Crucial Development: Criticality Is Important to Cell-to-Cell Communication and Information Transfer in Living Systems.

In the fourth paper of this Special Issue, we bridge the theoretical debate on the role of memory and criticality discussed in the three earlier manuscripts, with a review of key concepts in biology and focus on cell-to-cell communication in organismal development. While all living organisms are dynamic complex networks of organization and disorder, most studies in biology have used energy and biochemical exchange to explain cell differentiation without considering the importance of information (entropy) transfer. While all complex networks are mixtures of patterns of complexity (non-crucial and crucial events), it is the crucial events that determine the efficiency of information transfer, especially during key transitions, such as in embryogenesis. With increasing multicellularity, emergent relationships from cell-to-cell communication create reaction-diffusion exchanges of different concentrations of biochemicals or morphogenetic gradients resulting in differential gene expression. We suggest that in conjunction with morphogenetic gradients, there exist gradients of information transfer creating cybernetic loops of stability and disorder, setting the stage for adaptive capability. We specifically reference results from the second paper in this Special Issue, which correlated biophotons with lentil seed germination to show that phase transitions accompany changes in complexity patterns during development. Criticality, therefore, appears to be an important factor in the transmission, transfer and coding of information for complex adaptive system development.

Approaching Bounded Rationality: From Quantum Probability to Criticality.

The bounded rationality mainstream is based on interesting experiments showing human behaviors violating classical probability (CP) laws. Quantum probability (QP) has been shown to successfully figure out such issues, supporting the hypothesis that quantum mechanics is the central fundamental pillar for brain function and cognition emergence. We discuss the decision-making model (DMM), a paradigmatic instance of criticality, which deals with bounded rationality issues in a similar way as QP, generating choices that cannot be accounted by CP. We define this approach as criticality-induced bounded rationality (CIBR). For some aspects, CIBR is even more satisfactory than QP. Our work may contribute to considering criticality as another possible fundamental pillar in order to improve the understanding of cognition and of quantum mechanics as well.

Problem behavior in autism spectrum disorders: A paradigmatic self-organized perspective of network structures.

Autism spectrum disorder (ASD) subjects can present temporary behaviors of acute agitation and aggressiveness, named problem behaviors. They have been shown to be consistent with the self-organized criticality (SOC), a model wherein occasionally occurring "catastrophic events" are necessary in order to maintain a self-organized "critical equilibrium." The SOC can represent the psychopathology network structures and additionally suggests that they can be considered as self-organized systems.

The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with biophotons and use them for proper brain function. Further, as auxin drives the "arborescence" of roots within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastrointestinal tract. This auxin/serotonin parallel suggests the root-branch axis in plants may be an evolutionary precursor to the gastrointestinal-brain axis in humans. Finally, it is hypothesized that light might be an important factor, both in gastrointestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness.

A dialogue on the issue of the "quantum brain" between consciousness and unconsciousness.

In this paper, we present some diverse points of view on the issue of the quantum brain.The paper is structured in the form of opening statements by each of the co-authors followed by comments and critique presented by the other co-authors. The main focus of the discussion is on the interplay between the state of being alive and consciousness, both of which possess characteristics of quantum physical states.

Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

In this paper we present a mechanistic model that integrates subneuronal structures, namely ion channels, membrane fatty acids, lipid rafts, G proteins and the cytoskeleton in a dynamic system that is finely tuned in a healthy brain. We also argue that subtle changes in the composition of the membrane's fatty acids may lead to down-stream effects causing dysregulation of the membrane, cytoskeleton and their interface. Such exquisite sensitivity to minor changes is known to occur in physical systems undergoing phase transitions, the simplest and most studied of them is the so-called Ising model, which exhibits a phase transition at a finite temperature between an ordered and disordered state in 2- or 3-dimensional space. We propose this model in the context of neuronal dynamics and further hypothesize that it may involve quantum degrees of freedom dependent upon variation in membrane domains associated with ion channels or microtubules. Finally, we provide a link between these physical characteristics of the dynamical mechanism to psychiatric disorders such as major depression and antidepressant action.

Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology.

