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At least 37 records · Page 2Linked to original sources

arXiv2007

Ascorbic acid enhances the inhibitory effect of aspirin on neuronal cyclooxygenase-2-mediated prostaglandin E2 production

In the present study, we show that ascorbic acid dose-dependently inhibited interleukin-1beta (IL-1beta)-mediated PGE2 synthesis in the human neuronal cell line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic acid had no synergistic effect along with other COX inhibitors (SC-58125 and indomethacin). The inhibition of IL-1beta-mediated PGE2 synthesis by ascorbic acid was not due to the inhibition of the expression of COX-2 or microsomal prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently (0.1-100 microM) produced a significant reduction in IL-1beta-mediated production of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable indicator of free radical formation, suggesting that the effects of ascorbic acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance of the neuronal redox status since COX activity is known to be enhanced by oxidative stress. Our results provide in vitro evidence that the neuroprotective effects of ascorbic acid may depend, at least in part, on its ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its antioxidant properties. Further, these experiments suggest that a combination of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with lower doses of aspirin, thereby avoiding the side effects of the usually high dose aspirin treatment.

q-bio.SC↗

arXiv2007

Cancer Genesis and Progression as Dynamics in Functional Landscape of Endogenous Molecular-Cellular Network

An endogenous molecular-cellular network for both normal and abnormal functions is assumed to exist. This endogenous network forms a nonlinear stochastic dynamical system, with many stable attractors in its functional landscape. Normal or abnormal robust states can be decided by this network in a manner similar to the neural network. In this context cancer is hypothesized as one of its robust intrinsic states. This hypothesis implies that a nonlinear stochastic mathematical cancer model is constructible based on available experimental data and its quantitative prediction is directly testable. Within such model the genesis and progression of cancer may be viewed as stochastic transitions between different attractors. Thus it further suggests that progressions are not arbitrary. Other important issues on cancer, such as genetic vs epigenetics, double-edge effect, dormancy, are discussed in the light of present hypothesis. A different set of strategies for cancer prevention, cure, and care, is therefore suggested.

q-bio.SC↗

arXiv2007

Membrane adhesion and domain formation

We review theoretical results for the adhesion-induced phase behavior of biomembranes. The focus is on models in which the membranes are represented as discretized elastic sheets with embedded adhesion molecules. We present several mechanism that lead to the formation of domains during adhesion, and discuss the time-dependent evolution of domain patterns obtained in Monte-Carlo simulations. The simulated pattern dynamics has striking similarities to the pattern evolution observed during T cell adhesion.

cond-mat.soft↗

arXiv2007

MAPK Cascades as Feedback Amplifiers

Interconvertible enzyme cascades, exemplified by the mitogen activated protein kinase (MAPK) cascade, are a frequent mechanism in signal transduction pathways. There has been much speculation as to the role of these pathways, and how their structure is related to their function. A common conclusion is that the cascades serve to amplify biochemical signals so that a single bound ligand molecule might produce a multitude of second messengers. Some recent work has focused on a particular feature present in some MAPK pathways -- a negative feedback loop which spans the length of the cascade. This is a feature that is shared by a man-made engineering device, the feedback amplifier. We propose a novel interpretation: that by wrapping a feedback loop around an amplifier, these cascades may be acting as biochemical feedback amplifiers which imparts i) increased robustness with respect to internal perturbations; ii) a linear graded response over an extended operating range; iii) insulation from external perturbation, resulting in functional modularization. We also report on the growing list of experimental evidence which supports a graded response of MAPK with respect to Epidermal Growth Factor. This evidence supports our hypothesis that in these circumstances MAPK cascade, may be acting as a feedback amplifier.

q-bio.MN↗

arXiv2007

The insulin-RB synapse in health and disease: cellular rocket science

Time has come for a survey of our knowledge on the physical interaction between the growth-promoting insulin molecule and retinoblastoma tumor suppressor protein (RB). Theoretical and experimental observations over the past 15 years reviewed here indicate that the insulin-RB dimer may represent an essential molecular crossroads involved in major physiological and pathological conditions. Within this system, the putative tumor suppressor insulin-degrading enzyme (IDE) should be an important modulator. Perhaps most remarkably, the abstraction of this encounter between insulin and RB, two growth-regulatory giants acting either in concert or against each other depending on the respective cellular requirements, reveals that Nature may compute in controlling cell fate and we could follow in its footsteps towards developing more efficient therapeutics as well as novel technical devices.

