Palmitoylation And Polarity: Regulation Of Asymmetric Partitioning Of Notch And Wnt Signaling By Reversible Lipid Modification In Dividing Cells

Protein palmitoylation is a reversible lipid modification that regulates protein-membrane interaction, activity, trafficking, and stability in a spatio-temporal manner similar to phosphorylation and ubiquitination. Asymmetric cell division results in two distinctly fated daughter cells, by unequally partitioning proteins known as cell fate determinants. I have characterized a mechanism for protein palmitoylation to asymmetrically partition cell fate determinants, e.g. Numb and β-catenin, through the activity of the depalmitoylating enzyme APT1. Using point mutations, I have found specific palmitoylated residues on Numb are required for its asymmetric localization in dividing cells. By live-cell imaging, I have also identified a reciprocal interaction between APT1 and the Rho family GTPase, CDC42, which promotes asymmetric localization of Numb and β-catenin to the plasma membrane. In turn, this mechanism restricts Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, I show that altering APT1 expression levels alters the transcriptional signatures of MDA-MB-231 triple receptor-negative breast cancer cells, resembling altered Notch and β-catenin-mediated Wnt signaling. Furthermore, loss of APT1 depletes a specific subpopulation of tumorigenic cells. Together, this dissertation presents palmitoylation as a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions

Addressing Cognitive Decline: Evaluating the Effects of a Cognitive Training Program for Individuals with Mild to Moderate Cognitive Impairment

Cognitive training offers a nonpharmacological method for increasing or stabilizing cognitive functioning through the use of guided practice on a set of tasks designed to reflect particular cognitive functions, such as memory, attention, language, or executive function. The purpose of the current study was to evaluate the efficacy of a cognitive training program for individuals with mild to moderate cognitive impairment. Six participants who displayed mild to moderate cognitive impairment were recruited at a local care facility and participated in a cognitive training program that consisted of 24 sessions conducted over 12 weeks. At the request of the facility’s activities staff, the program was repeated in its entirety a second time. Thus, participants were evaluated with a battery of neuropsychological assessments in a pre-post-secondary-post manner. Effect size data indicates that the cognitive training program offers promise for improvement or stabilization on a number of cognitive domains, although patterns are variable. Results of this study suggest that this cognitive training program may be a useful tool for individuals with mild cognitive impairment

Alocação ótima de compensação de potência reativa

Este trabalho propõe uma metodologia para enumerar soluções, que indiquem a barra e a compensação de potência reativa necessária para o sistema elétrico sob análise, que atendam aos requisitos avaliados pela função objetivo e as restrições. Nessa alocação de compensação ótima de potência reativa, obtemos as melhores barras e configurações de potências e tecnologias de dispositivos de compensação, minimizando as perdas totais de potência ativa da rede. Em redes fracas com conversores de frequência (por exemplo, para conexão de fontes renováveis, ou interligações utilizando conversores HVDC), esta metodologia proposta busca a melhor relação de curto-circuito trifásico (SCR) no ponto de conexão do conversor de frequência, melhorando a conexão da barra de interesse. O método busca soluções para alocar um único dispositivo de compensação, e soluções alocando simultaneamente dois dispositivos. A metodologia proposta baseia-se na enumeração exaustiva das soluções, e o estudo de caso nos sistemas de 14 e 30 barras do IEEE mostrou a aplicabilidade e funcionalidade da metodologia proposta.This work proposes a methodology to enumerate solutions, which indicate the bar and the reactive power compensation required for the electrical system under analysis, that meet the requirements evaluated by the objective function and the constraints. In this allocation of optimal compensation of reactive power, we obtain the optimal bars and technologies of compensation devices, minimizing the total losses of active power of the network. In weak networks with frequency converters (e.g. for connection of renewable sources, or interconnections using HVDC converters), the proposed methodology seeks the best threephase short-circuit (SCR) relation at the connection point, improving the connection of the new generation. The method looks for solutions to allocate a single compensation device, and solutions to allocate two devices simultaneously. The proposed methodology is based on the exhaustive enumeration of the solutions. A case study carried out in the IEEE 14 and 30 bus systems shows the applicability and performance of the proposed methodology

Um dado problema de argumentação na decisão “artificial” : seria possível uma fundamentação algorítmica?

