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This short article is divided into two parts. The first part explains how the concept of ›surprise‹ is understood in theoretical neuroscience today. The second part shows how remarkably closely the modern neuroscientific conception of the brain maps onto Freud’s classical metapsychological model of the mind. It shows also how the modern concepts expand upon some of Freud’s original concepts. The essential mechanism of surprise is that it reduces confidence in an existing belief about the world, and that this brings the belief in question to consciousness. However, special considerations apply to repressed unconscious beliefs. [ABSTRACT FROM AUTHOR]

The interaction between avidin and its counterpart biotin is one of central importance in biology and has been reproposed and studied at length. However, the binding pocket of avidin is prone to promiscuous binding, able to accommodate even non‐biotinylated ligands. Comprehending the factors that distinguish the extremely strong interaction with biotin to other ligands is an important step to fully picture the thermodynamics of these low‐affinity complexes. Here, we present the complex between chicken white egg avidin and theophylline (TEP), the xanthine derivative used in the therapy of asthma. In the crystal structure, TEP lies in the biotin‐binding pocket with the same orientation and planarity of the aromatic ring of 8‐oxodeoxyguanosine. Indeed, its affinity for avidin measured by isothermal titration calorimetry is in the same μM range as those obtained for the previously characterized nucleoside derivatives. By the use of molecular dynamic simulations, we have investigated the most important intermolecular interactions occurring in the avidin‐TEP binding pocket and compared them with those obtained for the avidin 8‐oxodeoxyguanosine and avidin‐biotin complexes. These results testify the capability of avidin to complex purely aromatic molecules. [ABSTRACT FROM AUTHOR]

The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.

Interactions between DNA and graphene are paramount for a wide range of applications, such as biosensing and nanoelectronics; nonetheless, the molecular details of such interactions remain largely unexplored. We employ atomically detailed molecular dynamics simulations with an enhanced sampling technique to investigate the adsorption and mobility of double-stranded DNA along the basal plane of graphene, in an electrolytic aqueous medium. The study focuses on physiologically relevant conditions, using a buffer of [NaCl] = 134 mM. DNA physisorption is shown to be fast and irreversible, leading to deformation and partial melting of the double helix as a result of π–π stacking between the terminal nucleobases and graphene. Denaturation occurs primarily at the termini, with ensemble averaged H-bond ratios of 47.8–62%; these can, however, reach a minimum of 15%. Transition between free-energy minima occurs via a thermodynamical pathway driving the nucleic acid from a radius of gyration of 1.5 nm to 1.35 nm. Mobility along the basal plane of graphene is dominant, accounting for ~90% of all centre-of-mass translation and revealing that the DNA’s apparent diffusivity is similar to diffusion along the endohedral volume of carbon nanotubes, but one order of magnitude faster than in other 2D materials, such as BC3 and C3N.

A free energy-based conceptual theoretical framework from which the conditional equilibrium constant can be comprehensibly understood is presented. This constant is found to be a weighted geometric mean of the equilibrium constants of the reactions of all forms of the conditioned species under buffering conditions, where the weight is given by a function of their predominance in terms of their mole fractions. Once it is shown that this type of equilibrium constant can be easily deduced form free energy functions, it is shown how corrections for activity coefficient can be incorporated as well. The framework additionally permits to interpret side-reactions coefficients as free energy terms related to the chemical speciation of the system, allowing the use of the generalization of Hess' law to obtain conditional constants and a straightforward deduction of multiconditional equilibrium constants. Furthermore, different uses of the conditional constants along the actual literature are reviewed as well allowing to have a complete and updated panorama of the employment of this important concept in chemical and speciation analysis in many areas of research. [ABSTRACT FROM AUTHOR]

Interactions between DNA and graphene are paramount for a wide range of applications, such as biosensing and nanoelectronics; nonetheless, the molecular details of such interactions remain largely unexplored. We employ atomically detailed molecular dynamics simulations with an enhanced sampling technique to investigate the adsorption and mobility of double-stranded DNA along the basal plane of graphene, in an electrolytic aqueous medium. The study focuses on physiologically relevant conditions, using a buffer of [NaCl] = 134 mM. DNA physisorption is shown to be fast and irreversible, leading to deformation and partial melting of the double helix as a result of π–π stacking between the terminal nucleobases and graphene. Denaturation occurs primarily at the termini, with ensemble averaged H-bond ratios of 47.8–62%; these can, however, reach a minimum of 15%. Transition between free-energy minima occurs via a thermodynamical pathway driving the nucleic acid from a radius of gyration of 1.5 nm to 1.35 nm. Mobility along the basal plane of graphene is dominant, accounting for ~90% of all centre-of-mass translation and revealing that the DNA's apparent diffusivity is similar to diffusion along the endohedral volume of carbon nanotubes, but one order of magnitude faster than in other 2D materials, such as BC3 and C3N. [ABSTRACT FROM AUTHOR]

