Analysis of a transcriptional network involving PU.1, Notch, and Gata3 in the lymphomyeloid lineage decision during early T-cell development

Hematopoiesis is a well-established system used to study developmental choices amongst cells with multiple lineage potentials, as well as the transcription factor network interactions that drive these developmental paths. Multipotent progenitors travel from the bone marrow to the thymus where T-cell development is initiated and these early T-cell precursors retain lineage plasticity even after initiating a T-cell program. The development of these early cells is driven by Notch signaling and the combinatorial expression of many transcription factors, several of which are also involved in the development of other cell lineages. The ETS family transcription factor PU.1 is involved in the development of progenitor, myeloid, and lymphoid cells, and can divert progenitor T-cells from the T-lineage to a myeloid lineage. This diversion of early T-cells by PU.1 can be blocked by Notch signaling. The PU.1 and Notch interaction creates a switch wherein PU.1 in the presence of Notch promotes T-cell identity and PU.1 in the absence of Notch signaling promotes a myeloid identity. Here we characterized an early T-cell cell line, Scid.adh.2c2, as a good model system for studying the myeloid vs. lymphoid developmental choice dependent on PU.1 and Notch signaling. We then used the Scid.adh.2c2 system to identify mechanisms mediating PU.1 and Notch signaling interactions during early T-cell development. We show that the mechanism by which Notch signaling is protecting pro-T cells is neither degradation nor modification of the PU.1 protein. Instead we give evidence that Notch signaling is blocking the PU.1-driven inhibition of a key set of T-regulatory genes including Myb, Tcf7, and Gata3. We show that the protection of Gata3 from PU.1-mediated inhibition, by Notch signaling and Myb, is important for retaining a T-lineage identity. We also discuss a PU.1-driven mechanism involving E-protein inhibition that leads to the inhibition of Notch target genes. This is mechanism may be used as a lockdown mechanism in pro-T-cells that have made the decision to divert to the myeloid pathway.

Panel discussion: U.S. EPA using modeling and ecosystem services to enhance coastal decision making

This panel will discuss the research being conducted, and the models being used in three current coastal EPA studies being conducted on ecosystem services in Tampa Bay, the Chesapeake Bay and the Coastal Carolinas. These studies are intended to provide a broader and more comprehensive approach to policy and decision-making affecting coastal ecosystems as well as provide an account of valued services that have heretofore been largely unrecognized. Interim research products, including updated and integrated spatial data, models and model frameworks, and interactive decision support systems will be demonstrated to engage potential users and to elicit feedback. It is anticipated that the near-term impact of the projects will be to increase the awareness by coastal communities and coastal managers of the implications of their actions and to foster partnerships for ecosystem services research and applications. (PDF contains 4 pages)

To pave or not to pave: A social landscape analysis of land use decision-making in the towns of the lamprey watershed

Population pressure in coastal New Hampshire challenges land use decision-making and threatens the ecological health and functioning of Great Bay, an estuary designated as both a NOAA National Estuarine Research Reserve and an EPA National Estuary Program site. Regional population in the seacoast has quadrupled in four decades resulting in sprawl, increased impervious surface cover and larger lot rural development (Zankel, et.al., 2006). All of Great Bay’s contributing watersheds face these challenges, resulting in calls for strategies addressing growth, development and land use planning. The communities within the Lamprey River watershed comprise this case study. Do these towns communicate upstream and downstream when making land use decisions? Are cumulative effects considered while debating development? Do town land use groups consider the Bay or the coasts in their decision-making? This presentation, a follow-up from the TCS 2008 conference and a completed dissertation, will discuss a novel social science approach to analyze and understand the social landscape of land use decision-making in the towns of the Lamprey River watershed. The methods include semi-structured interviews with GIS based maps in a grounded theory analytical strategy. The discussion will include key findings, opportunities and challenges in moving towards a watershed approach for land use planning. This presentation reviews the results of the case study and developed methodology, which can be used in watersheds elsewhere to map out the potential for moving towns towards EBM and watershed-scaled, land use planning. (PDF contains 4 pages)

Using climate extension to assist coastal decision-makers with climate adaptation

