No evidence for an effect of testosterone administration on delay discounting in male university students

SummaryIntertemporal choices between a smaller sooner and a larger delayed reward are one of the most important types of decisions humans face in their everyday life. The degree to which individuals discount delayed rewards correlates with impulsiveness. Steep delay discounting has been associated with negative outcomes over a wide range of behaviors such as addiction. However, little is known about the biological foundations of delay discounting. Here, we examine a potential causal link between delay discounting and testosterone, a hormone which has been associated with other types of impulsive behavior. In our double-blind placebo-controlled study 91 healthy young men either received a topical gel containing 50mg of testosterone (N=46) or a placebo (N=45) before participating in a delay discounting task with real incentives. Our main finding is that a single dose administration of testosterone did not lead to significant differences in discount rates between the placebo and the testosterone group. Within groups and in the pooled sample, no significant relationship between testosterone and discount rates was observed. At the same time, we do replicate standard findings from the delay discounting literature such as a magnitude-of-rewards effect on discount rates. In sum, our findings suggest that circulating testosterone does not have a significant effect on delay discounting in young men

T160‐phosphorylated CDK2 defines threshold for HGF‐dependent proliferation in primary hepatocytes

Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF

Geothermal Casimir Phenomena

We present first worldline analytical and numerical results for the nontrivial interplay between geometry and temperature dependencies of the Casimir effect. We show that the temperature dependence of the Casimir force can be significantly larger for open geometries (e.g., perpendicular plates) than for closed geometries (e.g., parallel plates). For surface separations in the experimentally relevant range, the thermal correction for the perpendicular-plates configuration exhibits a stronger parameter dependence and exceeds that for parallel plates by an order of magnitude at room temperature. This effect can be attributed to the fact that the fluctuation spectrum for closed geometries is gapped, inhibiting the thermal excitation of modes at low temperatures. By contrast, open geometries support a thermal excitation of the low-lying modes in the gapless spectrum already at low temperatures.Comment: 8 pages, 3 figures, contribution to QFEXT07 proceedings, v2: discussion switched from Casimir energy to Casimir force, new analytical results included, matches JPhysA versio

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range

Quantitative analysis of time-resolved data in primary erythroid progenitor cells reveals that a dual negative transcriptional feedback mechanism underlies the ability of STAT5 to respond to the broad spectrum of physiologically relevant Epo concentrations

Worldline Monte Carlo for fermion models at large N_f

Strongly-coupled fermionic systems can support a variety of low-energy phenomena, giving rise to collective condensation, symmetry breaking and a rich phase structure. We explore the potential of worldline Monte Carlo methods for analyzing the effective action of fermionic systems at large flavor number N_f, using the Gross-Neveu model as an example. Since the worldline Monte Carlo approach does not require a discretized spacetime, fermion doubling problems are absent, and chiral symmetry can manifestly be maintained. As a particular advantage, fluctuations in general inhomogeneous condensates can conveniently be dealt with analytically or numerically, while the renormalization can always be uniquely performed analytically. We also critically examine the limitations of a straightforward implementation of the algorithms, identifying potential convergence problems in the presence of fermionic zero modes as well as in the high-density region.Comment: 40 pages, 13 figure

Thermal corrections to the Casimir effect

The Casimir effect, reflecting quantum vacuum fluctuations in the electromagnetic field in a region with material boundaries, has been studied both theoretically and experimentally since 1948. The forces between dielectric and metallic surfaces both plane and curved have been measured at the 10 to 1 percent level in a variety of room-temperature experiments, and remarkable agreement with the zero-temperature theory has been achieved. In fitting the data various corrections due to surface roughness, patch potentials, curvature, and temperature have been incorporated. It is the latter that is the subject of the present article. We point out that, in fact, no temperature dependence has yet been detected, and that the experimental situation is still too fluid to permit conclusions about thermal corrections to the Casimir effect. Theoretically, there are subtle issues concerning thermodynamics and electrodynamics which have resulted in disparate predictions concerning the nature of these corrections. However, a general consensus has seemed to emerge that suggests that the temperature correction to the Casimir effect is relatively large, and should be observable in future experiments involving surfaces separated at the few micrometer scale.Comment: 21 pages, 9 eps figures, uses iopart.cls. Final version to be published in New Journal of Physics, contains Conclusion and clarified remark

Casimir forces and non-Newtonian gravitation

The search for non-relativistic deviations from Newtonian gravitation can lead to new phenomena signalling the unification of gravity with the other fundamental interactions. Various recent theoretical frameworks indicate a possible window for non-Newtonian forces with gravitational coupling strength in the micrometre range. The major expected background in the same range is attributable to the Casimir force or variants of it if dielectric materials, rather than conducting ones, are considered. Here we review the measurements of the Casimir force performed so far in the micrometre range and how they determine constraints on non-Newtonian gravitation, also discussing the dominant sources of false signals. We also propose a geometry-independent parameterization of all data in terms of the measurement of the constant c. Any Casimir force measurement should lead, once all corrections are taken into account, to a determination of the constant c which, in order to assess the accuracy of the measurement, can be compared with its more precise value known through microscopic measurements. Although the last decade of experiments has resulted in solid demonstrations of the Casimir force, the situation is not conclusive with respect to being able to discover new physics. Future experiments and novel phenomenological analysis will be necessary to discover non-Newtonian forces or to push the window for their possible existence into regions of the parameter space which theoretically appear unnatural.Comment: Also available at http://www.iop.org/EJ/abstract/1367-2630/8/10/23

Genome-Wide DNA Methylation Profiling in Early Stage I Lung Adenocarcinoma Reveals Predictive Aberrant Methylation in the Promoter Region of the Long Noncoding RNA PLUT: An Exploratory Study

Introduction: Surgical procedure is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable number of patients experience recurrence within the first 2 years after complete resection. Suitable prognostic biomarkers that identify patients at high risk of recurrence (who may probably benefit from adjuvant treatment) are still not available. This study aimed at identifying methylation markers for early recurrence that may become important tools for the development of new treatment modalities. Methods: Genome-wide DNA methylation profiling was performed on 30 stage I lung adenocarcinomas, comparing 14 patients with early metastatic recurrence with 16 patients with a long-term relapse-free survival period using methylated-CpG-immunoprecipitation followed by high-throughput next-generation sequencing. The differentially methylated regions between the two subgroups were validated for their prognostic value in two independent cohorts using the MassCLEAVE assay, a high-resolution quantitative methylation analysis. Results: Unsupervised clustering of patients in the discovery cohort on the basis of differentially methylated regions identified patients with shorter relapse-free survival (hazard ratio: 2.23; 95% confidence interval: 0.66-7.53; p = 0.03). In two validation cohorts, promoter hypermethylation of the long noncoding RNA PLUT was significantly associated with shorter relapse-free survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93; p < 0.026) and could be reported as an independent prognostic factor in the multivariate Cox regression analysis. Conclusions: Promoter hypermethylation of the long noncoding RNA PLUT is predictive in patients with early stage I adenocarcinoma at high risk for early recurrence. Further studies are needed to validate its role in carcinogenesis and its use as a biomarker to facilitate patient selection and risk stratification

Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera

Modeling the TNFα-Induced Apoptosis Pathway in Hepatocytes

The proinflammatory cytokine TNFα fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Recently, we showed that TNFα is able to sensitize primary murine hepatocytes cultured on collagen to Fas ligand-induced apoptosis and presented a mathematical model of the sensitizing effect. Here, we analyze how TNFα induces apoptosis in combination with the transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen species (ROS) in response to TNFR activation turns out to be critical for sustained activation of JNK which then triggers mitochondrial pathway-dependent apoptosis. In addition, the amount of JNK is strongly upregulated in a ROS-dependent way. In contrast to TNFα plus cycloheximide no cFLIP degradation is observed suggesting a different apoptosis pathway in which the Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not involved. Time-resolved data of the respective pro- and antiapoptotic factors are obtained and subjected to mathematical modeling. On the basis of these data we developed a mathematical model which reproduces the complex interplay regulating the phosphorylation status of JNK and generation of ROS. This model was fully integrated with our model of TNFα/Fas ligand sensitizing as well as with a published NF-κB-model. The resulting comprehensive model delivers insight in the dynamical interplay between the TNFα and FasL pathways, NF-κB and ROS and gives an example for successful model integration