Living systems are complex dynamic information processing energy consuming entities with properties of consciousness, intelligence, sapience, and sentience. Sapience and sentience are autonomous attributes of consciousness. While sapience has been well studied over the years, that of sentience is relatively rare. The nature of sapience and sentience will be considered, and a metacybernetic framework using structural information will be adopted to explore the metaphysics of consciousness. Metacybernetics delivers a cyberintrinsic model that is cybernetic in nature, but also uses the theory of structural information arising from Frieden's work with Fisher information. This will be used to model sapience and sentience and their relationship. Since living systems are energy-consuming entities, it is also natural for thermodynamic metaphysical models to arise, and most of the theoretical studies of sentience have been set within a thermodynamic framework. Hence, a thermodynamic approach will also be introduced and connected to cyberintrinsic theory. In metaphysical contexts, thermodynamics uses free-energy, which plays the same role in cyberintrinsic modelling as intrinsic structural information. Since living systems exist at the dynamical interface of information and thermodynamics, the overall purpose of this paper is to explore sentience from the alternative cyberintrinsic perspective of metacybernetics. [ABSTRACT FROM AUTHOR]

COX-2 and 5-LOX are major enzymes implicated in inflammatory processes and have a crucial role in the pathogenesis of inflammatory disorders and malignancies. Designing antagonists that may concurrently interact with several receptors is a viable technique; thus, blocking these two targets with a single chemical compound might provide an efficient therapeutic approach. In-silico approaches have been employed to find polypharmacological inhibitors, especially for drug repurposing and multitarget drug design. Here, virtual screening of designed oxygen-containing heterocyclic series from prior literature was used to locate a feasible dual inhibitor against COX-2 and 5-LOX. Among these, 5-phenyl-2-(pyridin-3-yl)oxazol-4-yl cyclohexyl(methyl)sulfamate (N 14 ) and 5-phenyl-2-(pyridin-4-yl)oxazol-4-yl benzenesulfonate (N 16 ) was found to more promising with good interaction energy against COX-2 (-9.5 and -9.4 kcal/mol) and 5-LOX (-8.6 and -7.6 kcal/mol). Additionally, it also fulfilled the ADME/T parameters revealed to be drug-like, as anticipated by Lipinski's rule of five and Veber's rule. Furthermore, the molecular dynamics, free binding energy and post-processing analysis indicate N 14 and N 16 appears as a promising candidates with a novel molecular scaffold that could be examined further as a polypharmacological anticancer therapeutic candidate to explore further for the development.

Glutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze the nucleophilic addition of the thiol group of reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, which occurs spontaneously but is dramatically accelerated by the enzyme, protects cells against damages caused by harmful molecules. With some exceptions, GSTs are catalytically active as homodimers, with monomers generally constituted of 200 to 250 residues organized into two subdomains. The first is the N-terminal subdomain, which contains an active site named G site, where GSH is hosted in catalytic conformation and which is generally highly conserved among GSTs. The second subdomain, hydrophobic, which binds the substrate counterpart (H site), can vary from one GST to another, resulting in structures able to recognize different substrates. In the present work, we performed all-atom molecular dynamics simulations in explicit solvent of human GSTA1 in its APO form, bound to GSH ligand and bound to GS-conjugated ligand. From MD, two probes were analyzed to (i) decipher the local conformational changes induced by the presence of the ligand and (ii) map the communication pathways involved in the ligand-binding process. These two local probes are, first, coarse-grained angles (θ , γ) , representing the local conformation of the protein main chain and, second, dihedral angles χ representing the local conformation of the amino-acid side chains. From the local probes time series, effective free-energy landscapes along the amino-acid sequence were analyzed and compared between the three different forms of GSTA1. This methodology allowed us to extract a network of 33 key residues, some of them being located in the experimentally well-known binding sites G and H of GSTA1 and others being located as far as 30Å from the original binding sites. Finally, the collective motions associated with the network of key residues were established, showing a strong dynamical coupling between residues Gly14-Arg15 and Gln54-Val55, both in the same binding site (intrasite) but also between binding sites of each monomer (intersites). [ABSTRACT FROM AUTHOR]

