Linear combination methods for prediction of drug skin permeation

YesMany in-vitro methods for prediction of skin permeability have been reported in literature. Cerasome electrokinetic chromatography is one of the most sophisticated approaches representing a maximum level of similarity to the lipid phase of the stratum corneum. One goal of this study was to investigate the affinity pattern of Cerasome and to compare it with the permeability profile of human skin. Another purpose was to study the applicability of Hansen solubility parameters for modelling skin permeation and to investigate the predictive and explanatory potential of this method. Visualisation in Hansen diagrams revealed very similar profiles of Cerasome electrokinetic chromatography retention factors and skin permeability coefficients. In both cases, the characteristic pattern with two clusters of highly retained or highly permeable substances could be shown to be mainly caused by two groups of compounds, one of them with high affinity to ceramides, fatty acids and lecithin and the other being more affine to cholesterol. If based on a sufficiently comprehensive experimental dataset, model-independent predictions of skin permeability data using three-component Hansen solubility parameters are able to achieve similar accuracy as calculations made with an Abraham linear free energy relationship model in which the compounds are characterized by seven physicochemical descriptors

Counterion condensation and effective charge of PAMAM dendrimers

PAMAM dendrimers are used as a model system to investigate the effects of counterion condensation and the effective charge for spherical polyelectrolytes. Because of their amino groups, PAMAM dendrimers are weak polyelectrolytes. Lowering the pH results in an increasing protonation of the amino groups which is monitored via the proton chemical shifts of the adjacent CH2 groups. The effective charge is determined from a combination of diffusion and electrophoresis NMR. The fraction of the charges, which are effective for the interaction with an external electric field or other charges, decreases with increasing generation (size) of the dendrimers

Self-diffusion of low-generation PAMAM dendrimers with hydroxyl surface groups in solutions: A general regularity

An experimental study of the self-diffusion and nuclear magnetic relaxation of poly(amidoamine) dendrimers with hydroxyl surface groups (PAMAM-OH) dissolved in methanol over a wide range of concentration (ψ) is reported. It is shown that experimental concentration dependences of PAMAM-OH self-diffusion coefficients (D) can be reduced to the so-called generalized ψ dependence. Over macromolecular concentration range studied, the generalized concentration dependence of PAMAM-OH D coincides with analogous curve obtained for poly(allylcarbosilane) dendrimers of high generations. This result confirms the existence of common regularities of the dendritic macromolecule self-diffusion, and their independence of the individual physicochemical and structural properties of dendrimer, solvent, and features of their interactions in the given systems. The concentration dependence of the PAMAM-OH diffusion also exhibits a clear signature of an inflexible molecule. © 2003 Elsevier Ltd. All rights reserved

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

Bodily feeling in depersonalisation: a phenomenological account

publication-status: Publishedtypes: ArticlePre-print - please cite published version at Sage web site: http://emr.sagepub.com/content/4/2/145.full.pdf+htmlThis paper addresses the phenomenology of bodily feeling in depersonalisation disorder. We argue that not all bodily feelings are intentional states that have the body or part of it as their object. We distinguish three broad categories of bodily feeling: noematic feeling, noetic feeling and existential feeling. Then we show how an appreciation of the differences between them can contribute to an understanding of the depersonalisation experience.ER

Self-Diffusion and Nuclear Magnetic Relaxation of Dendritic Macromolecules in Solutions

The self-diffusion and nuclear magnetic relaxation of poly(butylcarbosilane) and poly(allylcarbosilane) dendrimers dissolved in deuterated chloroform and poly(amidoamine) dendrimers with hydroxyl surface groups in solutions with methanol have been studied. The diffusion rates (D) have been measured by the pulsed-field-gradient nuclear magnetic resonance. It is shown that experimental concentration dependences D(φ) obtained for macromolecules in the dendrimer-solvent systems studied can be reduced to a unified view, and thus, the generalized concentration dependence of the normalized diffusion rates of dendrimers can be obtained. In the macromolecular volume concentration range from 0.01 up to 0.55, the generalized dependence of the normalized diffusion rates for dendrimers coincides with the analogous dependence for globular proteins in aqueous solutions; the last result suggests that self-diffusion features of dendrimers and globular proteins are in general similar. It is also shown that the experimental data obtained permit one to characterize the changes of the own monomer density of dendrimers depending on their molecular weight and, as a consequence, to make a conclusion about the swelling of dendritic macromolecules in the solutions studied