q-bio.BM↗

arXiv2007

Across and beyond the cell are peptide strings

Until presently, most approaches for understanding physiological or pathological phenomena have been based on the assumption that these processes start from individual cells, a concept introduced primarily by Virchow in the 19th century. Yet, it has also been increasingly recognized that this perception is insufficient, at least when it comes to grasping the mechanisms underlying largely incurable diseases such as metastatic cancer or rheumatoid arthritis. Despite this insight, even recently founded disciplines such as systems biology are still locked in this century-old mind-set of cellular building blocks and thus predictably of limited usefulness. Other studies conducted over the past years, however, suggest that there is something more fundamental to life and its various conditions than the cell: peptide strings. Here, I review the origin and nature of these sub- and trans-cellular elements as well as their potential to provide the long-sought answers hitherto inaccessible to cell biology.

q-bio.SC↗

arXiv2008

Monte Carlo simulations of proteins in cages: influence of confinement on the stability of intermediate states

We present a theoretical study of the folding of small proteins inside confining potentials. Proteins are described in the framework of an effective potential model which contains the Ramachandran angles as degrees of freedom and does not need any {\it a priori} information about the native state. Hydrogen bonds, dipole-dipole- and hydrophobic interactions are taken explicitly into account. An interesting feature displayed by this potential is the presence of some intermediates between the unfolded and native states. We consider different types of confining potentials in order to study the structural properties of proteins folding inside cages with repulsive or attractive walls. Using the Wang-Landau algorithm we determine the density of states (DOS) and analyze in detail the thermodynamical properties of the confined proteins for different sizes of the cages. We show that confinement dramatically reduces the phase space available to the protein and that the presence of intermediate states can be controlled by varying the properties of the confining potential. Cages with strongly attractive walls lead to the disappearance of the intermediate states and to a two-state folding into a less stable configuration. However, cages with slightly attractive walls make the native structure more stable than in the case of pure repulsive potentials, and the folding process occurs through intermediate configurations. In order to test the metastable states we analyze the free energy landscapes as a function of the configurational energy and of the end-to-end distance as an order parameter.

q-bio.BM↗

arXiv2007

Transcriptional pulsing and consequent stochasticity in gene expression

Transcriptional pulsing has been observed in both prokaryotes and eukaryotes and plays a crucial role in cell to cell variability of protein and mRNA numbers. The issue is how the time constants associated with episodes of transcriptional bursting impact cellular mRNA and protein distributions and reciprocally, to what extent experimentally observed distributions can be attributed to transcriptional pulsing. We address these questions by investigating the exact time-dependent solution of the Master equation for a transcriptional pulsing model of mRNA distributions. We find a plethora of results: we show that, among others, bimodal and long-tailed (power law) distributions occur in the steady state as the rate constants are varied over biologically significant time scales. Since steady state distributions may not be reached experimentally we present results for the time evolution of the distributions. Because cellular behavior is essentially determined by proteins, we investigate the effect of the different mRNA distributions on the corresponding protein distributions. We delineate the regimes of rate constants for which the protein distribution mimics the mRNA distribution and those for which the protein distribution deviates significantly from the mRNA distribution.

q-bio.QM↗

arXiv2007

Mechanical deformation of monocytic THP-1 cells : occurrence of two seqential phases with differential sensitivity to metabolic inhibitors

Blood leukocytes can exhibit extensive morphological changes during their passage through small capillary vessels. The human monocytic THP-1 cell line was used to explore the metabolic dependence of these shape changes. Cells were aspirated into micropipettes for determination of the rate of protrusion formation. They were then released and the kinetics of morphological recovery was studied. Results were consistent with Evans' model (Blood, 64 : 1028, 1984) of a viscous liquid droplet surrounded by a tensile membrane. The estimated values of cytoplasmic viscosity and membrane tension were 162 Pa.s and 0.0142 millinewton/m respectively. The influence of metabolic inhibitors on cell mechanical behaviour was then studied : results strongly suggested that deformation involved two sequential phases. The cell elongation rate measured during the first 30 seconds following the onset of aspiration was unaffected by azide, an inhibitor of energy production, and it was about doubled by cytochalasin D, a microfilament inhibitor, and colchicine, a microtubule inhibitor. However, during the following two minutes, deformation was almost abolished in cells treated with azide and cytochalasin D, whereas the protrusion of control cells exhibited about threefold length increase. It is concluded that, although cells seemed to deform as passive objects, active metabolic processes were required to allow extensive morphological changes triggered by external forces.