Due to their large deformation, high energy density, and high compliance, dielectric elastomer actuators (DEAs) have found a number of applications in several areas of mechatronics and robotics. Among the many types of DEAs proposed in the literature, rolled DEAs (RDEAs) represent one of the most popular configurations. RDEAs can be effectively used as compact muscle-like actuators for soft robots, since they allow eliminating the need for external motors or compressors while providing at the same time a flexible and lightweight structure with self-sensing capabilities. To effectively design and control complex RDEA-driven systems and robots, accurate and numerically efficient mathematical models need to be developed. In this work, we propose a novel lumped-parameter model for silicone-based, thin and tightly rolled RDEAs. The model is grounded on a free-energy approach, and permits to describe the electro-mechanically coupled response of the transducer with a set of nonlinear ordinary differential equations. After deriving the constitutive relationships, the model is validated by means of an extensive experimental campaign, conducted on three RDEA specimens having different geometries. It is shown how the developed model permits to accurately predict the effects of several parameters (external load, applied voltage, actuator geometry) on the RDEA electro-mechanical response, while maintaining an overall simple mathematical structure. [ABSTRACT FROM AUTHOR]

We find the free-energy in the thermodynamic limit of a one-dimensional XY model associated to a system of N qubits. The coupling among the σ i z is a long range two-body random interaction. The randomness in the couplings is the typical interaction of the Hopfield model with p patterns ( p < N ), where the patterns are p sequences of N independent identically distributed random variables (i.i.d.r.v.), assuming values ± 1 with probability 1 / 2 . We show also that in the case p ≤ α N , α ≠ 0 , the free-energy is asymptotically independent from the choice of the patterns, i.e., it is self-averaging.

We employ a free energy density for Mg–Al alloys that is dependent on concentration, strain, and temperature, and derived from quantum mechanical calculations by Ghosh & Bhattacharya (Acta Mater 193:28–39, 2020) , to model the dynamic precipitation of the Mg 17 Al 12 phase during creep experiments in Mg–Al alloys. Our calculations show that the overall volume fraction of the dynamically formed precipitates is influenced by stress, and furthermore, this influence is anisotropic and asymmetric. Specifically, when the stress is volumetric or along the c-axis direction, the volume fraction of the precipitate phase is greater in compression and lower in tension. Surprisingly, stress along the a- or b-axis directions does not alter the volume fraction of the precipitates. The resistance to creep is improved by the presence of finely dispersed precipitates with a small aspect ratio, closer to spherical or ellipsoidal in shape and high number density. A greater volume fraction of these fine particles are produced during compressive creep tests than tensile creep experiments and thereby explaining the higher creep rate observed in tension than in compression in these alloys. Overall, our calculations explain the tension–compression asymmetry of the creep rate observed in creep experiments in Mg–Al alloys (Agnew et al. in Magn Technol 2000:285–290, 2000; Agnew et al. in Magn. Alloys Appl. 685–692, 2000). [ABSTRACT FROM AUTHOR]

The adsorption of two-dimensional (2-D) graphene oxide (GO) nanosheets at the air-water interface has broad technological implications for GO-based functional material preparations. Molecular-level understanding of the adsorption mechanism and interfacial behaviour is of great significance. Here, the adsorption free energy of GO nanosheets at the air-water interface was simulated, in which the effect of functional groups and deprotonation has been investigated. It was observed that the neutral GOs are generally thermodynamically favourable for the interface adsorption, while the deprotonated GO sheet has no such interface activity. Although the carboxyl group can enhance the interface adsorption minimum in the free energy profile, thereby improving the interfacial activity of the GO sheet, the oxidisation degree on GO is the main controlling factor determining the interface affinity. The interfacial morphology and dynamics of GO nanosheets have also been simulated, in which a parallel movement with a 2-D anisotropic rotation along the interface was revealed. Our simulation results provide new insights into the adsorption mechanism and behaviour of GO at the air-water interface. [ABSTRACT FROM AUTHOR]

Glutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze the nucleophilic addition of the thiol group of reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, which occurs spontaneously but is dramatically accelerated by the enzyme, protects cells against damages caused by harmful molecules. With some exceptions, GSTs are catalytically active as homodimers, with monomers generally constituted of 200 to 250 residues organized into two subdomains. The first is the N-terminal subdomain, which contains an active site named G site, where GSH is hosted in catalytic conformation and which is generally highly conserved among GSTs. The second subdomain, hydrophobic, which binds the substrate counterpart (H site), can vary from one GST to another, resulting in structures able to recognize different substrates. In the present work, we performed all-atom molecular dynamics simulations in explicit solvent of human GSTA1 in its APO form, bound to GSH ligand and bound to GS-conjugated ligand. From MD, two probes were analyzed to (i) decipher the local conformational changes induced by the presence of the ligand and (ii) map the communication pathways involved in the ligand-binding process. These two local probes are, first, coarse-grained angles (θ,γ), representing the local conformation of the protein main chain and, second, dihedral angles χ representing the local conformation of the amino-acid side chains. From the local probes time series, effective free-energy landscapes along the amino-acid sequence were analyzed and compared between the three different forms of GSTA1. This methodology allowed us to extract a network of 33 key residues, some of them being located in the experimentally well-known binding sites G and H of GSTA1 and others being located as far as 30Å from the original binding sites. Finally, the collective motions associated with the network of key residues were established, showing a strong dynamical coupling between residues Gly14-Arg15 and Gln54-Val55, both in the same binding site (intrasite) but also between binding sites of each monomer (intersites).

