Multimodal, longitudinal assessment of intracortical microstimulation

The fundamental obstacle to neuroprostheses based on penetrating microstimulation is the tissue’s response to the device insertion and to the application of the electrical stimulation. Our long-term goal is to develop multichannel microstimulation of central nervous tissue for clinical therapy. The overall objective of this research is to identify the optimal parameters for a chronically implanted microstimulation device. In particular, the work presented here focuses on the effects of repeated stimulation and the reactive tissue response on the efficacy of stimulation-driven behavior. To this end, psychophysical experiments were performed using multichannel cortical implants in the auditory cortex of rats. Further, we investigated the effect of the device–tissue interfacial quality on the psychophysical threshold. Here, we report the effects of cortical depth, days postimplant on the psychophysical threshold of auditory cortical microstimulation, along with correlated impedance spectral changes and post vivo histology. We expect that these data will further enable neuroprosthetic development

Optogenetic inhibitor of the transcription factor CREB

Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue light controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events

Optogenetic inhibitor of the transcription factor CREB

Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue light controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events

Bilateral Remote Ischemic Conditioning in Children:a two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis.Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants.Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 μg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 μg/L/h, n = 58) (mean difference, 13.2 μg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups.Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

Constraining the Age-Activity Relation for Cool Stars: The SDSS DR5 Low-Mass Star Spectroscopic Sample

We present a spectroscopic analysis of over 38,000 low-mass stars from the Sloan Digital Sky Survey (SDSS) Data Release 5 (DR5). Analysis of this unprecedentedly large sample confirms the previously detected decrease in the fraction of magnetically active stars (as traced by H-alpha emission) as a function of vertical distance from the Galactic Plane. The magnitude and slope of this effect varies as a function of spectral type. Using simple 1-D dynamical models, we demonstrate that the drop in activity fraction can be explained by thin disk dynamical heating and a rapid decrease in magnetic activity. The timescale for this rapid activity decrease changes according to the spectral type. By comparing our data to the simulations, we calibrate the age-activity relation at each M dwarf spectral type. We also present evidence for a possible decrease in the metallicity as a function of height above the Galactic Plane. In addition to our activity analysis, we provide line measurements, molecular band indices, colors, radial velocities, 3-D space motions and mean properties as a function of spectral type for the SDSS DR5 low-mass star sample.Comment: 10 pages, 10 figures. Accepted for publication in A

MIDA boronates are hydrolysed fast and slow by two different mechanisms

MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative 'neutral' hydrolysis does not require an exogenous acid or base and involves rate-limiting B-N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by (18)O incorporation. Whether hydrolysis is 'fast' or 'slow' is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis

Livro didático público paranaense "lingua portuguesa e literatura" : o professor-autor e o gênero discursivo

Orientadora: Profa. Dra. Iara Bemquerer CostaAutor não autorizou a divulgação do arquivo digitalTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Humanas, Letras e Artes, Programa de Pós-Graduação em Letras. Defesa: Curitiba, 23/04/2012Bibliografia: fls. 163-178Área de concentração :Resumo: Esta pesquisa descritivo-explicativa tem como objetivo averiguar a relacao dialogica entre o Livro Didatico Publico Paranaense \Lingua Portuguesa e Literatura. (LDP-PR) e os livros representantes do genero discursivo Livro Didatico de Lingua Portuguesa (LD-LP). A partir de uma perspectiva socio-historico-discursiva e empregando fontes bibliografica e documental, desenvolvemos esta pesquisa em duas etapas. Na primeira, procuramos efetuar uma reflexao teorica sobre os Generos Discursivos (BAKHTIN) e sobre como a abordagem sociointeracionista se apropria desta concepcao bakhtiniana e discute a questao da didatizacao dos generos (SCHNEUWLY e DOLZ). Na segunda, aplicamos estes pressupostos ao LDP-PR com o intuito de averiguar o encaminhamento didatico dado aos textos de generos discursivos empregados neste material didatico. A partir desta averiguacao do conteudo tematico do LDP-PR, realizada pelo trabalho com as praticas de leitura, escrita e oralidade, buscamos sustentacao para a analise deste LD como um exemplar do genero LD-LP. Nossos resultados mostram que o LDP-PR inova na escolha do conteudo tematico, mas mantem o estilo (marcado pelo emprego de discursos injuntivos, explicativos e expositivos) e a construcao composicional (de textualidade multimodal) tipicos do genero LD-LP. Creditamos a autoria multipla (constituida por professores da rede escolar), marcada pela experiencia reduzida e a merce da Secretaria de Estado da Educacao do Parana (SEED-PR) este apego ao genero consolidado.Abstract: This descriptive-explanatory research aims to investigate the dialogic relationship between the Parana‘s Public Textbook "Portuguese and Literature" (LDP-PR) and the representative books of the discursive genre of Portuguese Textbook (LP-LD). From a socio-historic-discursive perspective and by the use of bibliographical and documentary sources, we developed this research in two stages. In the first one, we carried out a theoretical reflection about the Discursive Genres (BAKHTIN) and how the social interactionist approach appropriates this Bakhtinian concept and discusses the issue of making genre educational (SCHNEUWLY and DOLZ). In the second one, we applied these assumptions to the LDP-PR with the intent of investigating the educational directions given to the texts of discursive genres employed in such a teaching materials. From this investigation of the LDP-PR‘s thematic contents, performed through the work with reading, writing and speaking skills practices, we sought support for the analysis of this LD as an exemplar of the LD-LP genre. Our results reveal that the LDP-PR innovates the choice of the thematic content but retains the style (marked by the use of injunctive, explanatory and expository discourses) and compositional construction (multimodal textuality) that is typical of the LD-LP genre. We attribute to the multiple authorship (made up of teachers from the public educational system), marked by limited experience and at the mercy of the Parana‘s State Department of Education (SEED-PR), this attachment to the consolidated genre

Neural dysfunction during temporal discounting in paediatric Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder

Both Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD) are associated with choice impulsivity, i.e. the tendency to prefer smaller immediate rewards over larger delayed rewards. However, the extent to which this impulsivity is mediated by shared or distinct underlying neural mechanisms is unclear. Twenty-six boys with ADHD, 20 boys with OCD and 20 matched controls (aged 12–18) completed an fMRI version of an individually adjusted temporal discounting (TD) task which requires choosing between a variable amount of money now or £100 in one week, one month or one year. Activations to immediate and delayed reward choices were compared between groups using a three-way ANCOVA. ADHD patients had steeper discounting rates on the task relative to controls. OCD patients did not differ from controls or patients with ADHD. Patients with ADHD and OCD showed predominantly shared activation deficits during TD in fronto-striato-insular-cerebellar regions responsible for self-control and temporal foresight, suggesting that choice impulsivity is mediated by overlapping neural dysfunctions in both disorders. OCD patients alone showed dysfunction relative to controls in right orbitofrontal and rostrolateral prefrontal cortex, extending previous findings of abnormalities in these regions in OCD to the domain of choice impulsiveness