The accepted paradigms of mainstream neuropsychiatry appear to be incompletely adequate and in various cases offer equivocal analyses. However, a growing number of new approaches are being proposed that suggest the emergence of paradigm shifts in this area. In particular, quantum theories of mind, brain and consciousness seem to offer a profound change to the current approaches. Unfortunately these quantum paradigms harbor at least two serious problems. First, they are simply models, theories, and assumptions, with no convincing experiments supporting their claims. Second, they deviate from contemporary mainstream views of psychiatric illness and do so in revolutionary ways. We suggest a possible way to integrate experimental neuroscience with quantum models in order to address outstanding issues in psychopathology. A key role is played by the phenomenon called the "stream of consciousness", which can be linked to the so-called "Gamma Synchrony" (GS), which is clearly demonstrated by EEG data. In our novel proposal, a unipolar depressed patient could be seen as a subject with an altered stream of consciousness. In particular, some clues suggest that depression is linked to an "increased power" stream of consciousness. It is additionally suggested that such an approach to depression might be extended to psychopathology in general with potential benefits to diagnostics and therapeutics in neuropsychiatry.

On the possible quantum role of serotonin in consciousness.

Cell membrane's fatty acids (FAs) have been carefully investigated in neurons and platelets in order to study a possible connection to psychopathologies. An important link between the FA distribution and membrane dynamics appears to emerge with the cytoskeleton dynamics. Microtubules (MTs) in particular have been implicated in some recent quantum consciousness models and analyses. The recently proposed quantum model of Craddock et al. (2014) states that MTs possess structural and functional characteristics that are consistent with collective quantum coherent excitations in the aromatic groups of their tryptophan residues. These excitations are consistent with a clocking mechanism on a sub-nanosecond scale. This mechanism and analogous phenomena in light-harvesting complexes in plants and bacteria, are induced by photons and have been touted as evidence of quantum processes in biology. A possible source of intra-cellular photons could be membrane lipid peroxidation processes, so the FA profile could then be linked to the bio-photon emission. The model presented here suggests new ways to understand the role serotonin plays in relation to FAs. In plants, tryptophan conversion of light to exciton energy can participate in the directional orientation of leaves toward sunlight. Since serotonin is structurally similar to tryptophan, in the human brain, neurons could use tryptophan to capture photons and also use serotonin to initiate movement toward the source of light. Hence, we postulate two possible new roles for serotonin: (1) as an antioxidant, in order to counter-balance the oxidative effect of FAs, and (2) to participate in quantum interactions with MTs, in the same way as anesthetics and psychoactive compounds have been recently shown to act. In this latter case, the FA profile could provide an indirect measure of serotonin levels.

Data mining-based statistical analysis of biological data uncovers hidden significance: clustering Hashimoto's thyroiditis patients based on the response of their PBMC with IL-2 and IFN-γ secretion to stimulation with Hsp60.

The pathogenesis of Hashimoto's thyroiditis includes autoimmunity involving thyroid antigens, autoantibodies, and possibly cytokines. It is unclear what role plays Hsp60, but our recent data indicate that it may contribute to pathogenesis as an autoantigen. Its role in the induction of cytokine production, pro- or anti-inflammatory, was not elucidated, except that we found that peripheral blood mononucleated cells (PBMC) from patients or from healthy controls did not respond with cytokine production upon stimulation by Hsp60 in vitro with patterns that would differentiate patients from controls with statistical significance. This "negative" outcome appeared when the data were pooled and analyzed with conventional statistical methods. We re-analyzed our data with non-conventional statistical methods based on data mining using the classification and regression tree learning algorithm and clustering methodology. The results indicate that by focusing on IFN-γ and IL-2 levels before and after Hsp60 stimulation of PBMC in each patient, it is possible to differentiate patients from controls. A major general conclusion is that when trying to identify disease markers such as levels of cytokines and Hsp60, reference to standards obtained from pooled data from many patients may be misleading. The chosen biomarker, e.g., production of IFN-γ and IL-2 by PBMC upon stimulation with Hsp60, must be assessed before and after stimulation and the results compared within each patient and analyzed with conventional and data mining statistical methods.

Predicting five-year recurrence rates of kidney stones: an artificial neural network model.