Interfacial tensions play an important role in dewatering of hydrophilic materials like nanofibrillated cellulose, and are affected by the molecular organization of water at the interface. Application of an electric field influences the orientation of water molecules along the field direction. Hence, it should be possible to alter the interfacial free energies to tune the wettability of cellulose surface through application of an external electric field thus, aiding the dewatering process. Molecular dynamics simulations of cellulose surface in contact with water under the influence of an external electric field have been conducted with GLYCAM-06 forcefield. The effect of variation in electric field intensity and directions on the spreading coefficient has been addressed via orientational preference of water molecules and interfacial free energy analyses. The application of electric field influences the interfacial free energy difference at the cellulose-water interface. The spreading coefficient increases with the electric field directed parallel to the cellulose-water interface while it decreases in the perpendicular electric field. Variation in interfacial free energies seems to explain the change in contact angle adequately in presence of an electric field. The wettability of cellulose surface can be tuned by the application of an external electric field. [ABSTRACT FROM AUTHOR]

Chlorhexidine (CHX), a popular antibacterial drug, is widely used for oral health. Emerging pieces of evidence suggest that commercially available chlorhexidine mouthwash formulations are effective in suppressing the spread of SARS-CoV-2, possibly through destabilization of the viral lipid envelope. CHX is known for its membrane-active properties; however, the molecular mechanism revealing how it damages the viral lipid envelope is yet to be understood. Here we used extensive conventional and umbrella sampling simulations to quantify the effects of CHX on model membranes mimicking the composition of the SARS-CoV-2 outer lipid membrane as well as the host plasma membrane. Our results show that the lipid composition and physical properties of the membrane play an important role in binding and insertion, with CHX binding favorably to the viral membrane over the plasma membrane. Among the simulated lipids, CHX preferentially binds to anionic lipids, PS and PI, which are more concentrated in the viral membrane. The deeper and stable binding of CHX to the viral membrane results in more pronounced swelling of the membrane laterally with a thinning of the bilayer. The overall free energies of pore formation are strongly reduced for the viral membrane compared to the plasma membrane; however, CHX has a larger concentration-dependent effect on free energies of pore formation in the plasma membrane than the viral membrane. The results indicate that CHX is less toxic to the human plasma membrane at low concentrations. Our simulations reveal that CHX facilitates pore formation by the combination of thinning the membrane and accumulation at the water defect. This study provides insights into the mechanism underlying the anti-SARS-CoV-2 potency of CHX, supporting its potential for application as an effective and safe oral rinse agent for preventing viral transmission.

Unconscious emotions are of central importance to psychoanalysis. They do, however, raise conceptual problems. The most pertinent concerns the intuition, shared by Freud, that consciousness is essential to emotion, which makes the idea of unconscious emotion seem paradoxical. In this paper, I address this paradox from the perspective of the philosopher R. C. Roberts’ account of emotions as concern-based construals. I provide an interpretation of this account in the context of affective neuroscience and explore the form of Freudian repression that emotions may be subject to under such an interpretation. This exploration draws on evidence from research on alexithymia and utilises ideas from free-energy neuroscience. The free-energy framework, moreover, facilitates an account of repression that avoids the homunculus objection and coheres with recent work on hysteria.

This article proposes a formal model that integrates cognitive and psychodynamic psychotherapeutic models of psychopathy to show how two major psychopathic traits called lacks remorse and self-aggrandizing can be understood as a form of abnormal Bayesian inference about the self. This model draws on the predictive coding (i.e., active inference) framework, a neurobiologically plausible explanatory framework for message passing in the brain that is formalized in terms of hierarchical Bayesian inference. In summary, this model proposes that these two cardinal psychopathic traits reflect entrenched maladaptive Bayesian inferences about the self, which defend against the experience of deep-seated, self-related negative emotions, specifically shame and worthlessness. Support for the model in extant research on the neurobiology of psychopathy and quantitative simulations are provided. Finally, we offer a preliminary overview of a novel treatment for psychopathy that rests on our Bayesian formulation.

