Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Deletion of PKBalpha/Akt1 affects thymic development

BACKGROUND: The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether PKB mediates PI3K signaling in the thymus, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBalpha(-/-) neonates and an accumulation of early thymocyte subsets in PKBalpha(-/-) adult mice. Using thymic grafting and fetal liver cell transfer experiments, the latter finding was specifically attributed to the lack of PKBalpha within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBalpha in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. CONCLUSIONS/SIGNIFICANCE: This report highlights the specific requirements of PKBalpha for thymic development and opens up new prospects as to the mechanism downstream of PKBalpha in early thymocytes

The Independent Contribution of Neighborhood Disadvantage and Individual-Level Socioeconomic Position to Self-Reported Oral Health: A Multilevel Analysis

Objectives: To examine the association between neighborhood disadvantage and individual-level socioeconomic position (SEP) and self-reported oral health. Methods: A population-based cross-sectional study conducted in 2003 among males and females aged 43-57 years. The sample comprised 2915 individuals and 60 neighborhoods and was selected using a stratified two-stage cluster design. Data were collected using a mail survey (69.4% response rate). Neighborhood disadvantage was measured using a census based composite index, and individual-level SEP was measured using education and household income. Oral health was indicated by self-reports of the impact of oral conditions on quality of life (0=none or minor, 1=severe), self-rated oral health (0=excellent-good, 1=fair/poor) and missing teeth (measured as a quantitative outcome). Data were analyzed using multilevel modeling. Results: After adjusting for age, sex, education, and household income, residents of socioeconomically disadvantaged neighborhoods were significantly more likely than those in more advantaged neighborhoods to indicate negative impacts of oral conditions on quality of life, to assess their oral health as fair or poor, and to report greater tooth loss. In addition, respondents with low levels of education and those from a low income household reported poorer oral health for each outcome independent of neighborhood disadvantage. Conclusions: The socioeconomic characteristics of neighborhoods are important for oral health over-and-above the socioeconomic characteristics of the people living in those neighborhoods. Policies and interventions to improve population oral health should be directed at the social, physical and infrastructural characteristics of places as well as individuals (i.e. the traditional target of intervention efforts)

Nondestructive, Continuous Rapid Measurement and Control of Flock Density

A nondestructive technique for rapidly and continuously measuring the density of flocked fabric was developed and used to continuously monitor an experimental flocking range. A sensing device measured the capacitance of a capacitor when the fabric with adhesive passed through it. This value was saved and compared with the value read when the flocked substrate passed through a second transducer downstream. A process monitoring computer received these signals and output a signal to a strip chart recorder proportional to the mass of flock on the substrate. The recorded signal could then be used to control the uniformity of flock deposition on the substrate.</jats:p