OBJECTIVE: Due to high recurrence rates of urolithiasis, many attempts have been performed to identify tools for predicting the risk of stone formation. The application of Artificial Neural Networks (ANNs) seems to be a valid candidate for reaching this endpoint. The aim of this study was to find a set of parameters able to predict recurrence episodes immediately after clinical and metabolic evaluation performed at the first visit in a 5-year window. MATERIAL AND METHODS: Data were collected from 80 outpatients who presented idiopathic calcium stone disease both at baseline and after 5 years; patients underwent treatment including both general measures and medical therapy. After 5 years, patients were classified into two subsets, namely SSFs (without recurrence episodes), consisting of 45 subjects (56.25%) and RSFs, with at least one episode of recurrence after the baseline, consisting of 35 subjects (43.75%). Helped by conventional statistics (One-way ANOVA and three Discriminant Analyses: standard, backward stepwise and forward stepwise), an Artificial Neural Network (ANN) approach was used to predict recurrence episodes. RESULTS: An optimal set of 6 parameters was identified from amongst the different combinations in order to efficiently predict the outcome of stone recurrence in approximately 90% of cases. This set consist of serum Na and K as well as Na, P, Oxalate and AP (CaP) index from urine. The results obtained with ANN seem to suggest that some kind of relationship is present between the identified parameters and future stone recurrence. This relationship is probably very complex (in the mathematical sense) and non-linear In fact, a Logistic Regression was built as a comparative method and performed less good results at least in terms of accuracy and sensitivity. CONCLUSIONS: The application of ANN to the database led to a promising predicting algorithm and suggests that a strongly non-linear relationship seems to exist between the parameters and the recurrence episodes. In particular, the ANN approach identifies as optimal parameters serum concentration of Na and K as well as urinary excretion of Na, P, Oxalate and AP (CaP) index. This study suggest that ANNs could potentially be a useful approach because of their ability to work with complex dynamics such as recurrent stone formation seems to have.

Depression, osteoporosis, serotonin and cell membrane viscosity between biology and philosophical anthropology.

Due to the relationship between biology and culture, we believe that depression, understood as a cultural and existential phenomenon, has clear markers in molecular biology. We begin from an existential analysis of depression constituting the human condition and then shift to analysis of biological data confirming, according to our judgment, its original (ontological) structure. In this way philosophy is involved at the anthropological level, in as much as it detects the underlying meanings of depression in the original biological-cultural horizon of human life. Considering the integration of knowledge it is the task of molecular biology to identify the aforementioned markers, to which the existential aspects of depression are linked to. In particular, recent works show the existence of a link between serotonin and osteoporosis as a result of a modified expression of the low-density lipoprotein receptor-related protein 5 gene. Moreover, it is believed that the hereditary or acquired involvement of tryptophan hydroxylase 2 (Tph2) or 5-hydroxytryptamine transporter (5-HTT) is responsible for the reduced concentration of serotonin in the central nervous system, causing depression and affective disorders. This work studies the depression-osteoporosis relationship, with the aim of focusing on depressive disorders that concern the quantitative dynamic of platelet membrane viscosity and interactome cytoskeleton modifications (in particular Tubulin and Gsα protein) as a possible condition of the involvement of the serotonin axis (gut, brain and platelet), not only in depression but also in connection with osteoporosis.

Fatty acids, membrane viscosity, serotonin and ischemic heart disease.

Novel markers for ischemic heart disease are under investigation by the scientific community at international level.This work focuses on a specific platelet membrane fatty acid condition of viscosity which is linked to molecular aspects such as serotonin and G proteins, factors involved in vascular biology.A suggestive hypothesis is considered about the possibility to use platelet membrane viscosity, in relation to serotonin or, indirectly, the fatty acid profile, as indicator of ischemic risk.

Human depression: a new approach in quantitative psychiatry.

The biomolecular approach to major depression disorder is explained by the different steps that involve cell membrane viscosity, Gsalpha protein and tubulin. For the first time it is hypothesised that a biomolecular pathway exists, moving from cell membrane viscosity through Gsalpha protein and Tubulin, which can condition the conscious state and is measurable by electroencephalogram study of the brain's gamma wave synchrony.

Bio molecular considerations in major depression and ischemic cardiovascular disease.

In our study we have evaluated the theme of the platelet fatty acid composition in subjects with a clinical diagnosis of Major Depression (MD), in subjects with a clinical diagnosis of Ischemic Heart Disease (IHD) according to the coronary angiography and in control subjects. We have analyzed all the groups without taking in account therapies, gender and age. As far as we know, the platelet fatty acid composition has never been analyzed before, in MD. The results obtained with the Self Organizing Map (SOM) show the evidence of three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA), and Palmitic Acid (PA) in a peculiar position with respect to the biochemical characterization of MD and three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA) and Oleic Acid (OA) in a peculiar position with respect to the biochemical characterization of the IHD. Bio molecular considerations are made about the possibility of controlling positive changes in platelet viscosity, in both pathologies.