We present a framework based on iterative free-energy optimization with spiking neural networks for modeling the fronto-striatal system (PFC-BG) for the generation and recall of audio memory sequences. In line with neuroimaging studies carried out in the PFC, we propose a genuine coding strategy using the gain-modulation mechanism to represent abstract sequences based solely on the rank and location of items within them. Based on this mechanism, we show that we can construct a repertoire of neurons sensitive to the temporal structure in sequences from which we can represent any novel sequences. Free-energy optimization is then used to explore and to retrieve the missing indices of the items in the correct order for executive control and compositionality. We show that the gain-modulation mechanism permits the network to be robust to variabilities and to have long-term dependencies as it implements a gated recurrent neural network. This model, called Inferno Gate, is an extension of the neural architecture Inferno standing for Iterative Free-Energy Optimization of Recurrent Neural Networks with Gating or Gain-modulation. In experiments performed with an audio database of ten thousand MFCC vectors, Inferno Gate is capable of encoding efficiently and retrieving chunks of fifty items length. We then discuss the potential of our network to model the features of working memory in the PFC-BG loop for structural learning, goal-direction and hierarchical reinforcement learning. • We present a Neural architecture based on Iterative Free-Energy Optimization and on a Gating mechanism for sequence encoding, generation and retrieving in spiking Recurrent Networks (Inferno Gate). • We present a novel gating mechanism based on rank-order coding for structure learning. • The gated network extracts temporal structure from feature to encode memory sequences. • It represents sequences based solely on the rank and location of items, not the items. • Experiments show fast learning and efficient retrieving of long memory sequences. • Its features are compositionality, robustness to noise and long-term dependencies. [ABSTRACT FROM AUTHOR]

Integrative psychotherapies have become the mainstay in mental health care. The most researched therapy, CBT, being integrative itself, continues to integrate such new elements as mindfulness, spirituality, and experiential techniques. There is no commonly accepted strategy for psychotherapy integration. New elements are sometimes added on a trial and error basis with a following post-hoc theoretical and empirical justification. Other times, they are incorporated based on an ad-hoc theoretical premise, and empirical studies follow to support or invalidate it. Nevertheless, four main integrative strategies have been identified as technical eclecticism, common factors integration, principle-based assimilative integration, and theoretical integration (Norcross, 2005). Strategies outside of these four have also been suggested. Recently, a principle of nested hierarchy has been proposed as a way of integrating different strategies into a general roadmap for building an integrative therapy (Krupnik, 2018). The nested hierarchy principle does not, however, offer a strategy for theoretical integration at the top of its hierarchy. In this report, I suggest using the Bayesian theory of psychopathology for such strategy. I propose to apply Bayesian framework to psychotherapy integration and discuss a possibility of using it as a universal strategy called Strategic Modification of Priors (SMOP). I illustrate SMOP's application with a synopsis of a clinical case.

Although macrophages are part of the human immune system, it has been remarkably observed in laboratory experiments that decreasing its number can slow down the tumor progression. We analyze through a recently mathematical model proposed in the literature, necessary conditions for aggregation of tumor cells and macrophages. In order to do so, we prove the possibility of having blow-up in finite time. Next, we study if the aggregation of macrophages can occur when having a low density of tumor cells, and vice versa. With this purpose, we consider the problem of analyzing the existence or not of a simultaneous blow-up. We achieve this goal thanks to a novel process that allows us to compare the entropy functional associated with the density of each population, which turns out to be also a method to find enough conditions for having a simultaneous blow-up. [ABSTRACT FROM AUTHOR]

• An availability analysis is studied for heterogeneous 2D nucleation. • Free-energy maximization is adopted for thermodynamic formulation. • The effects of system geometry and substrate wettability are discussed. • Nucleation barrier height has lower values in case of concave substrate. • Barrier related to flat substrate is in between that of convex and concave substrates. Within the framework of the classical availability of heterogeneous nucleation, a scaled exergetic model has been developed to elucidate the two-dimensionality effects on the potency factor which is an explicit dimensionless scaled parameter for the nucleation barrier height. The effects of system geometry and substrate wettability on the thermodynamics of heterogeneous nucleation on a two-dimensional curved substrate are studied. The difference in the potency factor between two-dimensional nucleation on a convex and a flat substrate is always positive and has a maximum value for a given size factor. The regime of the associated contact angle related to maxima are in the cluster-phase-philic regime irrespective of the substrate size or the three phases associated with heterogeneous nucleation. On the other hand, the difference in the potency factor between heterogeneous nucleation on a concave and a planar substrate is always negative and has a minimum value for a given size factor. In this case, the regime of the associated contact angle related to maxima are in the cluster-phase-phobic regime irrespective of the substrate size or the three phases associated with heterogeneous nucleation. The potency factor has lower values in case of concave substrate and has higher values in case of convex substrate and heterogeneous nucleation on a flat substrate is always in between that of the convex substrate and the concave substrate. [ABSTRACT FROM AUTHOR]

