Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin.

Knowledge of A/A'-dependencies on subject extraction with two types of infinitives in non-native Portuguese adult bilingualism

Within generative L2 acquisition research there is a longstanding debate as to what underlies observable differences in L1/L2 knowledge/ performance. On the one hand, Full Accessibility approaches maintain that target L2 syntactic representations (new functional categories and features) are acquirable (e.g., Schwartz & Sprouse, 1996). Conversely, Partial Accessibility approaches claim that L2 variability and/or optionality, even at advanced levels, obtains as a result of inevitable deficits in L2 narrow syntax and is conditioned upon a maturational failure in adulthood to acquire (some) new functional features (e.g., Beck, 1998; Hawkins & Chan, 1997; Hawkins & Hattori, 2006; Tsimpli & Dimitrakopoulou, 2007). The present study tests the predictions of these two sets of approaches with advanced English learners of L2 Brazilian Portuguese (n = 21) in the domain of inflected infinitives. These advanced L2 learners reliably differentiate syntactically between finite verbs, uninflected and inflected infinitives, which, as argued, only supports Full Accessibility approaches. Moreover, we will discuss how testing the domain of inflected infinitives is especially interesting in light of recent proposals that Brazilian Portuguese colloquial dialects no longer actively instantiate them (Lightfoot, 1991; Pires, 2002, 2006; Pires & Rothman, 2009; Rothman, 2007).

Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Dissociation between the impact of evidence on eye movement target choice and confidence judgements

It has been suggested that the evidence used to support a decision to move our eyes and the confidence we have in that decision are derived from a common source. Alternatively, confidence may be based on further post-decisional processes. In three experiments we examined this. In Experiment 1, participants chose between two targets on the basis of varying levels of evidence (i.e., the direction of motion coherence in a Random-Dot-Kinematogram). They indicated this choice by making a saccade to one of two targets and then indicated their confidence. Saccade trajectory deviation was taken as a measure of the inhibition of the non-selected target. We found that as evidence increased so did confidence and deviations of saccade trajectory away from the non-selected target. However, a correlational analysis suggested they were not related. In Experiment 2 an option to opt-out of the choice was offered on some trials if choice proved too difficult. In this way we isolated trials on which confidence in target selection was high (i.e., when the option to opt-out was available but not taken). Again saccade trajectory deviations were found not to differ in relation to confidence. In Experiment 3 we directly manipulated confidence, such that participants had high or low task confidence. They showed no differences in saccade trajectory deviations. These results support post-decisional accounts of confidence: evidence supporting the decision to move the eyes is reflected in saccade control, but the confidence that we have in that choice is subject to further post-decisional processes.

Cognitive emotion regulation as a mediator between posttraumatic stress symptoms and hypomanic personality within a non-clinical population

Background: There is a high prevalence of traumatic life events within individuals diagnosed with bipolar disorder. However, currently there is limited theoretical understanding of this relationship. Aims: To explore whether non-clinical symptoms of posttraumatic stress have a direct effect on the non-clinical symptoms of bipolar disorder, or whether this relationship is mediated by cognitive emotion regulation strategies. Method: A cross-sectional design within non-clinical participants completing an online survey including the Impact of Events Scale, Cognitive Emotion Regulation Questionnaire and the Hypomanic Personality Scale. Results: Posttraumatic stress symptoms were associated with hypomanic personality. Intrusive memories contributed a small but significant proportion of the variance between these two measures. Rumination of negative emotions mediated the relationship between posttraumatic stress and hypomanic personality. Conclusions: The relationship between traumatic events and an increased prevalence of bipolar disorder remains poorly understood. Further research should explore rumination as a potential target for treatment within those suffering from both posttraumatic stress and bipolar disorder.

The Acquisition of Aspect in L2 Portuguese & Spanish: Exploring Native/Non-Native Performance Differences.

This study investigates the possibility of native-like ultimate attainment by analyzing L2 knowledge of aspect as seen in the Preterit/Imperfect contrast of highly successful English L2 learners of Portuguese and Spanish. Building on innovative work by Montrul & Slabakova (2003) and Slabakova & Montrul (2003), we test knowledge of semantic entailments associated with the acquisition of [+/- perfective] features checked in higher AspP. Additionally, we investigate the possibility of a specific pattern of associated target-deviant L2 performance. We hypothesize that L2 performance can be affected by explicit positive evidence (pedagogical rules) despite otherwise demonstrable native-like competence. Indeed, the data reveal a pattern of target-deviant performance noted only in three specific contexts, all of which can be linked to traditional instruction: (a) with particular stative verbs not used in the Preterit (b) when preceded by certain adverbial phrases (e.g.,siempre) and (c) so-called semantic shifting verbs (e.g., sabía vs. supe).

Non-genomic actions of estrogens and their interaction with genomic actions in the brain

Ligands for the nuclear receptor superfamily have at least two mechanisms of action: (a) classical transcriptional regulation of target genes (genomic mechanisms); and (b) non-genomic actions, which are initiated at the cell membrane, which could also impact transcription. Though transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. This has led to considerable debate over the physiological relevance of membrane-initiated actions of hormones versus genomic actions of hormones, with genomic actions predominating in the endocrine field. There is good evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium and that these are linked to physiologically relevant scenarios in the brain. We show evidence in this review, that membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription in both the central nervous system and in non-neuronal cell lines. We present a theoretical scenario which can be used to understand this phenomenon. These signaling cascades may occur in parallel or in series but subsequently, converge at the modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other non-cognate hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription, though the relevance of this is less clear. The idea that coupling between membrane-initiated and genomic actions of hormones is a novel idea in neuroendocrinology and provides us with a unified view of hormone action in the central nervous system.

Membrane-initiated non-genomic signaling by estrogens in the hypothalamus: cross-talk with glucocorticoids with implications for behavior

The estrogen receptor and glucocorticoid receptor are members of the nuclear receptor superfamily that can signal using both non-genomic and genomic transcriptional modes. Though genomic modes of signaling have been well characterized and several behaviors attributed to this signaling mechanism, the physiological significance of non-genomic modes of signaling has not been well understood. This has partly been due to the controversy regarding the identity of the membrane ER (mER) or membrane GR (mGR) that may mediate rapid, non-genomic signaling and the downstream signaling cascades that may result as a consequence of steroid ligands binding the mER or the mGR. Both estrogens and glucocorticoids exert a number of actions on the hypothalamus, including feedback. This review focuses on the various candidates for the mER or mGR in the hypothalamus and the contribution of non-genomic signaling to classical hypothalamically driven behaviors and changes in neuronal morphology. It also attempts to categorize some of the possible functions of non-genomic signaling at both the cellular level and at the organismal level that are relevant for behavior, including some behaviors that are regulated by both estrogens and glucocorticoids in a potentially synergistic manner. Lastly, it attempts to show that steroid signaling via non-genomic modes may provide the organism with rapid behavioral responses to stimuli.

Creating a non-word list to match 226 of the Snodgrass standardised picture set

Creating non-word lists is a necessary but time consuming exercise often needed when conducting behavioural language tasks involving lexical decision-making or non-word reading. The following article describes the process whereby we created a list of 226 non-words matching 226 of the Snodgrass picture set (Snodgrass & Vanderwart, 1980).The non-words were matched for number of syllables, stress pattern, number of phonemes, bigram count and presence and location of the target sound when relevant.