physics.bio-ph↗

arXiv2007

Toward a quantitative analysis of virus and plasmid trafficking in cells

Intracellular transport of DNA carriers is a fundamental step of gene delivery. We present here a theoretical approach to study generically a single virus or DNA particle trafficking in a cell cytoplasm. Cellular trafficking has been studied experimentally mostly at the macroscopic level, but very little has been done so far at the microscopic level. We present here a physical model to account for certain aspects of cellular organization, starting with the observation that a viral particle trajectory consists of epochs of pure diffusion and epochs of active transport along microtubules. We define a general degradation rate to describe the limitations of the delivery of plasmid or viral particles to the nucleus imposed by various types of direct and indirect hydrolysis activity inside the cytoplasm. Following a homogenization procedure, which consists of replacing the switching dynamics by a single steady state stochastic description, not only can we study the spatio-temporal dynamics of moving objects in the cytosol, but also estimate the probability and the mean time to go from the cell membrane to a nuclear pore. Computational simulations confirm that our model can be used to analyze and interpret viral trajectories and estimate quantitatively the success of nuclear delivery.

q-bio.QM↗

arXiv2007

Theory of fluorescence correlation spectroscopy at variable observation area for two-dimensional diffusion on a meshgrid

It has recently been proposed, with the help of numerical investigations, that fluorescence correlation spectroscopy at variable observation area can reveal the existence of a meshgrid of semi-permeable barriers hindering the two-dimensional diffusion of tagged particles, such as plasmic membrane constituents. We present a complete theory confirming and accounting for these findings. It enables a reliable, quantitative exploitation of experimental data from which the sub-wavelength mesh size can be extracted. Time scales at which fluorescence correlation spectroscopy must be performed experimentally are discussed in detail.

cond-mat.stat-mech↗

arXiv2007

Cell-permeable tumor suppressor peptides for cancer therapy: back to the future

Miniaturization is a hallmark of modern technologies. Notably, this feature has not spared molecular biology and its potential applications. Towards developing more effective therapeutics against cancer, studies began to explore more than a decade ago how natural tumor suppression could be translated into antineoplastic drugs. To this end, investigators focused on major constituents of a central pathway that protects cells against neoplastic transformation: the nuclear retinoblastoma protein (RB) pathway. As such, peptide mimetics of RB, p16 and p21 were developed. Likewise, the p53 and von Hippel-Lindau gene products which affect indirectly the RB pathway provided additional templates for the development of anti-proliferative peptides. Each of the peptides derived from these distinct tumor suppressors was made cell-permeable by its ligation to an amino acid sequence conferring cellular internalization. Details reviewed here reveal that through the application of such anti-cancer peptide therapeutics alone or in conjunction whenever synergy is to expect, the dark era of chemotherapy will likely be overcome, at last.

q-bio.BM↗

arXiv2007

Conformational equilibria in monomeric alpha-synuclein at the single molecule level

Natively unstructured proteins defy the classical "one sequence-one structure" paradigm of protein science. Monomers of these proteins in pathological conditions can aggregate in the cell, a process that underlies socially relevant neurodegenerative diseases such as Alzheimer and Parkinson. A full comprehension of the formation and structure of the so-called misfolded intermediates from which the aggregated states ensue is still lacking. We characterized the folding and the conformational diversity of alpha-synuclein (aSyn), a natively unstructured protein involved in Parkinson disease, by mechanically stretching single molecules of this protein and recording their mechanical properties. These experiments permitted us to directly observe directly and quantify three main classes of conformations that, under in vitro physiological conditions, exist simultaneously in the aSyn sample, including disordered and "beta-like" structures. We found that this class of "beta-like" structures is directly related to aSyn aggregation. In fact, their relative abundance increases drastically in three different conditions known to promote the formation of aSyn fibrils: the presence of Cu2+, the occurrence of the pathogenic A30P mutation, and high ionic strength. We expect that a critical concentration of aSyn with a "beta-like" structure must be reached to trigger fibril formation. This critical concentration is therefore controlled by a chemical equilibrium. Novel pharmacological strategies can now be tailored to act upstream, before the aggregation process ensues, by targeting this equilibrium. To this end, Single Molecule Force Spectroscopy can be an effective tool to tailor and test new pharmacological agents.