In this work we present an analytical framework to calculate the average translocation time τ required for an ideal proteinogenic polypeptide chain to cross over a small pore on a membrane. Translocation is considered to proceed as a chain of non-interacting amino acid residues of sequence {X j } diffuses through the pore against an energy barrier Δℱ, set by chain entropy and unfolding-folding energetics. We analyze the effect of sequence heterogeneity on the dynamics of translocation by means of helical propensity of amino acid residues. In our calculations we use sequences of fifteen well-known proteins that are translocated which span two orders of magnitude in size according to the number of residues N. Results show non-symmetric free energy barriers as a consequence of sequence heterogeneity, such asymmetry in energy may be useful in differentiated directions of translocation. For the fifteen polypeptide chains considered we found conditions when sequence heterogeneity has not a significant effect on the time scale of translocation leading to a scaling law τ ∝ N ν , where ν ∼ 1.6 is an exponent that holds for most ground state energies. We also identify conditions when sequence heterogeneity has a great impact on the time scale of translocation, in consequence, no more scaling laws for τ there exist. [ABSTRACT FROM AUTHOR]

Highlights • Destructured sensory fields possess inadequate informational structure. • Exposure to such fields elicits autonomously generated perceptual effects. • Anomalous sensory fields provide a testing ground for predictive coding hypotheses. Abstract Destructured sensory fields, involving homogenous stimulation with little or no time-varying structure, provide a fertile ground for testing hypotheses about predictive coding in the human brain. Extended exposure to sensory patterns that deviate substantially from the statistics of natural environments can elicit a bewildering range of perceptual phenomena, up to and including vivid oneiric imagery. We illustrate how this large variety of perceptual effects can be understood as the experiential counterpart of auto-generated neuronal dynamics, unconstrained by parameters that tune the waking sensorium. We synthesize the literature on autonomous neuronal activity across multiple spatiotemporal scales with generative models of brain function and evidence from artificial neural architectures. Perception, we argue, emerges from a process of non-random sampling from an intrinsic distribution of hypotheses rather than a direct transfer of information from the world. The imagery that occurs in altered sensory environments is explained as the outcome of an iterative search through internal world models in which the structural typology of percepts reflects the brain's intrinsic functional architectures. [ABSTRACT FROM AUTHOR]

Integrative psychotherapies have become the mainstay in mental health care. The most researched therapy, CBT, being integrative itself, continues to integrate such new elements as mindfulness, spirituality, and experiential techniques. There is no commonly accepted strategy for psychotherapy integration. New elements are sometimes added on a trial and error basis with a following post-hoc theoretical and empirical justification. Other times, they are incorporated based on an ad-hoc theoretical premise, and empirical studies follow to support or invalidate it. Nevertheless, four main integrative strategies have been identified as technical eclecticism, common factors integration, principle-based assimilative integration, and theoretical integration (Norcross, 2005). Strategies outside of these four have also been suggested. Recently, a principle of nested hierarchy has been proposed as a way of integrating different strategies into a general roadmap for building an integrative therapy (Krupnik, 2018). The nested hierarchy principle does not, however, offer a strategy for theoretical integration at the top of its hierarchy. In this report, I suggest using the Bayesian theory of psychopathology for such strategy. I propose to apply Bayesian framework to psychotherapy integration and discuss a possibility of using it as a universal strategy called Strategic Modification of Priors (SMOP). I illustrate SMOP's application with a synopsis of a clinical case. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Distortion in γ -Cd opposes inclusion and binding. • Distortion is not significant in β -Cd, and larger guests promote higher binding constants. • Desolvation of host cavity and guest affect complex stability. • Complexes with γ -Cd are generally less stable than those with β -Cd. Abstract Cyclodextrins (Cds) are versatile carbohydrate hosts for developing multifunctional nanostructures of pharmaceutical interest. Factors affecting the thermodynamic signatures and stability of β - and γ -Cd complexes are detailed at the atomic level. The MD/PMF-based method is combined with the description of the nature and strength of the inter-partner affinity. Naphthalene, adamantane and lycorine derivatives are used as models of drug-leading structures. Guest size affects Cd-guest contact and the inclusion degree, inducing Cd deformation, which opposes inclusion. Complexation depends on the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 104). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in carbohydrate-mediated recognition phenomena. It corresponds to an increase in energy of ca. 90 kJ mol−1 in the simpler analyzed model system. [ABSTRACT FROM AUTHOR]

