Simple Cell Model Research Articles

Ca2+-activated Nucleotidase 1, a Novel Target Gene for the Transcriptional Repressor DREAM (Downstream Regulatory Element Antagonist Modulator), Is Involved in Protein Folding and Degradation

DREAM is a Ca(2+)-dependent transcriptional repressor highly expressed in neuronal cells. A number of genes have already been identified as the target of its regulation. Targeted analysis performed on cerebella from transgenic mice expressing a dominant active DREAM mutant (daDREAM) showed a drastic reduction of the amount of transcript of Ca(2+)-activated nucleotidase 1 (CANT1), an endoplasmic reticulum (ER)-Golgi resident Ca(2+)-dependent nucleoside diphosphatase that has been suggested to have a role in glucosylation reactions related to the quality control of proteins in the ER and the Golgi apparatus. CANT1 down-regulation was also found in neuroblastoma SH-SY5Y cells stably overexpressing wild type (wt) DREAM or daDREAM, thus providing a simple cell model to investigate the protein maturation pathway. Pulse-chase experiments demonstrated that the down-regulation of CANT1 is associated with reduced protein secretion and increased degradation rates. Importantly, overexpression of wtDREAM or daDREAM augmented the expression of the EDEM1 gene, which encodes a key component of the ER-associated degradation pathway, suggesting an alternative pathway to enhanced protein degradation. Restoring CANT1 levels in neuroblastoma clones recovered the phenotype, thus confirming a key role of CANT1, and of the regulation of its gene by DREAM, in the control of protein synthesis and degradation.

Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation

Neurodegeneration in protein-misfolding disease is generally assigned to toxic function of small, soluble protein aggregates. Largely, these assignments are based on observations of cultured neural cells where the suspect protein material is titrated directly into the growth medium. In the present study, we use this approach to shed light on the cytotoxic action of the metalloenzyme Cu/Zn superoxide dismutase 1 (SOD1), associated with misfolding and aggregation in amyotrophic lateral sclerosis (ALS). The results show, somewhat unexpectedly, that the toxic species of SOD1 in this type of experimental setting is not an aggregate, as typically observed for proteins implicated in other neuro-degenerative diseases, but the folded and fully soluble apo protein. Moreover, we demonstrate that the toxic action of apoSOD1 relies on the protein's ability to chelate Zn2+ ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn2+ homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn2+ affinity abolish completely the cytotoxic response. So does the addition of surplus Zn2+. Taken together, these observations point at a case where the toxic response of cultured cells might not be related to human pathology but stems from the intrinsic limitations of a simplified cell model. There are several ways proteins can kill cultured neural cells but all of these need not to be relevant for neurodegenerative disease.

Simulations of Complex and Microscopic Models of Cardiac Electrophysiology Powered by Multi-GPU Platforms

Key aspects of cardiac electrophysiology, such as slow conduction, conduction block, and saltatory effects have been the research topic of many studies since they are strongly related to cardiac arrhythmia, reentry, fibrillation, or defibrillation. However, to reproduce these phenomena the numerical models need to use subcellular discretization for the solution of the PDEs and nonuniform, heterogeneous tissue electric conductivity. Due to the high computational costs of simulations that reproduce the fine microstructure of cardiac tissue, previous studies have considered tissue experiments of small or moderate sizes and used simple cardiac cell models. In this paper, we develop a cardiac electrophysiology model that captures the microstructure of cardiac tissue by using a very fine spatial discretization (8 μm) and uses a very modern and complex cell model based on Markov chains for the characterization of ion channel's structure and dynamics. To cope with the computational challenges, the model was parallelized using a hybrid approach: cluster computing and GPGPUs (general-purpose computing on graphics processing units). Our parallel implementation of this model using a multi-GPU platform was able to reduce the execution times of the simulations from more than 6 days (on a single processor) to 21 minutes (on a small 8-node cluster equipped with 16 GPUs, i.e., 2 GPUs per node).

