Ultraviolet B radiation mediated generation of Platelet-activating factor agonists augments melanoma tumor growth

poster abstractPlatelet-activating factor (1-alkyl-2-acetyl-glycerophosphocholine; PAF) is a potent lipid mediator with diverse activities. Our previous studies have demonstrated that oxidized glycerophosphocholines (OxGPCs) that act as agonists for the Platelet-activating factor receptor (PAF-R) mediate ultraviolet B radiation (UVB) induced systemic immunosuppression in a process involving IL-10. However, the exact role of UVB-mediated systemic immunosuppression in pathophysiological processes remains unclear. The current studies sought to define whether UVB-induced systemic immunosuppression could modulate experimental murine melanoma tumor growth. Using a murine UVB model of systemic immunosuppression, we demonstrate that UVB exposure to a remote site from skin implanted with subcutaneous B16F10 melanoma results in enhanced tumor growth in C57BL/6 (wild-type) mice but not in PAF-R-deficient mice. We further show that intraperitoneal injection of the PAF agonist carbamoylPAF (CPAF) mimicked the UVB effect. Interestingly, neutralizing antibody against IL-10 blocked both CPAF- and UVB-mediated augmentation of B16F10 tumor growth. The next studies were designed to define whether the PAF-R effect was due to direct effects on B16F10 cells. Of note, B16F10 cells lack functional PAF-R expression. To address this question, we first generated PAF-R expressing B16F10 (B16-PAFR) and its vector control B16-MSCV cells by retroviral transduction and confirmed the presence of PAF-R in B16-PAF-R cells by intracellular Ca2+ flux in response to CPAF and qRT-PCR. Transplantation of B16-PAFR cells into mice did not result in an increased rate of tumor growth over control B16-MSCV cells either alone, or in response to UVB or CPAF. These studies provide a novel unreported effect of UVB-mediated PAF agonists, namely, that they can augment melanoma tumor growth via IL-10

Unravelling the size distribution of social groups with information theory on complex networks

The minimization of Fisher's information (MFI) approach of Frieden et al. [Phys. Rev. E {\bf 60} 48 (1999)] is applied to the study of size distributions in social groups on the basis of a recently established analogy between scale invariant systems and classical gases [arXiv:0908.0504]. Going beyond the ideal gas scenario is seen to be tantamount to simulating the interactions taking place in a network's competitive cluster growth process. We find a scaling rule that allows to classify the final cluster-size distributions using only one parameter that we call the competitiveness. Empirical city-size distributions and electoral results can be thus reproduced and classified according to this competitiveness, which also allows to correctly predict well-established assessments such as the "six-degrees of separation", which is shown here to be a direct consequence of the maximum number of stable social relationships that one person can maintain, known as Dunbar's number. Finally, we show that scaled city-size distributions of large countries follow the same universal distribution

Do Femtonewton Forces Affect Genetic Function? A Review

Protein-Mediated DNA looping is intricately related to gene expression. Therefore any mechanical constraint that disrupts loop formation can play a significant role in gene regulation. Polymer physics models predict that less than a piconewton of force may be sufficient to prevent the formation of DNA loops. Thus, it appears that tension can act as a molecular switch that controls the much larger forces associated with the processive motion of RNA polymerase. Since RNAP can exert forces over 20 pN before it stalls, a ‘substrate tension switch’ could offer a force advantage of two orders of magnitude. Evidence for such a mechanism is seen in recent in vitro micromanipulation experiments. In this article we provide new perspective on existing theory and experimental data on DNA looping in vitro and in vivo . We elaborate on the connection between tension and a variety of other intracellular mechanical constraints including sequence specific curvature and supercoiling. In the process, we emphasize that the richness and versatility of DNA mechanics opens up a whole new paradigm of gene regulation to explore.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41816/1/10867_2005_Article_9002.pd

Preexercise breakfast ingestion versus extended overnight fasting increases postprandial glucose flux after exercise in healthy men

The aim of this study was to characterize postprandial glucose flux after exercise in the fed versus overnight fasted state and to investigate the potential underlying mechanisms. In a randomized order, twelve men underwent breakfast-rest [(BR) 3 h semirecumbent], breakfast-exercise [(BE) 2 h semirecumbent before 60 min of cycling (50% peak power output)], and overnight fasted exercise [(FE) as per BE omitting breakfast] trials. An oral glucose tolerance test (OGTT) was completed after exercise (after rest on BR). Dual stable isotope tracers ([U-13C] glucose ingestion and [6,6-2H2] glucose infusion) and muscle biopsies were combined to assess postprandial plasma glucose kinetics and intramuscular signaling, respectively. Plasma intestinal fatty acid binding (I-FABP) concentrations were determined as a marker of intestinal damage. Breakfast before exercise increased postexercise plasma glucose disposal rates during the OGTT, from 44 g/120 min in FE {35 to 53 g/120 min [mean (normalized 95% confidence interval)] to 73 g/120 min in BE [55 to 90 g/120 min; P = 0.01]}. This higher plasma glucose disposal rate was, however, offset by increased plasma glucose appearance rates (principally OGTT-derived), resulting in a glycemic response that did not differ between BE and FE (P = 0.11). Plasma I-FABP concentrations during exercise were 264 pg/ml (196 to 332 pg/ml) lower in BE versus FE (P = 0.01). Breakfast before exercise increases postexercise postprandial plasma glucose disposal, which is offset (primarily) by increased appearance rates of orally ingested glucose. Therefore, metabolic responses to fed-state exercise cannot be readily inferred from studies conducted in a fasted state