• Molecular simulations investigate asphaltene behavior in realistic oil models. • Evaluated surfactants diminish asphaltene aggregation in oil phase. • Surfactant molecules alter interfacial ordering of asphaltene molecules. • Sorbitan-based surfactants increase interfacial sorption of asphaltenes. Oil/water interfacial properties play a crucial role in the chemical industry, especially in enhanced oil recovery (EOR) and emulsion behavior. Among the oil components, asphaltenes can form aggregates and increase the rigidity of the interfacial film, and this can enhance the stability of the emulsions. Here, all-atom molecular dynamics simulations are used to evaluate the molecular-level behavior of two ethoxylated surfactants in water/oil/asphaltene systems, where the oil phase is modeled as a realistic mixture of n-alkanes, cycloalkanes, and aromatic molecules. The addition of the evaluated surfactants considerably reduces the ordering of the asphaltene molecules in the bulk oil phase. In the oil/water systems, the interfacial region selectively absorbs the surfactant molecules, and there is a slight difference in the interfacial behavior of different asphaltene molecules, mostly originating from their molecular structure. The presence of the ethoxylated surfactant molecules considerably affects the interfacial ordering of the asphaltene molecule in the interfacial region, and free energy calculations indicate that the sorbitan-based surfactants result in a larger increase in the interfacial sorption of the studied asphaltenes. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract The primary phenomenon responsible for rock failure called damage is described as the nucleation and evolution of voids in the rock matrix. The damage of rocks especially under the extreme conditions of High Pressure and High Temperature (HPHT) is studied. Rocks demonstrate ductile behavior in HPHT conditions, which is attributed to high confining pressure due to which fragments are held together and a continuum flow is possible. A new 3D non-local macroscopic continuum ductile-damage model is developed for realistic modeling of behavior of rocks under HPHT conditions. The model uses a damage variable, which is a volumetric quantity, called the void-volume fraction. It is assumed that damage is initiated and then driven by the onset of plasticity in a coupled non-local system. The numerical model is applied to a uniaxial compression and the dynamic indentation problems respectively. The dynamic indentation problem is of particular interest to rock drilling at ultra deep depths. Numerically, indentation introduces high stress concentrations and strain localizations, which are generally very hard to handle, owing to issues like loss of hyperbolicity, material length scale and shear deformation bands, using classical methods. The selected problems are solved by local and non-local approaches respectively. The uniaxial compression problem demonstrates the large difference in failure strains of rocks under normal pressure and temperature conditions and HPHT conditions. Results obtained from the dynamic indentation problem show that the damage is incurred in a rock body under the action of an indentor in the form of damage-zones of varying degrees of damage. The results also indicate the importance of non-locality that provides stability and convergence to the numerical solution. Highlights • A nonlocal continuum ductile damage model is developed for rocks under High Pressure and High Temperature (HPHT). • The damage variable introduced is a volumetric quantity called the voidvolume fraction and is represented as a balance law. • The model consists of coupled governing equations; the balance of linear momentum and the void-volume fraction equations. • The model is applied to the dynamic indentation problem, which is complimentary to mechanical evacuation of rocks. ◦ Model performance for local and non-local numerical settings is demonstrated ◦ Non-local model damage results showing different damage zones are qualitatively compared to the experimental observations [ABSTRACT FROM AUTHOR]

Possible unwanted folding of biopharmaceuticals during manufacturing and storage has resulted in analysis schemes compared to small molecules that include bioanalytical characterization besides chemical characterization. Whether bioanalytical characterization is required for nucleotide-based drugs, may be decided on a case-by-case basis. Nucleotide-based pharmaceuticals, if chemically synthesized, occupy an intermediate position between small-molecule drugs and biologics. Here, we tested whether a physicochemical characterization of a nucleotide-based drug substance, BC 007, was adequate, using circular dichroism (CD) spectroscopy. Nuclear magnetic resonance confirmed CD data in one experimental setup. BC 007 forms a quadruplex structure under specific external conditions, which was characterized for its stability and structural appearance also after denaturation using CD and nuclear magnetic resonance. The amount of the free energy (ΔG 0 ) involved in quadruplex formation of BC 007 was estimated at +8.7 kJ/mol when dissolved in water and +1.4 kJ/mol in 154 mM NaCl, indicating structural instability under these conditions. However, dissolution of the substance in 5 mM of KCl reduced the ΔG 0 to −5.6 kJ/mol due to the stabilizing effect of cations. These results show that positive ΔG 0 of quadruplex structure formation in water and aqueous NaCl prevents BC 007 from preforming stable 3-dimensional structures, which could potentially affect drug function. [ABSTRACT FROM AUTHOR]