Induced dye leakage by PAMAM G6 does not imply dendrimer entry into vesicle lumen

Dendrimers are polymers with unique properties that make them promising in a variety of applications such as potential drug and gene delivery systems. Polyamidoamine (PAMAM) dendrimers, in particular, have been widely investigated since they enter rapidly into cells. The entry mechanism, however, is still not yet fully clarified as both passive and active uptake have been proposed. In this work we focus on understanding passive uptake, for which simple cell model systems are used in order to ensure that only dendrimer–lipid interactions are probed. We developed protocols for investigating independently the effect of the dendrimer on lipid bilayer integrity, in terms of permeability of small dyes and effective dendrimer translocation. This was achieved by the use of membrane labeled giant unilamellar vesicles (GUVs) either containing Alexa 488 hydrazide in the vesicle lumen or FITC-labeled PAMAM G6 dendrimers. Vesicle integrity and dendrimer–membrane binding were then assessed by fluorescence microscopy. The importance of membrane fluidity and charge was investigated using GUVs composed of various lipid compositions. A quartz crystal microbalance with dissipation was used to probe the effect of dendrimers on the rigidity of vesicle layers. The results indicate that PAMAM dendrimers can locally alter the membrane properties. An increased bilayer permeability towards soluble small dyes but no effective translocation, where PAMAM dendrimers could dissociate from the lipid membrane into the vesicle lumen, was observed. To our knowledge this is the first time it is shown that PAMAM G6 dendrimer does not effectively translocate the lipid bilayer although it readily interacts with the model membrane, regardless of lipid membrane properties. However, bilayer charge and fluidity modulate the dendrimer interaction in agreement with previous reports. The results clearly highlight the importance of the choice of the model system when investigating nanoparticles interaction with lipid membranes.

UDP-Glucuronosyltransferase (UGT) 1A9-Overexpressing HeLa Cells Is an Appropriate Tool to Delineate the Kinetic Interplay between Breast Cancer Resistance Protein (BRCP) and UGT and to Rapidly Identify the Glucuronide Substrates of BCRP

The interplay between phase II enzymes and efflux transporters leads to extensive metabolism and low bioavailability for flavonoids. To investigate the simplest interplay between one UDP-glucuronosyltransferase isoform and one efflux transporter in flavonoid disposition, engineered HeLa cells stably overexpressing UGT1A9 were developed, characterized, and further applied to investigate the metabolism of two model flavonoids (genistein and apigenin) and excretion of their glucuronides. The results indicated that the engineered HeLa cells overexpressing UGT1A9 rapidly excreted the glucuronides of genistein and apigenin. The kinetic characteristics of genistein or apigenin glucuronidation were similar with the use of UGT1A9 overexpressed in HeLa cells or the commercially available UGT1A9. Small interfering (siRNA)-mediated UGT1A9 silencing resulted in a substantial decrease in glucuronide excretion (>75%, p < 0.01). Furthermore, a potent inhibitor of breast cancer resistance protein (BCRP), 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143), caused, in a dose-dependent manner, a substantial and marked reduction of the clearance (74-94%, p < 0.01), and a substantial increase in the intracellular glucuronide levels (4-8-fold, p < 0.01), resulting in a moderate decrease in glucuronide excretion (19-59%, p < 0.01). In addition, a significant, albeit moderate, reduction in the fraction of genistein metabolized (f(met)) in the presence of Ko143 was observed. In contrast, leukotriene C₄ and siRNA against multidrug resistance protein (MRP) 2 and MRP3 did not affect excretion of flavonoid glucuronides. In conclusion, the engineered HeLa cells overexpressing UGT1A9 is an appropriate model to study the kinetic interplay between UGT1A9 and BCRP in the phase II disposition of flavonoids. This simple cell model should also be very useful to rapidly identify whether a phase II metabolite is the substrate of BCRP.