The use of artificial neural networks to study fatty acids in neuropsychiatric disorders.

BACKGROUND: The range of the fatty acids has been largely investigated in the plasma and erythrocytes of patients suffering from neuropsychiatric disorders. In this paper we investigate, for the first time, whether the study of the platelet fatty acids from such patients may be facilitated by means of artificial neural networks. METHODS: Venous blood samples were taken from 84 patients with a DSM-IV-TR diagnosis of major depressive disorder and from 60 normal control subjects without a history of clinical depression. Platelet levels of the following 11 fatty acids were analyzed using one-way analysis of variance: C14:0, C16:0, C16:1, C18:0, C18:1 n-9, C18:1 n-7, C18:2 n-6, C18:3 n-3, C20:3 n-3, C20:4 n-6 and C22:6 n-3. The results were then entered into a wide variety of different artificial neural networks. RESULTS: All the artificial neural networks tested gave essentially the same result. However, one type of artificial neural network, the self-organizing map, gave superior information by allowing the results to be described in a two-dimensional plane with potentially informative border areas. A series of repeated and independent self-organizing map simulations, with the input parameters being changed each time, led to the finding that the best discriminant map was that obtained by inclusion of just three fatty acids. CONCLUSION: Our results confirm that artificial neural networks may be used to analyze platelet fatty acids in neuropsychiatric disorder. Furthermore, they show that the self-organizing map, an unsupervised competitive-learning network algorithm which forms a nonlinear projection of a high-dimensional data manifold on a regular, low-dimensional grid, is an optimal type of artificial neural network to use for this task.

A comparison of oxidative stress in smokers and non-smokers: an in vivo human quantitative study of n-3 lipid peroxidation.

BACKGROUND: Cigarette smoking is believed to cause oxidative stress by several mechanisms, including direct damage by radical species and the inflammatory response induced by smoking, and would therefore be expected to cause increased lipid peroxidation. The aim was to carry out the first study of the relationship of smoking in humans to the level of n-3 lipid peroxidation indexed by the level of ethane in exhaled breath. METHODS: Samples of alveolar air were obtained from 11 smokers and 18 non-smokers. The air samples were analyzed for ethane using mass spectrometry. RESULTS: The two groups of subjects were matched with respect to age and gender. The mean cumulative smoking status of the smokers was 11.8 (standard error 2.5) pack-years. The mean level of ethane in the alveolar breath of the group of smokers (2.53 (0.55) ppb) was not significantly different from that of the group of non-smokers (2.59 (0.29) ppb; p = 0.92). With all 29 subjects included, the Spearman rank correlation coefficient between ethane levels and cumulative smoking status was -0.11 (p = 0.58), while an analysis including only the smokers yielded a corresponding correlation coefficient of 0.11 (p = 0.75). CONCLUSION: Our results show no evidence that cigarette smoking is related to increased n-3 lipid peroxidation as measured by expired ethane.

Fatty acids and oxidative stress in psychiatric disorders.

BACKGROUND: The aim of this study was to determine whether there is published evidence for increased oxidative stress in neuropsychiatric disorders. METHODS: A PubMed search was carried out using the MeSH search term 'oxidative stress' in conjunction with each of the DSM-IV-TR diagnostic categories of the American Psychiatric Association in order to identify potential studies. RESULTS: There was published evidence of increased oxidative stress in the following DSM-IV-TR diagnostic categories: mental retardation; autistic disorder; Rett's disorder; attention-deficit hyperactivity disorder; delirium; dementia; amnestic disorders; alcohol-related disorders; amphetamine (or amphetamine-like)-related disorders; hallucinogen-related disorders; nicotine-related disorders; opioid-related disorders; schizophrenia and other psychotic disorders; mood disorders; anxiety disorders; sexual dysfunctions; eating disorders; and sleep disorders. CONCLUSION: Most psychiatric disorders are associated with increased oxidative stress. Patients suffering from that subgroup of these psychiatric disorders in which there is increased lipid peroxidation might therefore benefit from fatty acid supplementation (preferably with the inclusion of an antioxidant-rich diet) while patients suffering from all these psychiatric disorders might benefit from a change to a whole-food plant-based diet devoid of refined carbohydrate products.