This study investigated the nucleophilic substitution reaction mechanisms of 5 oxatriquinane derivatives, namely: oxatriquinane (OTQ), 1,4,7-trimethyloxatriquinane (TMO), 1,4,7-triethyloxatriquinane (TEO), 1,4,7-tri-iso-propyloxatriquinane (TIO) and 1,4,7-tri-tert-butyloxatriquinane (TTO). In addition to the G3 conformation (one with the substituent groups at 1,4 and 7 positions pointing into the plane of the paper) originally proposed by the previous workers, Mascal et al. in 2008 and Gunbas et al. in 2013, one more geometrical isomer was considered again for each of the derivatives, the 2G1 isomer (one in which only 2 of the 3 substituent groups at 1,4 and 7 positions are into the paper plane). Geometry optimization and determination of transition state properties of the conformers corresponding to each molecule (in the presence of azide ion, N3-) provided theoretical evidences on the possible reaction mechanisms. The 2G1 conformer for TTO was found to be unstable. The reactions of OTQ, TMO and TEO with azide ion (N3-) followed SN2 pathway, with SN1mechanism completely lacking. This finding is in agreement with the first set of reports published on this subject in 2008 and 2010 by Mascal's group. For TIO (in the presence of azide ion), only the presence of SN1 mechanism could be proved without any observation of transition state (TS), even though, it possesses a 2G1 conformer. TTO surprisingly, showed marked evidence of SN1 mechanism also without any evidence of TS. The results obtained showed that OTQ derivatives up to TEO undergo nucleophilic substitution predominantly via SN2, and above which (i.e. for TIO and TTO) the mechanisms predominantly become SN1. [ABSTRACT FROM AUTHOR]

This article attempts to clarify the commitments of a predictive coding approach to perception. After summarizing predictive coding theory, the article addresses two questions. Is a predictive coding perceptual system also a Bayesian system? Is it a Kantian system? The article shows that the answer to these questions is negative. [ABSTRACT FROM AUTHOR]

Pleckstrin homology (PH) domains mediate protein–membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH–PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH–PIP interactions are largely unknown. Molecular dynamics simulations using a coarse-grained model enables estimation of free-energy landscapes for the interactions of 12 different PH domains with membranes containing PIP 2 or PIP 3 , allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes. Distinct binding modes, corresponding to different distributions of cationic residues on the PH domain, were observed, involving PIP interactions at either the “canonical” (C) and/or “alternate” (A) sites. PH domains can be grouped by the relative strength of their C- and A-site interactions, revealing that a higher affinity correlates with increased C-site interactions. These simulations demonstrate that simultaneous binding of multiple PIP molecules by PH domains contributes to high-affinity membrane interactions, informing our understanding of membrane recognition by PH domains in vivo . [ABSTRACT FROM AUTHOR]

The human visual system (HVS) has a limited sensitivity in perceiving visual information such that visual masking estimation is helpful to improve the performance of image processing techniques. Most existing research efforts only focus on the methods of assessing the visual masking for gray images. In this paper, a spatial masking estimation utilizing the free-energy principle to measure just noticeable color difference (JNCD) in the uniform color space is explored for color images. According to the free-energy principle introduced recently, the HVS is sensitive to the orderly stimulus possessing structural regularity which is easily to be predicted and is insensitive to the disorderly stimulus containing structural irregularity. We reasonably deduce that the spatial masking in color images may be overestimated in the region with orderly structures and underestimated in the region with disorderly structures. Based on a simple prediction model imitating the brain works of the HVS, the structural irregularity is computed to formulate a more accurate spatial masking function of color images in the uniform color space for measuring variable just noticeable color difference (JNCD). The estimated variable just noticeable color difference is further extended to build a color visual model of estimating the visibility thresholds of color images for performance comparison. Simulation results demonstrate that the proposed spatial masking estimation for color images has better consistency with the HVS than the existing method. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) represent a class of proteins that lack a persistent folded conformation and exist as dynamic ensembles in their native state. Inherent lack of a well-defined structure and remarkable structural plasticity have facilitated their functioning in a wide range of crucial cellular processes such as signalling transduction and cell cycle regulation as well as responsible for their aberrant toxic amyloidogenic conformations implicated in a wide range of neurodegenerative diseases, cancer, etc. Their ubiquitous presence in nature, role in biological function and diseases have spurred interest in the biophysical and conformational characterization of IDPs. Conventional methods of structure determination are less feasible owing to structural and spatiotemporal heterogeneity of IDPs, which demand the development of novel biophysical methods as well as rigorous computational techniques for their characterization. In this review, we provide a brief overview of the widely used computational techniques probing the rugged conformational energy landscape of IDPs, their kinetics of structural transitions and molecular interactions key to their functions. Advances in the development of calibrated computational approaches for statistical representation of highly dynamic structural ensemble of IDPs are provided with examples. Challenges in modelling this unique class of proteins as well as the existing and futuristic avenues are also discussed. [ABSTRACT FROM AUTHOR]