We show that phase-repulsive coupling eliminates oscillations in a population of synthetic genetic clocks. For this, we propose an experimentally feasible synthetic genetic network that contains phase repulsively coupled repressilators with broken temporal symmetry. As the coupling strength increases, silencing of oscillations is found to occur via the appearance of an inhomogeneous limit cycle, followed by oscillation death. Two types of oscillation death are observed: For lower couplings, the cells cluster in one of two stationary states of protein expression; for larger couplings, all cells end up in a single (stationary) cellular state. Several multistable regimes are observed along this route to oscillation death.

Purpose: Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1, and REG3A are present before clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis. Experimental Design: This nested case–control study within the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1, and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times before diagnosis and for prognosis was evaluated. Results: At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9–negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR, 2.69 and 3.15, respectively). Conclusions: CA19-9 and CA125 have encouraging sensitivity for detecting preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development. Clin Cancer Res; 21(3); 622–31. ©2014 AACR.

We consider an ensemble of coupled nonlinear noisy oscillators demonstrating in the thermodynamic limit an Ising-type transition. In the ordered phase and for finite ensembles stochastic flips of the mean field are observed with the rate depending on the ensemble size. When a small periodic force acts on the ensemble, the linear response of the system has a maximum at a certain system size, similar to the stochastic resonance phenomenon. We demonstrate this effect of system size resonance for different types of noisy oscillators and for different ensembles—lattices with nearest neighbors coupling and globally coupled populations. The Ising model is also shown to demonstrate the system size resonance.

We consider an overdamped bistable oscillator subject to the action of a biharmonic force with very different frequencies, and study the response of the system when the parameters of the high-frequency force are varied. A resonantlike behavior is obtained when the amplitude or the frequency of this force is modified in an experiment performed by means of an analog circuit. This behavior, confirmed by numerical simulations, is explained on the basis of a theoretical approach.

We report the effect of doubly stochastic resonance which appears in nonlinear extended systems if the influence of noise is twofold: A multiplicative noise induces bimodality of the mean field of the coupled network and an independent additive noise governs the dynamic behavior in response to small periodic driving. For optimally selected values of the additive noise intensity stochastic resonance is observed, which is manifested by a maximal coherence between the dynamics of the mean field and the periodic input. Numerical simulations of the signal-to-noise ratio and theoretical results from an effective two state model are in good quantitative agreement.