Characterizing slurry hydrodynamic transport in a large overflow tubular ball mill by an improved mixing cell model based on tracer response data

Overflow tubular ball mills are depicted by an intrinsic pool of slurry at the toe of the ball charge, which facilitates the discharge of fine progenies (finished product) from the mill. To ensure that adequate slurry removal capacity is achieved while keeping the ball charge well saturated with slurry at all times (for efficient grinding), good knowledge of slurry transport inside the mill is essential. Most existing ball mill simulation models either inadequately account for the continuous exchange of slurry between the ball charge and the slurry pool or do not consider the realities such as back-mixing or bypasses in the system thereby leading to inaccurate prediction of slurry transport. To close that gap, a model is proposed here, in which both axial and radial flow parameters as well as a short-circuit component are incorporated as an improvement to the simple mixing cell model to correctly describe the inherent in-mill slurry transport dynamics. The model fits adequately to the experimental data for all conditions tested. Further, the model results show that the slurry axial back-mixing and the radial exchange rate are both affected by slurry solids concentration and ball load volume. Also, the model reveals that under conditions of low slurry solids concentration (< 37 vol.%), a part of the feed slurry may simply short-circuit to the exit. These results just serve as a priori indication that, having correct knowledge of in-mill slurry transport dynamics would enable mill operational variables to be appropriately tuned to achieve desirable mill behavior that corresponds to maximum milling and energy efficiencies.

Luminescent spectral splitting: Efficient spatial division of solar spectrum at low concentration

The purpose of this study was to investigate the potential performance of a novel concept for dividing solar radiation into spectral components that separately illuminate photovoltaic (PV) cells of different band gaps using an optical design that (1) is simple, easily manufactured, and extensible to many spectral channels and (2) does not achieve high geometric concentration factors. The concept that we explore leverages the approach of stacked luminescent solar concentrators (LSCs) for dividing the solar spectrum using fluorophores that are tuned to different spectral bands. However, whereas multicolor LSCs must perform two functions using the same optical component—spectral division and concentration—we consider the performance of a similar design when only one demand—spectral division—is placed on it. We find that the optical quantum and power efficiencies can be quite high (QE>90%, PE>80%) compared to what one might intuitively expect. When we couple the light output to a simple detailed balance model of a solar cell using experimental performance parameters we find that solar-to-electric conversion could exceed 30% with four junctions, using existing PV materials. While this does not exceed what can be achieved by HCPV designs on multijunction epitaxially grown stacks, the concept presented here has the major advantage of being easily extensible to an arbitrarily large number of spectral channels. Because of this extensibility, the number of junctions in the system is limited only by the availability of PV cells with appropriate band gaps, so significantly higher system efficiencies should be accessible without major revision to the basic design presented here.

Phonon Frequencies of Ferroelectric Semiconductor SbSBr by First Principle Calculation

Phonon frequencies and band structure of SbSBr are calculated by first principle calculation. The results are in good agreement with the reported ones taken from Raman scattering spectra in para- and ferroelectric phases. It is shown that the simplified unit cell model used so far is valid. The band structure calculation reveals that SbSBr has an indirect gap in both phases, but that the minimum of the conduction band changes from S point to Γ-Y point in the Brillouin zone.

Suitability of V1 Energy Models for Object Classification

Simulations of cortical computation have often focused on networks built from simplified neuron models similar to rate models hypothesized for V1 simple cells. However, physiological research has revealed that even V1 simple cells have surprising complexity. Our computational simulations explore the effect of this complexity on the visual system's ability to solve simple tasks, such as the categorization of shapes and digits, after learning from a limited number of examples. We use recently proposed high-throughput methodology to explore what axes of modeling complexity are useful in these categorization tasks. We find that complex cell rate models learn to categorize objects better than simple cell models, and without incurring extra computational expense. We find that the squaring of linear filter responses leads to better performance. We find that several other components of physiologically derived models do not yield better performance.

