Mathematical modeling of drug-induced receptor internalization in the HER2-positive SKBR3 breast cancer cell-line

About 20% of breast cancer tumors over-express the HER2 receptor. Trastuzumab, an approved drug to treat this type of breast cancer, is a monoclonal antibody directly binding at the HER2 receptor and ultimately inhibiting cancer cell growth. The goal of our study was to understand the early impact of trastuzumab on HER2 internalization and recycling in the HER2-overexpressing breast cancer cell line SKBR3. To this end, fluorescence microscopy, monitoring the amount of HER2 expression in the plasma membrane, was combined with mathematical modeling to derive the flux of HER2 receptors from and to the membrane. We constructed a dynamic multi-compartment model based on ordinary differential equations. To account for cancer cell heterogeneity, a first, dynamic model was expanded to a second model including two distinct cell phenotypes, with implications for different conformational states of HER2, i.e. monomeric or homodimeric. Our mathematical model shows that the hypothesis of fast constitutive HER2 recycling back to the plasma membrane does not match the experimental data. It conclusively describes the experimental observation that trastuzumab induces sustained receptor internalization in cells with membrane ruffles. It is also concluded that for rare, non-ruffled (flat) cells, HER2 internalization occurs three orders of magnitude slower than for the bulk, ruffled cell population. © 2019, The Author(s)

Altered expression of immune-associated genes in first-trimester human decidua of pregnancies later complicated with hypertension or foetal growth restriction

During pregnancy the maternal immune system has to coordinate uterine spiral-artery remodelling, trophoblast invasion, and acceptance of the semi-allogenic fetus simultaneously. As dysregulation of the immune system is associated with adverse pregnancy outcomes, we analysed first-trimester deciduas of pregnancies for immune parameters in later complicated pregnancies. Higher IL6 and macrophage mRNA expression, and lower ratios of regulatory macrophages were found in first-trimester deciduas of pregnancies later complicated with pregnancy-induced hypertension. Lower Gata3 (Th2) mRNA expression was found in deciduas of pregnancies with later foetal growth restriction. Our results suggest that adverse pregnancy outcomes are associated with immunological disturbances in first-trimester deciduas. (C) 2012 Elsevier Ltd. All rights reserved

Talking quiescence: a rigorous theory that supports parallel composition, action hiding and determinisation

The notion of quiescence - the absence of outputs - is vital in both behavioural modelling and testing theory. Although the need for quiescence was already recognised in the 90s, it has only been treated as a second-class citizen thus far. This paper moves quiescence into the foreground and introduces the notion of quiescent transition systems (QTSs): an extension of regular input-output transition systems (IOTSs) in which quiescence is represented explicitly, via quiescent transitions. Four carefully crafted rules on the use of quiescent transitions ensure that our QTSs naturally capture quiescent behaviour. We present the building blocks for a comprehensive theory on QTSs supporting parallel composition, action hiding and determinisation. In particular, we prove that these operations preserve all the aforementioned rules. Additionally, we provide a way to transform existing IOTSs into QTSs, allowing even IOTSs as input that already contain some quiescent transitions. As an important application, we show how our QTS framework simplifies the fundamental model-based testing theory formalised around ioco.Comment: In Proceedings MBT 2012, arXiv:1202.582

Diagnostics of Neutron Star and Black Hole X-Ray Binaries with X-Ray Shot Widths

A statistic w, the differential coefficient of the mean absolute difference of an observed lightcurve, is proposed for timescale analysis of shot widths. The shortest width of random shots can be measured by the position of the lower cut-off in the timescale spectrum of w. We use the statistic to analyze X-ray lightcurves from a sample of neutron star and black hole binaries and the results show that the timescale analysis can help us distinguish between neutron star binaries and black hole binaries. The analysis can further reveal the structure and dynamics of accretion disks around black holes.Comment: 17 pages, 6 figures, accepted by Ap

Parameter estimation in spatially extended systems: The Karhunen-Loeve and Galerkin multiple shooting approach

Parameter estimation for spatiotemporal dynamics for coupled map lattices and continuous time domain systems is shown using a combination of multiple shooting, Karhunen-Loeve decomposition and Galerkin's projection methodologies. The resulting advantages in estimating parameters have been studied and discussed for chaotic and turbulent dynamics using small amounts of data from subsystems, availability of only scalar and noisy time series data, effects of space-time parameter variations, and in the presence of multiple time-scales.Comment: 11 pages, 5 figures, 4 Tables Corresponding Author - V. Ravi Kumar, e-mail address: [email protected]

