living alone using very low resolution thermal sensor arrays. The algorithms implemented were LSTM, GRU, and Bi-LSTM; the last one mentioned being that which obtained the best results at 93% in accuracy. The results obtained aim to be a valuable tool for accident prevention for those patients that use it and for clinicians who manage the data.

Entropy as a Robustness Marker in Genetic Regulatory Networks.

Genetic regulatory networks have evolved by complexifying their control systems with numerous effectors (inhibitors and activators). That is, for example, the case for the double inhibition by microRNAs and circular RNAs, which introduce a ubiquitous double brake control reducing in general the number of attractors of the complex genetic networks (e.g., by destroying positive regulation circuits), in which complexity indices are the number of nodes, their connectivity, the number of strong connected components and the size of their interaction graph. The stability and robustness of the networks correspond to their ability to respectively recover from dynamical and structural disturbances the same asymptotic trajectories, and hence the same number and nature of their attractors. The complexity of the dynamics is quantified here using the notion of attractor entropy: it describes the way the invariant measure of the dynamics is spread over the state space. The stability (robustness) is characterized by the rate at which the system returns to its equilibrium trajectories (invariant measure) after a dynamical (structural) perturbation. The mathematical relationships between the indices of complexity, stability and robustness are presented in case of Markov chains related to threshold Boolean random regulatory networks updated with a Hopfield-like rule. The entropy of the invariant measure of a network as well as the Kolmogorov-Sinaï entropy of the Markov transition matrix ruling its random dynamics can be considered complexity, stability and robustness indices; and it is possible to exploit the links between these notions to characterize the resilience of a biological system with respect to endogenous or exogenous perturbations. The example of the genetic network controlling the kinin-kallikrein system involved in a pathology called angioedema shows the practical interest of the present approach of the complexity and robustness in two cases, its physiological normal and pathological, abnormal, dynamical behaviors.

More Pieces of Ancient than Recent Theoretical Minimal Proto-tRNA-Like RNA Rings in Genes Coding for tRNA Synthetases.

Theoretical minimal RNA rings were designed to mimick life's primordial RNAs by forming stem-loop hairpins and coding once for each of the 20 amino acids, a start and a stop codon. At most 25 22-nucleotide long RNA rings follow these criteria. These align well with a consensus tRNA sequence, predicting for each RNA ring an anticodon and an associated cognate amino acid. Hypotheses on cognate amino acid order of inclusion in the genetic code produce evolutionary ranks for theoretical RNA rings. This evolutionary hypothesis predicts that pieces of RNA rings with more ancient cognate amino acid should be more frequent in modern genes than those from RNA rings with late cognate amino acids. Analyses of genes for tRNA synthetases, among the most ancient proteins, from archaeal, bacterial, eukaryote and viral superkingdoms overall confirm these predictions, least for tRNA synthetases with early cognate amino acids and for the neogene-enriched genome of the giant virus Tupanvirus. Hence early tRNA synthetase genes and late RNA rings evolved separately. Results indicate that RNA rings and tRNA synthetases with the same cognate amino acid are less separated for relatively recent cognate amino acids, suggesting that over evolutionary time the components of the molecular apparatus became more integrated, perhaps in cell-like membrane-bound systems. Results confirm that theoretical considerations in the design of minimal RNA rings recreated RNAs close to the actual primordial RNA population that produce genes by accretion, and confirm the hypothesis of homology of minimal RNA rings with tRNAs and their proto-tRNA status.

Theoretical minimal RNA rings recapitulate the order of the genetic code's codon-amino acid assignments.