Coastal managers need accessible, trusted, tailored resources to help them interpret climate information, identify vulnerabilities, and apply climate information to decisions about adaptation on regional and local levels. For decades, climate scientists have studied the impacts that short term natural climate variability and long term climate change will have on coastal systems. For example, recent estimates based on Intergovernmental Panel on Climate Change (IPCC) warming scenarios suggest that global sea levels may rise 0.5 to 1.4 meters above 1990 levels by 2100 (Rahmstorf 2007; Grinsted, Moore, and Jevrejeva 2009). Many low-lying coastal ecosystems and communities will experience more frequent salt water intrusion events, more frequent coastal flooding, and accelerated erosion rates before they experience significant inundation. These changes will affect the ways coastal managers make decisions, such as timing surface and groundwater withdrawals, replacing infrastructure, and planning for changing land use on local and regional levels. Despite the advantages, managers’ use of scientific information about climate variability and change remains limited in environmental decision-making (Dow and Carbone 2007). Traditional methods scientists use to disseminate climate information, like peer-reviewed journal articles and presentations at conferences, are inappropriate to fill decision-makers’ needs for applying accessible, relevant climate information to decision-making. General guides that help managers scope out vulnerabilities and risks are becoming more common; for example, Snover et al. (2007) outlines a basic process for local and state governments to assess climate change vulnerability and preparedness. However, there are few tools available to support more specific decision-making needs. A recent survey of coastal managers in California suggests that boundary institutions can help to fill the gaps between climate science and coastal decision-making community (Tribbia and Moser 2008). The National Sea Grant College Program, the National Oceanic and Atmospheric Administration's (NOAA) university-based program for supporting research and outreach on coastal resource use and conservation, is one such institution working to bridge these gaps through outreach. Over 80% of Sea Grant’s 32 programs are addressing climate issues, and over 60% of programs increased their climate outreach programming between 2006 and 2008 (National Sea Grant Office 2008). One way that Sea Grant is working to assist coastal decision-makers with using climate information is by developing effective methods for coastal climate extension. The purpose of this paper is to discuss climate extension methodologies on regional scales, using the Carolinas Coastal Climate Outreach Initiative (CCCOI) as an example of Sea Grant’s growing capacities for climate outreach and extension. (PDF contains 3 pages)

Deciding to evacuate: Gathering the information to make this important decision

When hazardous storms threaten coastal communities, people need information to decide how to respond to this potential emergency. NOAA and NC Sea Grant are funding a two-year project (Risk Perceptions and Emergency Communication Effectiveness in Coastal Zones) to learn how residents, government officials, businesses and other organizations are informed and use information regarding hurricane and tropical storms. (PDF contains 4 pages)

Characterization of the neural mechanisms supporting the implementation of cognitive control in human decision making

Humans are particularly adept at modifying their behavior in accordance with changing environmental demands. Through various mechanisms of cognitive control, individuals are able to tailor actions to fit complex short- and long-term goals. The research described in this thesis uses functional magnetic resonance imaging to characterize the neural correlates of cognitive control at two levels of complexity: response inhibition and self-control in intertemporal choice. First, we examined changes in neural response associated with increased experience and skill in response inhibition; successful response inhibition was associated with decreased neural response over time in the right ventrolateral prefrontal cortex, a region widely implicated in cognitive control, providing evidence for increased neural efficiency with learned automaticity. We also examined a more abstract form of cognitive control using intertemporal choice. In two experiments, we identified putative neural substrates for individual differences in temporal discounting, or the tendency to prefer immediate to delayed rewards. Using dynamic causal models, we characterized the neural circuit between ventromedial prefrontal cortex, an area involved in valuation, and dorsolateral prefrontal cortex, a region implicated in self-control in intertemporal and dietary choice, and found that connectivity from dorsolateral prefrontal cortex to ventromedial prefrontal cortex increases at the time of choice, particularly when delayed rewards are chosen. Moreover, estimates of the strength of connectivity predicted out-of-sample individual rates of temporal discounting, suggesting a neurocomputational mechanism for variation in the ability to delay gratification. Next, we interrogated the hypothesis that individual differences in temporal discounting are in part explained by the ability to imagine future reward outcomes. Using a novel paradigm, we imaged neural response during the imagining of primary rewards, and identified negative correlations between activity in regions associated the processing of both real and imagined rewards (lateral orbitofrontal cortex and ventromedial prefrontal cortex, respectively) and the individual temporal discounting parameters estimated in the previous experiment. These data suggest that individuals who are better able to represent reward outcomes neurally are less susceptible to temporal discounting. Together, these findings provide further insight into role of the prefrontal cortex in implementing cognitive control, and propose neurobiological substrates for individual variation.