The nature of the intranight variability of radio-quiet quasars

We select a sample of 10 radio-quiet quasars with confirmed intranight optical variability and with available X-ray data. We compare the variability properties and the broad band spectral constraints to the predictions of intranight variability by three models: (i) irradiation of an accretion disk by a variable X-ray flux (ii) an accretion disk instability (iii) the presence of a weak blazar component. We concluded that the third model, e.g. the blazar component model, is the most promising if we adopt a cannonball model for the jet variable emission. In this case, the probability of detecting the intranight variability is within 20-80%, depending on the ratio of the disk to the jet optical luminosity. Variable X-ray irradiation mechanism is also possible but only under additional requirement: either the source should have a very narrow Hbeta line or occasional extremely strong flares should appear at very large disk radii.Comment: MNRAS (in press

Limitations of the nested reverse transcriptase polymerase chain reaction on tyrosinase for the detection of malignant melanoma micrometastases in lymph nodes

The specificity and sensitivity of the nested reverse transcriptase polymerase chain reaction (RT-PCR) on tyrosinase was studied, for the detection of micrometastases of malignant melanoma. The specificity was assessed in the blood of six healthy donors, four patients with non-melanoma cancers of which one patient was treated with granulocyte-colony stimulating factor. Lymph nodes of nine patients without malignant melanoma were tested and four cell lines of various other tumours. Six of the nine non-melanoma lymph nodes were positive in this assay. The sensitivity was tested in a spike experiment in vitro, using a melanoma cell line. The detection limit was ten melanoma cells per 107peripheral blood lymphocytes. © 2000 Cancer Research Campaig

Point process model of 1/f noise versus a sum of Lorentzians

We present a simple point process model of $1/f^{\beta}$ noise, covering different values of the exponent $\beta$. The signal of the model consists of pulses or events. The interpulse, interevent, interarrival, recurrence or waiting times of the signal are described by the general Langevin equation with the multiplicative noise and stochastically diffuse in some interval resulting in the power-law distribution. Our model is free from the requirement of a wide distribution of relaxation times and from the power-law forms of the pulses. It contains only one relaxation rate and yields $1/f^ {\beta}$ spectra in a wide range of frequency. We obtain explicit expressions for the power spectra and present numerical illustrations of the model. Further we analyze the relation of the point process model of $1/f$ noise with the Bernamont-Surdin-McWhorter model, representing the signals as a sum of the uncorrelated components. We show that the point process model is complementary to the model based on the sum of signals with a wide-range distribution of the relaxation times. In contrast to the Gaussian distribution of the signal intensity of the sum of the uncorrelated components, the point process exhibits asymptotically a power-law distribution of the signal intensity. The developed multiplicative point process model of $1/f^{\beta}$ noise may be used for modeling and analysis of stochastic processes in different systems with the power-law distribution of the intensity of pulsing signals.Comment: 23 pages, 10 figures, to be published in Phys. Rev.

Correlation studies of open and closed states fluctuations in an ion channel: Analysis of ion current through a large conductance locust potassium channel

Ion current fluctuations occurring within open and closed states of large conductance locust potassium channel (BK channel) were investigated for the existence of correlation. Both time series, extracted from the ion current signal, were studied by the autocorrelation function (AFA) and the detrended fluctuation analysis (DFA) methods. The persistent character of the short- and middle-range correlations of time series is shown by the slow decay of the autocorrelation function. The DFA exponent $\alpha$ is significantly larger than 0.5. The existence of strongly-persistent long-range correlations was detected only for closed-states fluctuations, with $\alpha=0.98\pm0.02$. The long-range correlation of the BK channel action is therefore determined by the character of closed states. The main outcome of this study is that the memory effect is present not only between successive conducting states of the channel but also independently within the open and closed states themselves. As the ion current fluctuations give information about the dynamics of the channel protein, our results point to the correlated character of the protein movement regardless whether the channel is in its open or closed state.Comment: 12 pages, 5 figures; to be published in Phys. Rev.

Source-intrinsic near-infrared properties of Sgr A*: Total intensity measurements

We present a comprehensive data description for Ks-band measurements of Sgr A*. We characterize the statistical properties of the variability of Sgr A* in the near-infrared, which we find to be consistent with a single-state process forming a power-law distribution of the flux density. We discover a linear rms-flux relation for the flux-density range up to 12 mJy on a timescale of 24 minutes. This and the power-law flux density distribution implies a phenomenological, formally non-linear statistical variability model with which we can simulate the observed variability and extrapolate its behavior to higher flux levels and longer timescales. We present reasons why data with our cadence cannot be used to decide on the question whether the power spectral density of the underlying random process shows more structure at timescales between 25 min and 100 min compared to what is expected from a red noise random process.Comment: Accepted to ApJS, August 27, 201