BACKGROUND: Theoretical minimal RNA rings form stem-loop hairpins coding for each of the 20 amino acids and a stop, presumably mimicking life's first minimal coding and self-replicating RNAs. They resemble consensual tRNAs. Mean amino acid positions in proteins follow the genetic code's consensual amino acid inclusion order, a 5'-late-to-3'-early amino acid gradient. HYPOTHESIS: We translated minimal RNA rings to test whether translated peptides share that gradient with modern proteins, using a) ribosomal translation, non-overlapping consecutive codons; and b) frameless translation advancing nucleotide by nucleotide, producing partially overlapping codons. RESULTS: For frameless translation, most RNA rings code for a 5'-late-to-3'early amino acid gradient. Gradients indicate decreasing amino acid metabolic costs, from large to small amino acids. For ribosomal translation, the 5'-late-to-3'early amino acid gradient evolves from early to late RNA rings when ranked according to yields in Miller's experiment of their predicted anticodon's cognate amino acid. CONCLUSIONS: Simulations that produced in silico minimal RNA rings didn't account for coded amino acid properties. Yet, produced peptides remind actual proteins, and suggest ancestral frameless translation of partially overlapping trinucleotides advancing by single nucleotide steps, constrained by resource scarcity. Minimal RNA rings reflect the transition from frameless to ribosomal translation and are realistic candidates for ancestral tRNAs.

Memory in plants: Boolean modeling of the learning and store/recall memory functions in response to environmental stimuli.

This paper presents a new model of memory functions in plants, which improves the previous approaches done by René Thomas and colleagues. We have decomposed the plant memory processing into three main functions: learning, storing and recalling. We propose as main mechanism for these three functions the occurrence of a calcium wave consecutive to an environmental stimulus, followed by the activation of specific genes and proteins changing their phosphorylated state. Feedback is ensured by Calcium Dependent Protein Kinases and oxidative phosphorylation.

Theoretical minimal RNA rings designed according to coding constraints mimic deamination gradients.

Deaminations (A->G, C->T) increase with DNA singlestrandedness during replication, presumably creating spontaneous genomic mutational and nucleotide frequency gradients. Alternatively, genes are positioned to avoid deaminations. Deamination gradients affect directly mitogene third codon positions; conserved vertebrate mitochondrial tRNA and protein coding gene arrangements minimize deaminations in anticodons, and first and second codon positions in mitogenes. Here we describe deamination gradients across theoretical minimal RNA rings, 22 nucleotide-long RNAs designed to simulate prebiotic RNAs. These RNA rings code for a start/stop codon and a single codon for each amino acid, and form stem-loop hairpins slowing degradation. They resemble consensus tRNAs, defining potential anticodons and cognate amino acids. Theoretical minimal RNA rings are not designed to include deamination gradients, yet deamination gradients occur in RNA rings. tRNA homology produces stronger evidence for deamination gradients than RNA ring homology defined by coding properties. Deamination gradients start at predicted RNA ring anticodons, corresponding to known homologies between mitochondrial tRNAs and replication origins, and between bacterial tRNA synthetases and mitochondrial DNA polymerase gamma. Deamination gradients are strongest for RNA rings with predicted anticodons matching cognate amino acids that integrated early the genetic code. Presumably protections against deaminations evolved while amino acids integrated the genetic code. Results confirm tRNA-RNA ring homologies. Coding constraints defining RNA rings presumably produce deamination gradients starting at predicted anticodons. Hence, the universal genetic code determines nucleotide deamination gradients in theoretical minimal RNA rings, suggesting adaptation to prevent consequences of deamination mutations. Results also indicate that the genetic code's structure determined evolution of tRNAs, their cognates, tRNA synthetases, and polymerases.

The Uroboros Theory of Life's Origin: 22-Nucleotide Theoretical Minimal RNA Rings Reflect Evolution of Genetic Code and tRNA-rRNA Translation Machineries.