A intervenção judicial no âmbito das políticas públicas orientadas à concretização dos direitos fundamentais

O presente estudo se propõe a desvelar o espaço legítimo de controle de políticas públicas destinadas à concretização de direitos fundamentais pelo Poder Judiciário. Para tanto, inicialmente é apresentada uma teoria das políticas públicas, que compreende a busca de um conceito para a categoria e a apresentação de suas características e elementos mais relevantes. O estudo não prescinde da análise da teoria dos direitos fundamentais, em especial das questões atinentes à eficácia dos direitos ditos prestacionais, e também da chamada análise institucional, um campo de estudos recentemente reavivado nos Estados Unidos. Na segunda parte do trabalho, de natureza marcadamente propositiva, as políticas públicas são divididas segundo a sua natureza, e em seguida sugeridos diferentes níveis de controle jurídico. Para as políticas ligadas ao mínimo existencial, sustenta-se o controle por meio dos princípios da proibição da proteção insuficiente e vedação do retrocesso. Para as demais políticas públicas, o controle é analisado sob o prisma dos princípios da isonomia, eficiência e transparência. Após o estudo de questões incidentais, o trabalho segue para as modalidades de controle de políticas públicas, distinguindo-se entre o controle forte, em que a discricionariedade dos órgãos políticos é reduzida a zero, e o controle fraco, onde o Poder Judiciário apenas comprime o espaço de liberdade decisória.

O argumento pragmático ou consequencialista de cunho econômico e a modulação temporal dos efeitos das decisões do Supremo Tribunal Federal em matéria tributária

A tese analisa a relação íntima que há entre o pragmatismo ou o conseqüencialismo e a modulação temporal dos efeitos das decisões judiciais. Nesta relação, interessa ressaltar o ponto de interseção que certamente sobressai em várias ocasiões: o argumento de cunho econômico. Tal tipo de argumento pode assumir especial relevo quando do exame da oportunidade e conveniência na tomada das decisões eminentemente políticas. No âmbito jurisdicional, no entanto, o argumento pragmático ou consequencialista de cunho econômico não deve prevalecer como fundamento das decisões judiciais, especialmente cuidando-se de matéria tributária. Os problemas que centralizam o estudo podem ser colocados através das seguintes indagações: é possível que o Supremo Tribunal Federal compute, no julgamento de certa matéria tributária, argumento como o eventual rombo de X bilhões de reais que a decisão contrária ao Fisco possa acarretar para os cofres públicos? A fundamentação de eventual decisão judicial calcada exclusiva ou predominantemente em tal argumento é legítima ou ilegítima? Que importância pode ter na tomada de decisão judicial? Quando aplicada, há parâmetros a serem seguidos? Quais? Demonstramos que a prevalência de tal argumento é inadequada na seara judicial, ou seja, deve ter peso reduzido ou periférico, servindo para corroborar ou reforçar os argumentos jurídicos que centralizam o debate submetido ao exame do Poder Judiciário de modo geral, e do Supremo Tribunal Federal, de maneira particular. Em busca de esclarecer quais os principais limites e possibilidades de tal argumento, especialmente relacionando-o à modulação temporal dos efeitos da decisão judicial, explicitamos algumas regras necessárias para a sua adequada utilização, sob pena de inconcebível subversão de variados princípios e direitos fundamentais assegurados em sede constitucional. No exame das questões submetidas à apreciação da Corte Suprema em matéria tributária, o seu parâmetro consiste na maior efetividade e concretude ao texto constitucional. A modulação temporal dos efeitos se aplica a uma decisão que, declarando a inconstitucionalidade do ato normativo, se afastaria ainda mais da vontade constitucional, caso fosse aplicado o tradicional efeito ex tunc (retroativo até o nascimento da lei). Nestas situações específicas e excepcionais se justifica aplicar a modulação, com vistas a dar maior concretude e emprestar maior eficácia à Constituição. A tese proposta, ao final, consiste na reunião das regras explicitadas no trabalho e em proposta legislativa.