Innovative Decision Reference Based Algorithm for Photovoltaic Maximum Power Point Tracking

A novel decision reference based method for the maximum power point tracking (MPPT) of PV arrays is presented in this paper. The proposed decision reference was derived from a simplified solar cell model. This method solves the problems of conventional MPPT algorithms, such as oscillation of the operating point at the steady state and confusion under rapidly changing insolation. It is shown by simulation and experimental results that the method properly tracks a rapidly changing insolation profile. The signal to noise ratio (SNR) of the new decision reference is also higher than those of conventional P&O and INC methods. An updating subroutine was included in the proposed MPPT algorithm to compensate for temperature and aging effects.

Processing and mechanical properties of porous Fe–26Cr–1Mo for solid oxide fuel cell interconnects

Porous, ferritic steel was produced by blending, pressing and sintering Fe, Cr, Mo and NaCl powders. During sintering NaCl evaporated to form 40–58% interconnected open porosities, while the metal powders densified and interdiffused to create a nearly dense Fe–26Cr–1Mo matrix (E-Brite, developed for solid oxide fuel cell interconnects). The foam compressive properties at ambient temperature were in good agreement with the Gibson–Ashby scaling laws for stiffness and strength and demonstrate high mechanical energy absorption. The foam compressive creep response at 850 °C under an argon atmosphere followed the same power law stress dependence as the bulk material, suggesting similar deformation mechanisms in each case. Creep data under argon were compared with a variational composite model and a simple unit cell model taking into account thicker nodes connecting slender struts.

Symmetry Sensitivities of Derivative-of-Gaussian Filters

We consider the measurement of image structure using linear filters, in particular derivative-of-Gaussian (DtG) filters, which are an important model of V1 simple cells and widely used in computer vision, and whether such measurements can determine local image symmetry. We show that even a single linear filter can be sensitive to a symmetry, in the sense that specific responses of the filter can rule it out. We state and prove a necessary and sufficient, readily computable, criterion for filter symmetry-sensitivity. We use it to show that the six filters in a second order DtG family have patterns of joint sensitivity which are distinct for 12 different classes of symmetry. This rich symmetry-sensitivity adds to the properties that make DtG filters well-suited for probing local image structure, and provides a set of landmark responses suitable to be the foundation of a nonarbitrary system of feature categories.

An analysis of current transients during electrophoretic deposition (EPD) from colloidal TiO 2 suspensions

This is a simple quantitative analysis of the electrical current transients recorded during the electrophoretic deposition (EPD) of TiO 2 particles from ethanol-based suspensions in which the linear correlation between the mass deposited and the charge passed was verified experimentally. Using this experimental knowledge as our starting point, we were able to test a simple electrical model of a deposition cell for its consistency with electrical current density data measured during EPD. Assuming that the background electrochemistry was controlled resistively rather than diffusively, we then tentatively exploited the electrochemical data to gain information on the structure of the deposit during its growth.

A Modeling Study of the Effects of Membrane Afterhyperpolarization on Spike Interval Statistics and on ILD Encoding in the Lateral Superior Olive

The lateral superior olive (LSO) is the first nucleus in the ascending auditory pathway that encodes acoustic level information from both ears, the interaural level difference (ILD). This sensitivity is believed to result from the relative strengths of ipsilateral excitation and contralateral inhibition. The study reported here simulated sound-evoked responses of LSO chopper units with a focus on the role of the heterogeneity in membrane afterhyperpolarization (AHP) channels on spike interval statistics and on ILD encoding. A relatively simplified cell model was used so that the effects of interest could be isolated. Specifically, the amplitude and time constant of the AHP conductance within a leaky integrate-and-fire (LIF) cell model were studied. This extends the work of others who used a more physiologically detailed model. Results show that differences in these two parameters lead to both the distinctive chopper response patterns and to the level-dependent interval statistics as observed in vivo. In general, diverse AHP characteristics enable an enhanced contrast across population responses with respect to rate gain and temporal correlations. This membrane heterogeneity provides an internal, cell-specific dimension for the neural representation of stimulus information, allowing sensitivity to ILDs of dynamic stimuli.