Theoretical minimal RNA rings attempt to mimick life's primitive RNAs. At most 25 22-nucleotide-long RNA rings code once for each biotic amino acid, a start and a stop codon and form a stem-loop hairpin, resembling consensus tRNAs. We calculated, for each RNA ring's 22 potential splicing positions, similarities of predicted secondary structures with tRNA vs. rRNA secondary structures. Assuming rRNAs partly derived from tRNA accretions, we predict positive associations between relative secondary structure similarities with rRNAs over tRNAs and genetic code integration orders of RNA ring anticodon cognate amino acids. Analyses consider for each secondary structure all nucleotide triplets as potential anticodon. Anticodons for ancient, chemically inert cognate amino acids are most frequent in the 25 RNA rings. For RNA rings with primordial cognate amino acids according to tRNA-homology-derived anticodons, tRNA-homology and coding sequences coincide, these are separate for predicted cognate amino acids that presumably integrated late the genetic code. RNA ring secondary structure similarity with rRNA over tRNA secondary structures associates best with genetic code integration orders of anticodon cognate amino acids when assuming split anticodons (one and two nucleotides at the spliced RNA ring 5' and 3' extremities, respectively), and at predicted anticodon location in the spliced RNA ring's midst. Results confirm RNA ring homologies with tRNAs and CDs, ancestral status of tRNA half genes split at anticodons, the tRNA-rRNA axis of RNA evolution, and that single theoretical minimal RNA rings potentially produce near-complete proto-tRNA sets. Hence genetic code pre-existence determines 25 short circular gene- and tRNA-like RNAs. Accounting for each potential splicing position, each RNA ring potentially translates most amino acids, realistically mimicks evolution of the tRNA-rRNA translation machinery. These RNA rings 'of creation' remind the uroboros' (snake biting its tail) symbolism for creative regeneration.

Biological Networks Entropies: Examples in Neural Memory Networks, Genetic Regulation Networks and Social Epidemic Networks.

Networks used in biological applications at different scales (molecule, cell and population) are of different types: neuronal, genetic, and social, but they share the same dynamical concepts, in their continuous differential versions (e.g., non-linear Wilson-Cowan system) as well as in their discrete Boolean versions (e.g., non-linear Hopfield system); in both cases, the notion of interaction graph G(J) associated to its Jacobian matrix J, and also the concepts of frustrated nodes, positive or negative circuits of G(J), kinetic energy, entropy, attractors, structural stability, etc., are relevant and useful for studying the dynamics and the robustness of these systems. We will give some general results available for both continuous and discrete biological networks, and then study some specific applications of three new notions of entropy: (i) attractor entropy, (ii) isochronal entropy and (iii) entropy centrality; in three domains: a neural network involved in the memory evocation, a genetic network responsible of the iron control and a social network accounting for the obesity spread in high school environment.

Evolution of social networks: the example of obesity.

The present paper deals with the effect of the social transmission of nutrition habits in a social and biological age-dependent context on obesity, and accordingly on type II diabetes and among its complications, the neurodegenerative diseases. The evolution of social networks and inside a network the healthy weight of a person are depending on the context in which this person has contacts and exchanges concerning his alimentation, physical activity and sedentary habits, inside the dominant social network in which the person lives (e.g., scholar for young, professional for adult, home or institution for elderly people). Three successive steps of evolution will be considered for social networks (like for neural one's): initial random connectivity, destruction and consolidation of links following a new transition rule called homophilic until an asymptotic architectural organization and configuration of states. The application of such a network dynamics concerns the sequence overweight/obesity/type II diabetes and neurodegenerative diseases.

Spatial heterogeneity of type I error for local cluster detection tests.

BACKGROUND: Just as power, type I error of cluster detection tests (CDTs) should be spatially assessed. Indeed, CDTs' type I error and power have both a spatial component as CDTs both detect and locate clusters. In the case of type I error, the spatial distribution of wrongly detected clusters (WDCs) can be particularly affected by edge effect. This simulation study aims to describe the spatial distribution of WDCs and to confirm and quantify the presence of edge effect. METHODS: A simulation of 40 000 datasets has been performed under the null hypothesis of risk homogeneity. The simulation design used realistic parameters from survey data on birth defects, and in particular, two baseline risks. The simulated datasets were analyzed using the Kulldorff's spatial scan as a commonly used test whose behavior is otherwise well known. To describe the spatial distribution of type I error, we defined the participation rate for each spatial unit of the region. We used this indicator in a new statistical test proposed to confirm, as well as quantify, the edge effect. RESULTS: The predefined type I error of 5% was respected for both baseline risks. Results showed strong edge effect in participation rates, with a descending gradient from center to edge, and WDCs more often centrally situated. CONCLUSIONS: In routine analysis of real data, clusters on the edge of the region should be carefully considered as they rarely occur when there is no cluster. Further work is needed to combine results from power studies with this work in order to optimize CDTs performance.