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.

Orthographic facilitation in oral vocabulary acquisition

An experiment investigated whether exposure to orthography facilitates oral vocabulary learning. A total of 58 typically developing children aged 8-9 years were taught 12 nonwords. Children were trained to associate novel phonological forms with pictures of novel objects. Pictures were used as referents to represent novel word meanings. For half of the nonwords children were additionally exposed to orthography, although they were not alerted to its presence, nor were they instructed to use it. After this training phase a nonword-picture matching posttest was used to assess learning of nonword meaning, and a spelling posttest was used to assess learning of nonword orthography. Children showed robust learning for novel spelling patterns after incidental exposure to orthography. Further, we observed stronger learning for nonword-referent pairings trained with orthography. The degree of orthographic facilitation observed in posttests was related to children's reading levels, with more advanced readers showing more benefit from the presence of orthography.

Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including activating transcription factor 3 (Atf3), Egr1 and Ptgs2 are rapidly and transiently upregulated by endothelin-1 in cardiomyocytes. Atf3 regulates expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. Of upregulated mRNAs, expression of 23 (including Egr1, Ptgs2) was enhanced and expression of 25 was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on upregulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from dysregulation of target genes. Our data therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Can L2 learners learn new ways to conceptualise events? Evidence from motion event construal among English-speaking learners of French

This study tests Slobin’s (1996) claim that L2 learners struggle with conceptual restructuring in L2 acquisition. We suggest that learners can find themselves in four different reconceptualisation scenarios: the TRANSFER, RESTRUCTURING, CREATIVE/HYBRID and CONVERGENCE SCENARIOS. To test this proposal in the field of event conceptualisation, a comprehensive analysis was made of the frequency distribution of path, manner, caused motion and deictic verbs in narratives elicited from intermediate (N=20) and advanced learners (N=21) of French, as well as native speakers of French (N=23) and English (N=30). The productions of the intermediate level learners were found to correspond to the creative/hybrid scenario because they differed significantly in their motion expressions from English as well as French native speakers, except for path, which was verbalised in target-like ways early on. Advanced learners were found to be able to reconceptualise motion in the L2, as far as manner and path are concerned, but continued to struggle with deictic verbs and caused motion. The clearest evidence for transfer from the L1 was found in verbalisations among intermediate level learners of events which involved a boundary crossing.

Causal evidence for frontal involvement in memory target maintenance by posterior brain areas during distracter interference of visual working memory

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction.

Multi-target out-of-sequence data association: tracking using graphical models

When performing data fusion, one often measures where targets were and then wishes to deduce where targets currently are. There has been recent research on the processing of such out-of-sequence data. This research has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships among the algorithms so that any approximations made are explicit. Results for a multi-sensor scenario involving out-of-sequence data association are used to illustrate the utility of this approach in a specific context.

Multi-target out-of-sequence data association

In data fusion systems, one often encounters measurements of past target locations and then wishes to deduce where the targets are currently located. Recent research on the processing of such out-of-sequence data has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships between the algorithms so that any approximations made are explicit.

Knowledge acquisition in supply chain partnerships: the role of power

Knowledge is recognised as an important source of competitive advantage and hence there has been increasing academic and practitioner interest in understanding and isolating the factors that contribute to effective knowledge transfer between supply chain actors. The literature identifies power as a salient contributor to the effective operation of a supply chain partnership. However, there is a paucity of empirical research examining how power among actors influences knowledge acquisition and in turn the performance of supply chain partners. The aim of this research is to address this gap by examining the relationship between power, knowledge acquisition and supply chain performance among the supply chain partners of a focal Chinese steel manufacturer. A structured survey was used to collect the necessary data. Two conceptually independent variables – ‘availability of alternatives’ and ‘restraint in the use of power’ – were used to assess actual and realised power, respectively. Controlling for contingencies, we found that the flow of knowledge increased when supply chain actors had limited alternatives and when the more powerful actor exercised restraint in the use of power. Moreover, we found a positive relationship between knowledge acquisition and supply chain performance. This paper enriches the literature by empirically extending our understanding of how power affects knowledge acquisition and performance.