Tendo em vista a crescente utilização de Inteligência Artificial dentro do sistema de justiça que, diante da massiva demanda, fez-se necessária para minimizar a morosidade dos atos processuais, sendo utilizada em diversos tribunais e escritórios de advocacia, seja em sua forma preditiva (estatística) quanto descritiva (fazendo sugestões de decisões), o presente estudo trata sobre a possibilidade da fundamentação algorítmica dentro da decisão judicial automatizada. Para tanto, foi necessário investigar o funcionamento de um sistema de Inteligência Artificial, analisar as possibilidades e os riscos e benefícios de uma decisão algorítmica, bem como identificar as questões éticas envolvendo a decisão judicial, principalmente no que tange à fundamentação da decisão judicial. Desta forma, realizou-se uma pesquisa exploratória e qualitativa, a qual baseia-se na pesquisa bibliográfica e revisão de literatura, utilizando-se artigos, trabalhos monográficos e doutrinas especializadas, bem como na análise de artigos de lei.In view of the growing use of Artificial Intelligence within the justice system, which, given the massive demand, became necessary to minimize the length of procedural acts, being used in several courts and law firms, either in its predictive form (statistics or ) and descriptive (making suggestions for decisions), the present study deals with the possibility of algorithmic reasoning within the automated judicial decision. Therefore, it was necessary to investigate the functioning of an Artificial Intelligence system, analyze the possibilities and the risks and benefits of an algorithmic decision, as well as identify the ethical issues involving the judicial decision, especially regarding the reasoning of the judicial decision. In this way, an exploratory and qualitative research was carried out, which is based on bibliographic research and literature review, using articles, monographic works and specialized doctrines, as well as the analysis of articles of law

Launching a 148m-Long Tunnel Boring Machine from a 15m-Inner Diameter Shaft

The city of Doha has grown and expanded rapidly in the last 20 years, but this growth has strained the country's infrastructure, including its aging sewerage system and treatment facilities. ASHGHAL has therefore launched several schemes which involve shallow and deep sewer tunnels and new treatment works to serve Doha's growing population in the years to come. Wakrah and Wukair Drainage Tunnel (WWDT) project scope includes 13.3 km long of bored and lined tunnel using 2 no's 5.85m Diameter Earth Pressure Balance (EPB) TBMs, 8 Shafts, adits with provisions for future connections, ancillary hydraulic structures and Odour Control Facility. Based on WWDT project restrictions the Contractor was required to launch a 148m long Tunnel Boring Machine (TBM) inside a 15m Diameter shaft at a depth of 59.4m. This paper describes how the WWDT project contractor overcame these constraints and successfully launched both TBMs. The TBM launch and commissioning were a contract milestone. The methodology used involved partially mining a stub adit/logistics tunnels using a Sequential Excavation Method (SEM) to accommodate several TBM sections at the bottom of the shaft at the same time several of the TBM gantries were operational on the surface umbilically connected to the cutterhead. This paper will also provide a brief overview of 2 types of TBM launches used recently in Qatar for comparison.The writers acknowledge PWA (client) and PHM-JV (PORR-HBK-MIDMAC) for all the construction and design efforts and Parsons International Ltd. for actively supervising the project

The Effects of Cognitive Training Program for Cognitively Impaired Older Adults: A Pilot Randomized Control Trial

Objective: This pilot investigation evaluated the effectiveness of a cognitive training program for older adults with cognitive impairment.Methods: A sample of 23 individuals were randomly assigned to either a 24-session cognitive training program or a wait-list control group. Cognitive training sessions required participants to complete activities that targeted the following cognitive domains: attention, visual and verbal memory, visual spatial skills, processing speed, executive functioning, and language. A battery of cognitive tests were administered prior to and immediately after completion of the program. Depression, quality of life, agitated behavior, and daily functioning were also assessed.Results: Small to large effect sizes on half of the cognitive outcome measures were observed following participation in the program. No positive effects were found with regard to non-cognitive outcomes.Discussion: These results warrant further investigation into the benefits of this cognitive training program in larger randomized control trials.Clinical Implications: The cognitive training program may provide activity staff in assisted living or memory care settings a highly structured, manualized, and user-friendly intervention for older adults experiencing cognitive decline

Rescue and Regrowth of Sensory Nerves Following Deafferentation by Neurotrophic Factors

