A Fokker-Planck formalism for diffusion with finite increments and absorbing boundaries

Gaussian white noise is frequently used to model fluctuations in physical systems. In Fokker-Planck theory, this leads to a vanishing probability density near the absorbing boundary of threshold models. Here we derive the boundary condition for the stationary density of a first-order stochastic differential equation for additive finite-grained Poisson noise and show that the response properties of threshold units are qualitatively altered. Applied to the integrate-and-fire neuron model, the response turns out to be instantaneous rather than exhibiting low-pass characteristics, highly non-linear, and asymmetric for excitation and inhibition. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled systems of threshold units.Comment: Consists of two parts: main article (3 figures) plus supplementary text (3 extra figures

Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells

Altered Metabolism and Persistent Starvation Behaviors Caused by Reduced AMPK Function in Drosophila

Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKγ) and through expression of a dominant negative alpha (AMPKα) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O2 consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans

Public health and economic impact of vaccination with 7-valent pneumococcal vaccine (PCV7) in the context of the annual influenza epidemic and a severe influenza pandemic

Background: Influenza pandemic outbreaks occurred in the US in 1918, 1957, and 1968. Historical evidence suggests that the majority of influenza-related deaths during the 1918 US pandemic were attributable to bacterial pneumococcal infections. The 2009 novel influenza A (H1N1) outbreak highlights the importance of interventions that may mitigate the impact of a pandemic. Methods: A decision-analytic model was constructed to evaluate the impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal disease incidence and mortality during a typical influenza season (13/100) and a severe influenza pandemic (30/100). Outcomes were compared for current PCV7 vaccination practices vs. no vaccination. The model was estimated using published sources and includes indirect (herd) protection of non-vaccinated persons. Results: The model predicts that PCV7 vaccination in the US is cost saving for a normal influenza season, reducing pneumococcal-related costs by $1.6 billion. In a severe influenza pandemic, vaccination would save$7.3 billion in costs and prevent 512,000 cases of IPD, 719,000 cases of pneumonia, 62,000 IPD deaths, and 47,000 pneumonia deaths; 84% of deaths are prevented due to indirect (herd) protection in the unvaccinated. Conclusions: PCV7 vaccination is highly effective and cost saving in both normal and severe pandemic influenza seasons. Current infant vaccination practices may prevent >1 million pneumococcal-related deaths in a severe influenza pandemic, primarily due to herd protection

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior