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Tumor heterogeneity is a primary cause of treatment failure and acquired resistance in cancer patients. Even in cancers driven by a single mutated oncogene, variability in response to targeted therapies is well known. The existence of additional genomic alterations among tumor cells can only partially explain this variability. As such, nongenetic factors are increasingly seen as critical contributors to tumor relapse and acquired resistance in cancer. Here, we show that both genetic and nongenetic factors contribute to targeted drug response variability in an experimental model of tumor heterogeneity. We observe significant variability to epidermal growth factor receptor (EGFR) inhibition among and within multiple versions and clonal sublines of PC9, a commonly used EGFR mutant nonsmall cell lung cancer (NSCLC) cell line. We resolve genetic, epigenetic, and stochastic components of this variability using a theoretical framework in which distinct genetic states give rise to multiple epigenetic “basins of attraction,” across which cells can transition driven by stochastic noise. Using mutational impact analysis, single-cell differential gene expression, and correlations among Gene Ontology (GO) terms to connect genomics to transcriptomics, we establish a baseline for genetic differences driving drug response variability among PC9 cell line versions. Applying the same approach to clonal sublines, we conclude that drug response variability in all but one of the sublines is due to epigenetic differences; in the other, it is due to genetic alterations. Finally, using a clonal drug response assay together with stochastic simulations, we attribute subclonal drug response variability within sublines to stochastic cell fate decisions and confirm that one subline likely contains genetic resistance mutations that emerged in the absence of drug treatment.

Conventional metrics for assessing antiproliferative drug effect have time-dependent biases that may skew results. The drug-induced proliferation rate can be used as an alternative metric for accurate and reproducible assessment of drug performance. In vitro cell proliferation assays are widely used in pharmacology, molecular biology, and drug discovery. Using theoretical modeling and experimentation, we show that current metrics of antiproliferative small molecule effect suffer from time-dependent bias, leading to inaccurate assessments of parameters such as drug potency and efficacy. We propose the drug-induced proliferation (DIP) rate, the slope of the line on a plot of cell population doublings versus time, as an alternative, time-independent metric.

A method is presented to model cell proliferation from tracked automated time-lapse imaging of cell populations. The resulting fractional proliferation graphs permit visualization of dynamic changes in the dividing and nondividing subsets of the population. We present an integrated method that uses extended time-lapse automated imaging to quantify the dynamics of cell proliferation. Cell counts are fit with a quiescence-growth model that estimates rates of cell division, entry into quiescence and death. The model is constrained with rates extracted experimentally from the behavior of tracked single cells over time. We visualize the output of the analysis in fractional proliferation graphs, which deconvolve dynamic proliferative responses to perturbations into the relative contributions of dividing, quiescent (nondividing) and dead cells. The method reveals that the response of 'oncogene-addicted' human cancer cells to tyrosine kinase inhibitors is a composite of altered rates of division, death and entry into quiescence, a finding that challenges the notion that such cells simply die in response to oncogene-targeted therapy.

In order to precisely determine the magnesium level in a titanium reduction retort by inductive methods, many interfering influences have to be considered. By using a look-up-table method, the magnesium level can be reliably identified by taking into account the interfering effects of the titanium sponge rings forming at the walls with their unknown geometrical and electrical parameters. This new method uses a combination of numerical simulations and measurements, whereby the simulation model is calibrated so that it represents the experimental setup as closely as possible. Previously, purely theoretical studies on this method were presented. Here, the practical feasibility of that method is demonstrated by performing measurements on a model experiment. The method is not limited to the production of titanium but can also be applied to other applications in metal production and processing.

Аннотация. Экспериментально изучена одномерная динамика диска, свободно плавающего на фиксированной высоте в слое жидкости в условиях естественной конвекции, вызванной радиационным нагревом. Эксперименты показали, что динамика диска зависит от его оптических свойств. Обнаружено, что квазипериодические движения тела наблюдаются только в случае светоотражающей поверхности. Период колебаний при этом зависит как от длины полости, так и от глубины погружения диска. Светопоглощающий, либо прозрачный диск, после непродолжительных блужданий прижимается к боковой стенке и остается там до конца эксперимента.

Important role of helicity was theoretically predicted for the generation of large-scale magnetic fields and atmospheric vortices. Helicity can lead to a reduction of turbulent dissipation in the atmosphere or in a specific constrained flow, e.g. in pipe. We use the TomoPIV data (42 cube of grid points, resolution 0.84 mm) to measure 3D velocity field of turbulent swirling flows. We study spatial distribution of the mean and fluctuating components of energy and helicity. We find that helical turbulence excitation and decay along stream of the jet strongly depend on the inflow swirl. We observe spatial separation of turbulent flow with different sign of helicity while integrated values are conserves. It is shown that large scale swirling flow induces helicity at the small scales. Our results bring valuable materials for benchmark the modern numerical simulations with turbulent closure technique.

Important role of helicity was theoretically predicted for the generation of large-scale magnetic fields and atmospheric vortices. Helicity can lead to a reduction of turbulent dissipation in the atmosphere or in a specific constrained flow, e.g. in pipe. We use the TomoPIV data (42 cube of grid points, resolution 0.84 mm) to measure 3D velocity field of turbulent swirling flows. We study spatial distribution of the mean and fluctuating components of energy and helicity. We find that helical turbulence excitation and decay along stream of the jet strongly depend on the inflow swirl. We observe spatial separation of turbulent flow with different sign of helicity while integrated values are conserves. It is shown that large scale swirling flow induces helicity at the small scales. Our results bring valuable materials for benchmark the modern numerical simulations with turbulent closure technique.

Liquid metal flows, generated in a cylindrical cell by a strong electric current flowing from the central bottom electrode to the sidewall, are studied experimentally and numerically. In the absence of an external magnetic field, the flow is caused by the interaction of the electric current with its own magnetic field and is known as electro-vortex flows (EVF), which has a pure poloidal configuration. It is also well known that even a relatively weak azimuthal force (which immediately arises if a vertical external magnetic field is applied) induces a swirl that completely changes the structure of the flow, suppressing the poloidal motion (Davidson et al. , Eur. J. Mech. B Fluids , vol. 18, 1999, pp. 693–711). We study the steady-state modes and analyse the dynamics of transient modes, following the evolution of the flow structure at different ratios of azimuthal and poloidal Lorentz forces, governed by the applied current and vertical magnetic field. In the considered problem, the peculiarities of transient modes, leading to the suppression of the poloidal flow, are associated with the fact that the domain of acting forces is localized in the vicinity of the bottom electrode. The scenario of flow evolution strongly depends on the ratio of electro-vortex and rotational forces (whether the EVF has time to form before a noticeable swirl of the metal, or the swirl dominates from the beginning of flow evolution).

We present a concept for using long-wavelength broadband radio continuum observations of spiral galaxies to isolate magnetic structures that were only previously accessible from short-wavelength observations. The approach is based on combining the RM Synthesis technique with the 2D continuous wavelet transform. Wavelet analysis helps to isolate and recognize small-scale structures which are produced by Faraday dispersion. We find that these structures can trace galactic magnetic arms as illustrated by the case of the galaxy NGC 6946 observed at λ = 17 − 22 cm. We support this interpretation through the analysis of a synthetic observation obtained using a realistic model of a galactic magnetic field.

The paper presents the results of an experimental and numerical study of turbulent thermal convection in a rectangular box containing an extended immersed free-floating plate. Varying the values of control parameters, such as Rayleigh number, aspect ratio and vertical position of the plate, provides a wide range of possible modes, from immobile and purely periodic to stochastic. We have shown that stable periodic motions occur when the plate floats close to one of the heat exchangers. An increase in the distance between the plate and the heat exchanger breaks the periodic motion and (at moderate Rayleigh numbers) leads to a pronounced asymmetry, when the plate stays close to one of the walls most of the time, makes rare excursions to the opposite wall and immediately returns. As the Rayleigh number increases, the plate motions from one edge of the box to the other reappear, but always have an irregular character. Regarding the dependence of the system behaviour on the geometry of the box, both lower and upper limits of periodic plate motions were found in the experiments. In the numerical simulations, the upper limit was not achieved – the plate moves quasi-periodically through the chain of vortices of different signs even at the largest aspect ratio being considered. The heat-insulating floating plate provides the spatial and temporal variation of the heat flux and reduces the integral heat flux, but the reduction in heat flux depends significantly on the vertical position of the plate.