Trauma and loss of cochlear inner hair cells causes a series of events that result first in the retraction of the peripheral processes of the auditory nerve, scar formation in the organ of Corti, and over the course of weeks to months (depending on the species) the loss of auditory nerve cell bodies (spiral ganglion cells). Neurotrophic factors play an important role in the mature nervous system as survival factors for maintenance and protection and also can play a role in regrowth. Studies in the cochlea now show that application of exogenous neurotrophic factors can enhance survival of spiral ganglion cells after deafness and induce regrowth of peripheral processes, perhaps by replacing lost endogenous factors. Combinations of factors may be most effective for achieving greatest survival and regrowth. Our studies find that brain-derived neurotrophic factor (BDNF) and glial-line-derived neurotrophic factor (GDNF) are very effective at enhancing spiral ganglion cell survival following deafness from ototoxic drugs or noise. It has also been found that BDNF plus fibroblast growth factor (FGF) is very effective at inducing process regrowth. Electrical stimulation also acts to enhance spiral ganglion cell survival, and the combination of electrical stimulation and neurotrophic factors could prove a most effective intervention.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73558/1/j.1749-6632.1999.tb08650.x.pd

Programa de Educación Tutorial en salud bucal : la experiencia en atención primaria en el centro de salud de Itapoã-DF

Este artigo apresenta o relato de experiência do Programa de Educação Tutorial em Odontologia da Universidade de Brasília, durante o período de março a dezembro de 2010. O cenário de prática das atividades de campo é a Regional Administrativa do Itapoã, no Distrito Federal, e a atuação do grupo tutorial acontece junto às Equipes de Saúde da Família por meio de rotinas educativo-preventivas em saúde bucal durante as visitas domiciliares, atividades clínicas e desenvolvimento de pesquisas. Alunos e preceptores estão sendo capazes de reconhecer os determinantes sociais do processo saúdedoença, analisar os indicadores de saúde bucal da população, aprimorar práticas educativas utilizadas na Estratégia Saúde da Família e promover saúde no âmbito da comunidade. As principais dificuldades encontradas dizem respeito a limitação de espaço físico e de recursos capazes de atender a demanda do grupo tutorial e das famílias assistidas. Esta experiência tutorial junto à Estratégia Saúde da Família possibilita um aprendizado que vai muito mais além do que a tradição de ensino bio-tecnicista da odontologia, bem como permite aos discentes de odontologia da UnB ‘vivenciar uma experiência real’ e refletir sobre os conhecimentos teóricos obtidos nos ‘bancos da universidade’. _________________________________________________________________________________________________________________ ABSTRACTThis paper presents an experience report of the Tutorial Program in Dentistry from the University of Brasília, during the period from March to December, 2010. The scenario of practice is the Itapoã - an Administrative Area of the Distrito Federal - and the activities of the tutorial group take place in partnership with the Family Health Team through a preventive educational oral health routine during home visits, as well as clinical activities and development of research. Students and preceptors are being able to recognize the social determinants of the health-disease process, analyze oral health indicators of the population, improve educational practices and promote health within the community. The main barriers of the tutorial group are the lack of physical space and dental equipment capable of meeting the demand of the tutorial group and assisted families. This tutorial experience within the Family Health Strategy provides a learning experience that goes far beyond the tradition of teaching bio-technicalities of dentistry, as well as allows dental students real to live through a real field experience and reflect on the theoretical knowledge obtained from the ‘university seats’. _________________________________________________________________________________________________________________ RESUMENEste documento presenta el relato de la experiencia del Programa de Educación Tutorial en Odontología de la Universidad de Brasília, durante el período de Marzo a Diciembre de 2010. El escenário de práctica de las actividades de campo es el Sector Regional Administrativo de Itapoã, en el Distrito Federal, donde el trabajo del grupo tutorial acompaña el trabajo de los Equipos de Salud de la Família a través de la educación preventiva de rutina en la salud bucal de la población, mejorando las prácticas educativas utilizadas en la estrategia de salud familiar y promoviendo la salud en la comunidad. Las principales dificultades se refieren a la limitación del espacio físico y el equipo dental capaces de satisfacer la demanda del grupo tutorial y de las famílias atendidas. Esta actividad tutorial con la Estrategia de Salud de la Família ofrece una experiencia de aprendizaje que vá más allá de la tradición de la enseñanza de técnicas bio-odontológicas, así como permite a los estudiantes de odontología de la UnB “pasar una verdadera experiencia” y reflexionar sobre el conocimiento teórico obtenido en “los bancos de datos de la universidad”

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs

Tinnitus chronically affects between 10–15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6–10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis)