Regulatory activity revealed by dynamic correlations in gene expression noise

Gene regulatory interactions are context dependent, active in some cellular states but not in others. Stochastic fluctuations, or 'noise', in gene expression propagate through active, but not inactive, regulatory links^(1,2). Thus, correlations in gene expression noise could provide a noninvasive means to probe the activity states of regulatory links. However, global, 'extrinsic', noise sources generate correlations even without direct regulatory links. Here we show that single-cell time-lapse microscopy, by revealing time lags due to regulation, can discriminate between active regulatory connections and extrinsic noise. We demonstrate this principle mathematically, using stochastic modeling, and experimentally, using simple synthetic gene circuits. We then use this approach to analyze dynamic noise correlations in the galactose metabolism genes of Escherichia coli. We find that the CRP-GalS-GalE feed-forward loop is inactive in standard conditions but can become active in a GalR mutant. These results show how noise can help analyze the context dependence of regulatory interactions in endogenous gene circuits

Staircase polygons: moments of diagonal lengths and column heights

We consider staircase polygons, counted by perimeter and sums of k-th powers of their diagonal lengths, k being a positive integer. We derive limit distributions for these parameters in the limit of large perimeter and compare the results to Monte-Carlo simulations of self-avoiding polygons. We also analyse staircase polygons, counted by width and sums of powers of their column heights, and we apply our methods to related models of directed walks.Comment: 24 pages, 7 figures; to appear in proceedings of Counting Complexity: An International Workshop On Statistical Mechanics And Combinatorics, 10-15 July 2005, Queensland, Australi

Validation of Claims Data Algorithms to Identify Nonmelanoma Skin Cancer

Health maintenance organization (HMO) administrative databases have been used as sampling frames for ascertaining nonmelanoma skin cancer (NMSC). However, because of the lack of tumor registry information on these cancers, these ascertainment methods have not been previously validated. NMSC cases arising from patients served by a staff model medical group and diagnosed between 1 January 2007 and 31 December 2008 were identified from claims data using three ascertainment strategies. These claims data cases were then compared with NMSC identified using natural language processing (NLP) of electronic pathology reports (EPRs), and sensitivity, specificity, positive and negative predictive values were calculated. Comparison of claims data–ascertained cases with the NLP demonstrated sensitivities ranging from 48 to 65% and specificities from 85 to 98%, with ICD-9-CM ascertainment demonstrating the highest case sensitivity, although the lowest specificity. HMO health plan claims data had a higher specificity than all-payer claims data. A comparison of EPR and clinic log registry cases showed a sensitivity of 98% and a specificity of 99%. Validation of administrative data to ascertain NMSC demonstrates respectable sensitivity and specificity, although NLP ascertainment was superior. There is a substantial difference in cases identified by NLP compared with claims data, suggesting that formal surveillance efforts should be considered

Pure point diffraction and cut and project schemes for measures: The smooth case

We present cut and project formalism based on measures and continuous weight functions of sufficiently fast decay. The emerging measures are strongly almost periodic. The corresponding dynamical systems are compact groups and homomorphic images of the underlying torus. In particular, they are strictly ergodic with pure point spectrum and continuous eigenfunctions. Their diffraction can be calculated explicitly. Our results cover and extend corresponding earlier results on dense Dirac combs and continuous weight functions with compact support. They also mark a clear difference in terms of factor maps between the case of continuous and non-continuous weight functions.Comment: 30 page

Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates

Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS

Rigorous results on spontaneous symmetry breaking in a one-dimensional driven particle system

We study spontaneous symmetry breaking in a one-dimensional driven two-species stochastic cellular automaton with parallel sublattice update and open boundaries. The dynamics are symmetric with respect to interchange of particles. Starting from an empty initial lattice, the system enters a symmetry broken state after some time T_1 through an amplification loop of initial fluctuations. It remains in the symmetry broken state for a time T_2 through a traffic jam effect. Applying a simple martingale argument, we obtain rigorous asymptotic estimates for the expected times ~ L ln(L) and ln() ~ L, where L is the system size. The actual value of T_1 depends strongly on the initial fluctuation in the amplification loop. Numerical simulations suggest that T_2 is exponentially distributed with a mean that grows exponentially in system size. For the phase transition line we argue and confirm by simulations that the flipping time between sign changes of the difference of particle numbers approaches an algebraic distribution as the system size tends to infinity.Comment: 23 pages, 7 figure

Analysis of the Tribolium homeotic complex: insights into mechanisms constraining insect Hox clusters

The remarkable conservation of Hox clusters is an accepted but little understood principle of biology. Some organizational constraints have been identified for vertebrate Hox clusters, but most of these are thought to be recent innovations that may not apply to other organisms. Ironically, many model organisms have disrupted Hox clusters and may not be well-suited for studies of structural constraints. In contrast, the red flour beetle, Tribolium castaneum, which has a long history in Hox gene research, is thought to have a more ancestral-type Hox cluster organization. Here, we demonstrate that the Tribolium homeotic complex (HOMC) is indeed intact, with the individual Hox genes in the expected colinear arrangement and transcribed from the same strand. There is no evidence that the cluster has been invaded by non-Hox protein-coding genes, although expressed sequence tag and genome tiling data suggest that noncoding transcripts are prevalent. Finally, our analysis of several mutations affecting the Tribolium HOMC suggests that intermingling of enhancer elements with neighboring transcription units may constrain the structure of at least one region of the Tribolium cluster. This work lays a foundation for future studies of the Tribolium HOMC that may provide insights into the reasons for Hox cluster conservation