q-bio.BM↗

arXiv2007

Oncoprotein metastasis disjoined

As the past decade barely dawned, a fundamentally novel view of cancer relating to signal transduction through intracellular hormones/growth factors and their subunits began to unfold. Further along, it gained additional substance with the advent of the interdisciplinary fields of particle biology and peptide strings which explain (onco)protein dynamics in spacetime, for instance insulin-driven sub- and trans-cellular carcinogenesis, by physical principles. Here, this new understanding is expanded to introduce the concept of "oncoprotein metastasis" preceding cancer cell spread and, thereby, a particular emphasis is placed on its potential role in the emergence of the pre-metastatic niche. Consistent with this perception, yet unlike currently advocated treatments that target cancer cells only, future antineoplastic strategies should aim to mimic natural tumor suppressors as well as involve both (morphologically) normal and malignant cells. If validated in human patients with advanced cancer disease, its otherwise frequently lethal course may be halted and reversed just in time.

q-bio.SC↗

arXiv2007

Unidirectional rotary nanomotors powered by an electrochemical potential gradient

We examine the dynamics of biological nanomotors within a simple model of a rotor having three ion-binding sites. It is shown that in the presence of an external dc electric field in the plane of the rotor, the loading of the ion from the positive side of a membrane (rotor charging) provides a torque leading to the motor rotation. We derive equations for the proton populations of the sites and solve these equations numerically jointly with the Langevin-type equation for the rotor angle. Using parameters for biological systems, we demonstrate that the sequential loading and unloading of the sites lead to the unidirectional rotation of the motor. The previously unexplained phenomenon of fast direction-switching in the rotation of a bacterial flagellar motor can also be understood within our model.

cond-mat.other↗

arXiv2007

Effective Motion of a Virus Trafficking Inside a Biological Cell

Virus trafficking is fundamental for infection success and plasmid cytosolic trafficking is a key step of gene delivery. Based on the main physical properties of the cellular transport machinery such as microtubules, motor proteins, our goal here is to derive a mathematical model to study cytoplasmic trafficking. Because experimental results reveal that both active and passive movement are necessary for a virus to reach the cell nucleus, by taking into account the complex interactions of the virus with the microtubules, we derive here an estimate of the mean time a virus reaches the nucleus. In particular, we present a mathematical procedure in which the complex viral movement, oscillating between pure diffusion and a deterministic movement along microtubules, can be approximated by a steady state stochastic equation with a constant effective drift. An explicit expression for the drift amplitude is given as a function of the real drift, the density of microtubules and other physical parameters. The present approach can be used to model viral trafficking inside the cytoplasm, which is a fundamental step of viral infection, leading to viral replication and in some cases to cell damage.

q-bio.QM↗

arXiv2008

Signal duration and the time scale dependence of signal integration in biochemical pathways

Signal duration (e.g. the time scales over which an active signaling intermediate persists) is a key regulator of biological decisions in myriad contexts such as cell growth, proliferation, and developmental lineage commitments. Accompanying differences in signal duration are numerous downstream biological processes that require multiple steps of biochemical regulation. Here, we present an analysis that investigates how simple biochemical motifs that involve multiple stages of regulation can be constructed to differentially process signals that persist at different time scales. We compute the dynamic gain within these networks and resulting power spectra to better understand how biochemical networks can integrate signals at different time scales. We identify topological features of these networks that allow for different frequency dependent signal processing properties. Our studies suggest design principles for why signal duration in connection with multiple steps of downstream regulation is a ubiquitous control motif in biochemical systems.

q-bio.MN↗

arXiv2008

A microstructurally informed model for the mechanical response of three-dimensional actin networks

We propose a class of microstructurally informed models for the linear elastic mechanical behavior of cross-linked polymer networks such as the actin cytoskeleton. Salient features of the models include the possibility to represent anisotropic mechanical behavior resulting from anisotropic filament distributions, and a power-law scaling of the mechanical properties with the filament density. Mechanical models within the class are parameterized by seven different constants. We demonstrate a procedure for determining these constants using finite element models of three-dimensional actin networks. Actin filaments and cross-links were modeled as elastic rods, and the networks were constructed at physiological volume fractions and at the scale of an image voxel. We show the performance of the model in estimating the mechanical behavior of the networks over a wide range of filament densities and degrees of anisotropy.

q-bio.OT↗