Embedded Agency in Institutional Theory: Problem or Paradox

In “Beyond Constraining and Enabling: Toward New Microfoundations in Institutional Theory” Professor Cardinale (2018) seeks to expose and correct “shortcomings” (p.133) in institutional theory’s conceptualization of structure, agency and their relationship. To this end, he theorizes the “different mechanism[s] through which actors are embedded in structure” (p.134). We agree that institutional theory’s microfoundations merit theoretical attention and development. However, we question the premise that the issue of agency in institutional theory is adequately, or even plausibly, formulated as one of “embeddedness”. We also challenge the relevance of Professor Cardinale’s engagement of Husserl to help solve what we argue to be a phantom problem central to his theory

The structure of a class 3 nonsymbiotic plant haemoglobin from<i>Arabidopsis thaliana</i>reveals a novel N-terminal helical extension

Plant nonsymbiotic haemoglobins fall into three classes, each with distinct properties but all with largely unresolved physiological functions. Here, the first crystal structure of a class 3 nonsymbiotic plant haemoglobin, that fromArabidopsis thaliana, is reported to 1.77 Å resolution. The protein forms a homodimer, with each monomer containing a two-over-two α-helical domain similar to that observed in bacterial truncated haemoglobins. A novel N-terminal extension comprising two α-helices plays a major role in the dimer interface, which occupies the periphery of the dimer–dimer face, surrounding an open central cavity. The haem pocket contains a proximal histidine ligand and an open sixth iron-coordination site with potential for a ligand, in this structure hydroxide, to form hydrogen bonds to a tyrosine or a tryptophan residue. The haem pocket appears to be unusually open to the external environment, with another cavity spanning the entrance of the two haem pockets. The final 23 residues of the C-terminal domain are disordered in the structure; however, these domains in the functional dimer are adjacent and include the only two cysteine residues in the protein sequence. It is likely that these residues form disulfide bondsin vitroand it is conceivable that this C-terminal region may act in a putative complex with a partner moleculein vivo.</jats:p

Empathy, engagement, entrainment: the interaction dynamics of aesthetic experience

A recent version of the view that aesthetic experience is based in empathy as inner imitation explains aesthetic experience as the automatic simulation of actions, emotions, and bodily sensations depicted in an artwork by motor neurons in the brain. Criticizing the simulation theory for committing to an erroneous concept of empathy and failing to distinguish regular from aesthetic experiences of art, I advance an alternative, dynamic approach and claim that aesthetic experience is enacted and skillful, based in the recognition of others’ experiences as distinct from one’s own. In combining insights from mainly psychology, phenomenology, and cognitive science, the dynamic approach aims to explain the emergence of aesthetic experience in terms of the reciprocal interaction between viewer and artwork. I argue that aesthetic experience emerges by participatory sense-making and revolves around movement as a means for creating meaning. While entrainment merely plays a preparatory part in this, aesthetic engagement constitutes the phenomenological side of coupling to an artwork and provides the context for exploration, and eventually for moving, seeing, and feeling with art. I submit that aesthetic experience emerges from bodily and emotional engagement with works of art via the complementary processes of the perception–action and motion–emotion loops. The former involves the embodied visual exploration of an artwork in physical space, and progressively structures and organizes visual experience by way of perceptual feedback from body movements made in response to the artwork. The latter concerns the movement qualities and shapes of implicit and explicit bodily responses to an artwork that cue emotion and thereby modulate over-all affect and attitude. The two processes cause the viewer to bodily and emotionally move with and be moved by individual works of art, and consequently to recognize another psychological orientation than her own, which explains how art can cause feelings of insight or awe and disclose aspects of life that are unfamiliar or novel to the viewer