Simple Rectangular Columnar Phase of Goethite Nanorods and Its Martensitic Transition to the Centered Rectangular Columnar Phase

Using high-resolution small-angle X-ray scattering, we observed a new type of the columnar phase with a simple rectangular (R(S)) structure in colloidal goethite dispersions. Furthermore, it displays a martensitic transition into the usual centered rectangular (R(C)) structure in an external magnetic field. The findings are rationalized in terms of entropic effects within a simple cell model. We interpret the results as an effect of the particle shape and the available degrees of freedom on the delicate balance between the space available for particle translations and rotations within the two structures.

Lüttgau &amp; Niedergerke; the classic study of calcium–sodium antagonism half a century on

Lüttgau &amp; Niedergerke; the classic study of calcium–sodium antagonism half a century on

Intracellular DNA damage induced by non-thermal, intense narrowband electric fields

Intracellular DNA damages caused by intense burst sinusoidal electric fields (IBSEFs) were investigated by means of an alkaline comet assay method. Non-thermal, 200 mus-long IBSEF with various frequency values (300 kHz-100 MHz) and strengths (up to 200 kV/m) was applied to Chinese hamster ovary (CHO) cells in a suspending medium between 1 mm gap parallel electrodes. The comet assay suggests that 100 kV/m IBSEF with frequencies exceeding 1 MHz or 100 MHz IBSEFs with field strengths exceeding 3 kV/m induces significant DNA damage. According to the numerical calculation of the electric field over a simplified cell model under an alternating electric field, the intracellular field strength increases with increasing alternating frequency. The minimum level of the field strength that induces the DNA damage is in the range of 10-30 kV/m. This intracellular strong field might trigger biological processes leading to the DNA damage.

Effective thermal conductivity of various filling materials for vacuum insulation panels

Three thermal transport mechanisms of various filling materials for Vacuum Insulation Panels (VIPs) are theoretically investigated with special emphasis on the solid conduction. As the first, the solid conductivities of porous materials such as powder, foam, fiber and staggered beam subject to external atmospheric compression are derived using simplified elementary cell models. The results show that the solid conductivities of the fiber and staggered beam insulation are lower than those of the powder and foam due to the relatively long thermal path. The second mechanism, i.e., gaseous conductivity shows the lowest for the fine powder among the considered materials due to its smallest pore size. The radiative conductivity as the last is calculated using the diffusion approximation. If radiation shields are installed for the staggered beam, the radiation effect can be lowered to a negligible order of magnitude. The predicted total effective conductivities suggest that the fiber and staggered beam structures are promisingly proper filling materials for VIPs.

A neurophysiologically plausible population code model for human contrast discrimination

The pedestal effect is the improvement in the detectability of a sinusoidal grating in the presence of another grating of the same orientation, spatial frequency, and phase-usually called the pedestal. Recent evidence has demonstrated that the pedestal effect is differently modified by spectrally flat and notch-filtered noise: The pedestal effect is reduced in flat noise but virtually disappears in the presence of notched noise (G. B. Henning & F. A. Wichmann, 2007). Here we consider a network consisting of units whose contrast response functions resemble those of the cortical cells believed to underlie human pattern vision and demonstrate that, when the outputs of multiple units are combined by simple weighted summation-a heuristic decision rule that resembles optimal information combination and produces a contrast-dependent weighting profile-the network produces contrast-discrimination data consistent with psychophysical observations: The pedestal effect is present without noise, reduced in broadband noise, but almost disappears in notched noise. These findings follow naturally from the normalization model of simple cells in primary visual cortex, followed by response-based pooling, and suggest that in processing even low-contrast sinusoidal gratings, the visual system may combine information across neurons tuned to different spatial frequencies and orientations.

Depolarization‐activated calcium channels shape the calcium signatures induced by low‐temperature stress

Depolarization‐activated calcium channels shape the calcium signatures induced by low‐temperature stress