Stability of pulse-like earthquake ruptures

Pulse-like ruptures arise spontaneously in many elastodynamic rupture simulations and seem to be the dominant rupture mode along crustal faults. Pulse-like ruptures propagating under steady-state conditions can be efficiently analysed theoretically, but it remains unclear how they can arise and how they evolve if perturbed. Using thermal pressurisation as a representative constitutive law, we conduct elastodynamic simulations of pulse-like ruptures and determine the spatio-temporal evolution of slip, slip rate and pulse width perturbations induced by infinitesimal perturbations in background stress. These simulations indicate that steady-state pulses driven by thermal pressurisation are unstable. If the initial stress perturbation is negative, ruptures stop; conversely, if the perturbation is positive, ruptures grow and transition to either self-similar pulses (at low background stress) or expanding cracks (at elevated background stress). Based on a dynamic dislocation model, we develop an elastodynamic equation of motion for slip pulses, and demonstrate that steady-state slip pulses are unstable if their accrued slip $b$ is a decreasing function of the uniform background stress $\tau_\mathrm{b}$. This condition is satisfied by slip pulses driven by thermal pressurisation. The equation of motion also predicts quantitatively the growth rate of perturbations, and provides a generic tool to analyse the propagation of slip pulses. The unstable character of steady-state slip pulses implies that this rupture mode is a key one determining the minimum stress conditions for sustainable ruptures along faults, i.e., their ``strength''. Furthermore, slip pulse instabilities can produce a remarkable complexity of rupture dynamics, even under uniform background stress conditions and material properties

Pulse-like and crack-like ruptures in experiments mimicking crustal earthquakes

Theoretical studies have shown that the issue of rupture modes has important implications for fault constitutive laws, stress conditions on faults, energy partition and heat generation during earthquakes, scaling laws, and spatiotemporal complexity of fault slip. Early theoretical models treated earthquakes as crack-like ruptures, but seismic inversions indicate that earthquake ruptures may propagate in a self-healing pulse-like mode. A number of explanations for the existence of slip pulses have been proposed and continue to be vigorously debated. This study presents experimental observations of spontaneous pulse-like ruptures in a homogeneous linear-elastic setting that mimics crustal earthquakes; reveals how different rupture modes are selected based on the level of fault prestress; demonstrates that both rupture modes can transition to supershear speeds; and advocates, based on comparison with theoretical studies, the importance of velocity-weakening friction for earthquake dynamics

Number of Common Sites Visited by N Random Walkers

We compute analytically the mean number of common sites, W_N(t), visited by N independent random walkers each of length t and all starting at the origin at t=0 in d dimensions. We show that in the (N-d) plane, there are three distinct regimes for the asymptotic large t growth of W_N(t). These three regimes are separated by two critical lines d=2 and d=d_c(N)=2N/(N-1) in the (N-d) plane. For d<2, W_N(t)\sim t^{d/2} for large t (the N dependence is only in the prefactor). For 2<d<d_c(N), W_N(t)\sim t^{\nu} where the exponent \nu= N-d(N-1)/2 varies with N and d. For d>d_c(N), W_N(t) approaches a constant as t\to \infty. Exactly at the critical dimensions there are logaritmic corrections: for d=2, we get W_N(t)\sim t/[\ln t]^N, while for d=d_c(N), W_N(t)\sim \ln t for large t. Our analytical predictions are verified in numerical simulations.Comment: 5 pages, 3 .eps figures include

Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer

BACKGROUND: Genomic analysis of plasma cell-free DNA is transforming lung cancer care; however, available assays are limited by cost, turnaround time, and imperfect accuracy. Here, we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1, and other rare genotypes) were collected while on therapy and analyzed blinded to tumor genotype. Plasma NGS was carried out using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes, as well as intronic coverage for detection of ALK/ROS1 fusions. Diagnostic accuracy was compared with plasma droplet digital PCR (ddPCR) and tumor genotype. RESULTS: A total of 168 specimens from 46 patients were studied. Matched plasma NGS and ddPCR across 120 variants from 80 samples revealed high concordance of allelic fraction (R2 = 0.95). Pretreatment, sensitivity of plasma NGS for the detection of EGFR driver mutations was 100% (30/30), compared with 87% for ddPCR (26/30). A full spectrum of rare driver oncogenic mutations could be detected including sensitive detection of ALK/ROS1 fusions (8/9 detected, 89%). Studying 25 patients positive for EGFR T790M that developed resistance to osimertinib, 15 resistance mechanisms could be detected including tertiary EGFR mutations (C797S, Q791P) and mutations or amplifications of non-EGFR genes, some of which could be detected pretreatment or months before progression. CONCLUSIONS: This blinded analysis demonstrates the ability of amplicon-based plasma NGS to detect a full range of targetable genotypes in NSCLC, including fusion genes, with high accuracy. The ability of plasma NGS to detect a range of preexisting and acquired resistance mechanisms highlights its potential value as an alternative to single mutation digital PCR-based plasma assays for personalizing treatment of TKI resistance in lung cancer

Evidence for tuning adipocytes ICER levels for obesity care.

Abnormal adipokine production, along with defective uptake and metabolism of glucose within adipocytes, contributes to insulin resistance and altered glucose homeostasis. Recent research has highlighted one of the mechanisms that accounts for impaired production of adiponectin (ADIPOQ) and adipocyte glucose uptake in obesity. In adipocytes of human obese subjects and mice fed with a high fat diet, the level of the inducible cAMP early repressor (ICER) is diminished. Reduction of ICER elevates the cAMP response element binding protein (CREB) activity, which in turn increases the repressor activating transcription factor 3. In fine, the cascade triggers reduction in the ADIPOQ and GLUT4 levels, which ultimately hampers insulin-mediated glucose uptake. The c-Jun N-terminal kinase (JNK) interacting-protein 1, also called islet brain 1 (IB1), is a target of CREB/ICER that promotes JNK-mediated insulin resistance in adipocytes. A rise in IB1 and c-Jun levels accompanies the drop of ICER in white adipose tissues of obese mice when compared with mice fed with a chow diet. Other than the expression of ADIPOQ and glucose transport, decline in ICER expression might impact insulin signaling. Impairment of ICER is a critical issue that will need major consideration in future therapeutic purposes

Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets

Aims/hypothesis: Pro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL. Methods: Isolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. Results: Exposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions. Conclusions/interpretation: Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatmen

Generation and escape of local waves from the boundary of uncoupled cardiac tissue

We aim to understand the formation of abnormal waves of activity from myocardial regions with diminished cell-to-cell coupling. In route to this goal, we studied the behavior of a heterogeneous myocyte network in which a sharp coupling gradient was placed under conditions of increasing network automaticity. Experiments were conducted in monolayers of neonatal rat cardiomyocytes using heptanol and isoproterenol as means of altering cell-to-cell coupling and automaticity respectively. Experimental findings were explained and expanded using a modified Beeler-Reuter numerical model. The data suggests that the combination of a heterogeneous substrate, a gradient of coupling and an increase in oscillatory activity of individual cells creates a rich set of behaviors associated with self-generated spiral waves and ectopic sources. Spiral waves feature a flattened shape and a pin-unpin drift type of tip motion. These intercellular waves are action-potential based and can be visualized with either voltage or calcium transient measurements. A source/load mismatch on the interface between the boundary and well-coupled layers can lock wavefronts emanating from both ectopic sources and rotating waves within the inner layers of the coupling gradient. A numerical approach allowed us to explore how: i) the spatial distribution of cells, ii) the amplitude and dispersion of cell automaticity, iii) and the speed at which the coupling gradient moves in space, affects wave behavior, including its escape into well-coupled tissue.Comment: 28 pages, 10 figures, submitted to Biophysical Journa

Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets

AIMS/HYPOTHESIS: Pro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL. METHODS: Isolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. RESULTS: Exposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions. CONCLUSIONS/INTERPRETATION: Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment

Acoustic radiation controls friction: Evidence from a spring-block experiment

Brittle failures of materials and earthquakes generate acoustic/seismic waves which lead to radiation damping feedbacks that should be introduced in the dynamical equations of crack motion. We present direct experimental evidence of the importance of this feedback on the acoustic noise spectrum of well-controlled spring-block sliding experiments performed on a variety of smooth surfaces. The full noise spectrum is quantitatively explained by a simple noisy harmonic oscillator equation with a radiation damping force proportional to the derivative of the acceleration, added to a standard viscous term.Comment: 4 pages including 3 figures. Replaced with version accepted in PR

Conditions for propagation and block of excitation in an asymptotic model of atrial tissue

Detailed ionic models of cardiac cells are difficult for numerical simulations because they consist of a large number of equations and contain small parameters. The presence of small parameters, however, may be used for asymptotic reduction of the models. Earlier results have shown that the asymptotics of cardiac equations are non-standard. Here we apply such a novel asymptotic method to an ionic model of human atrial tissue in order to obtain a reduced but accurate model for the description of excitation fronts. Numerical simulations of spiral waves in atrial tissue show that wave fronts of propagating action potentials break-up and self-terminate. Our model, in particular, yields a simple analytical criterion of propagation block, which is similar in purpose but completely different in nature to the `Maxwell rule' in the FitzHugh-Nagumo type models. Our new criterion agrees with direct numerical simulations of break-up of re-entrant waves.Comment: Revised manuscript submitted to Biophysical Journal (30 pages incl. 10 figures