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Register a new userQuantitative Kinetic Models from Intravital Microcopy: A Case Study Using Hepatic Transport
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The liver performs critical physiological functions, including metabolizing and removing substances, such as toxins and drugs, from the bloodstream. Hepatotoxicity itself is intimately linked to abnormal hepatic transport and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market. For this reason, we propose to analyze, across liver compartments, the transport kinetics of fluorescein-a fluorescent marker used as a proxy for drug molecules-using intravital microscopy data. To resolve the transport kinetics quantitatively from fluorescence data, we account for the effect that different liver compartments (with different chemical properties) have on fluoresceins emission rate. To do so, we develop ordinary differential equation transport models from the data where the kinetics are related to the observable fluorescence levels by measurement parameters that vary across different liver compartments. On account of the steep non-linearities in the kinetics and stochasticity inherent to the model, we infer kinetic and measurement parameters by generalizing the method of parameter cascades. For this application, the method of parameter cascades ensures fast and precise parameter estimates from noisy time traces.
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Multifocal microscopy (MFM) offers high-speed three-dimensional imaging through the simultaneous image capture from multiple focal planes. Conventional MFM systems use a fabricated grating in the emission path for a single emission wavelength band and one set of focal plane separations. While a Spatial Light Modulator (SLM) can add more flexibility, the relatively small number of pixels in the SLM chip, cross-talk between the pixels, and aberrations in the imaging system can produce non-uniform intensity in the different axially separated image planes. We present an in situ iterative SLM calibration algorithm that overcomes these optical- and hardware-related limitations to deliver near-uniform intensity across all focal planes. Using immobilized gold nanoparticles under darkfield illumination, we demonstrate superior intensity evenness compared to current methods. We also demonstrate applicability across emission wavelengths, axial plane separations, imaging modalities, SLM settings, and different SLM manufacturers. Therefore, our microscope design and algorithms provide an alternative to fabricated gratings in MFM, as they are relatively simple and could find broad applications in the wider research community.
Semantic equivalences are used in process algebra to capture the notion of similar behaviour, and this paper proposes a semi-quantitative equivalence for a stochastic process algebra developed for biological modelling. We consider abstracting away from fast reactions as suggested by the Quasi-Steady-State Assumption. We define a fast-slow bisimilarity based on this idea. We also show congruence under an appropriate condition for the cooperation operator of Bio-PEPA. The condition requires that there is no synchronisation over fast actions, and this distinguishes fast-slow bisimilarity from weak bisimilarity. We also show congruence for an operator which extends the reactions available for a species. We characterise models for which it is only necessary to consider the matching of slow transitions and we illustrate the equivalence on two models of competitive inhibition.
Genetic and environmental factors are traditionally seen as the sole causes of congenital anomalies. In this paper we introduce a third possible cause, namely random manufacturing discrepancies with respect to ``design values. A clear way to demonstrate the existence of this component is to ``shut the two others and to see whether or not there is remaining variability. Perfect clones raised under well controlled laboratory conditions fulfill the conditions for such a test. Carried out for four different species, the test reveals a variability remainder of the order of 10%-20% in terms of coefficient of variation. As an example, the CV of the volume of E.coli bacteria immediately after binary fission is of the order of 10%. In short, ``manufacturing discrepancies occur randomly, even when no harmful mutation or environmental factors are involved. Not surprisingly, there is a strong connection between congenital defects and infant mortality. In the wake of birth there is a gradual elimination of defective units and this screening accounts for the post-natal fall of infant mortality. Apart from this trend, post-natal death rates also have humps and peaks associated with various inabilities and defects.qL In short, infant mortality rates convert the case-by-case and mostly qualitative problem of congenital malformations into a global quantitative effect which, so to say, summarizes and registers what goes wrong in the embryonic phase. Based on the natural assumption that for simple organisms (e.g. rotifers) the manufacturing processes are shorter than for more complex organisms (e.g. mammals), fewer congenital anomalies are expected. Somehow, this feature should be visible on the infant mortality rate. How this conjecture can be tested is outlined in our conclusion.
In this paper, we develop a quantitative comparison method for two arbitrary protein structures. This method uses a root-mean-square deviation (RMSD) characterization and employs a series expansion of the proteins shape function in terms of the Wigner-D functions to define a new criterion, which is called a similarity value. We further demonstrate that the expansion coefficients for the shape function obtained with the help of the Wigner-D functions correspond to structure factors. Our method addresses the common problem of comparing two proteins with different numbers of atoms. We illustrate it with a worked example.
Large-scale research endeavors can be hindered by logistical constraints limiting the amount of available data. For example, global ecological questions require a global dataset, and traditional sampling protocols are often too inefficient for a small research team to collect an adequate amount of data. Citizen science offers an alternative by crowdsourcing data collection. Despite growing popularity, the community has been slow to embrace it largely due to concerns about quality of data collected by citizen scientists. Using the citizen science project Floating Forests (http://floatingforests.org), we show that consensus classifications made by citizen scientists produce data that is of comparable quality to expert generated classifications. Floating Forests is a web-based project in which citizen scientists view satellite photographs of coastlines and trace the borders of kelp patches. Since launch in 2014, over 7,000 citizen scientists have classified over 750,000 images of kelp forests largely in California and Tasmania. Images are classified by 15 users. We generated consensus classifications by overlaying all citizen classifications and assessed accuracy by comparing to expert classifications. Matthews correlation coefficient (MCC) was calculated for each threshold (1-15), and the threshold with the highest MCC was considered optimal. We showed that optimal user threshold was 4.2 with an MCC of 0.400 (0.023 SE) for Landsats 5 and 7, and a MCC of 0.639 (0.246 SE) for Landsat 8. These results suggest that citizen science data derived from consensus classifications are of comparable accuracy to expert classifications. Citizen science projects should implement methods such as consensus classification in conjunction with a quantitative comparison to expert generated classifications to avoid concerns about data quality.
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