pwc-archive/papers-with-abstracts huggingface dataset:
Steady-state fluctuations of a genetic feedback loop with fluctuating rate parameters using the unified colored noise approximation
Authors: James Holehouse, Abhishek Gupta, Ramon Grima
Date: 2020-04-04 00:00:00
Tasks: Translation

A common model of stochastic auto-regulatory gene expression describes promoter switching via cooperative protein binding, effective protein production in the active state and dilution of proteins. Here we consider an extension of this model whereby colored noise with a short correlation time is added to the reaction rate parameters -- we show that when the size and timescale of the noise is appropriately chosen it accounts for fast reactions that are not explicitly modelled, e.g., in models with no mRNA description, fluctuations in the protein production rate can account for rapid multiple stages of nuclear mRNA processing which precede translation in eukaryotes. We show how the unified colored noise approximation can be used to derive expressions for the protein number distribution that is in good agreement with stochastic simulations. We find that even when the noise in the rate parameters is small, the protein distributions predicted by our model can be significantly different than models assuming constant reaction rates.
Anomalous subdiffusion in living cells: bridging the gap between experiments and realistic models through collaborative challenges
Authors: Maxime Woringer, Ignacio Izeddin, Cyril Favard, Hugues Berry
Date: 2020-04-02 00:00:00
Tasks: Art Analysis

The life of a cell is governed by highly dynamical microscopic processes. Two notable examples are the diffusion of membrane receptors and the kinetics of transcription factors governing the rates of gene expression. Different fluorescence imaging techniques have emerged to study molecular dynamics. Among them, fluorescence correlation spectroscopy (FCS) and single-particle tracking (SPT) have proven to be instrumental to our understanding of cell dynamics and function. The analysis of SPT and FCS is an ongoing effort, and despite decades of work, much progress remains to be done. In this paper, we give a quick overview of the existing techniques used to analyze anomalous diffusion in cells and propose a collaborative challenge to foster the development of state-of-the-art analysis algorithms. We propose to provide labelled (training) and unlabelled (evaluation) simulated data to competitors all over the world in an open and fair challenge. The goal is to offer unified data benchmarks based on biologically-relevant metrics in order to compare the diffusion analysis software available for the community.
Membrane morphologies induced by mixtures of arc-shaped particles with opposite curvature
Authors: Francesco Bonazzi, Carol K. Hall, Thomas R. Weikl
Date: 2020-04-02 00:00:00
Tasks: ARC

Biological membranes are shaped by various proteins that either generate inward or outward membrane curvature. In this article, we investigate the membrane morphologies induced by mixtures of arc-shaped particles with coarse-grained modeling and simulations. The particles bind to the membranes either with their inward, concave side or their outward, convex side and, thus, generate membrane curvature of opposite sign. We find that small fractions of convex-binding particles can stabilize three-way junctions of membrane tubules, as suggested for the protein lunapark in the endoplasmic reticulum of cells. For comparable fractions of concave-binding and convex-binding particles, we observe lines of particles of the same type, and diverse membrane morphologies with grooves and bulges induced by these particle lines. The alignment and segregation of the particles is driven by indirect, membrane-mediated interactions.
Cell-penetrating pepducins targeting the neurotensin receptor type 1 relieve pain
Authors: Rebecca L. Brouillette, Élie Besserer-Offroy, Christine E. Mona, Magali Chartier, Sandrine Lavenus, Marc Sousbie, Karine Belleville, Jean-Michel Longpré, Éric Marsault, Michel Grandbois, Philippe Sarret
Date: 2020-03-06 00:00:00
Tasks: Vocal Bursts Type Prediction

Pepducins are cell-penetrating, membrane-tethered lipopeptides designed to target the intracellular region of a G protein-coupled receptor (GPCR) in order to allosterically modulate the receptor's signaling output. In this proof-of-concept study, we explored the pain-relief potential of a pepducin series derived from the first intracellular loop of neurotensin receptor type 1 (NTS1), a class A GPCR that mediates many of the effects of the neurotensin (NT) tridecapeptide, including hypothermia, hypotension and analgesia. We used BRET-based biosensors to determine the pepducins' ability to engage G protein signaling pathways associated with NTS1 activation. We observed partial Gq and G13 activation at a 10 {\mu}M concentration, indicating that these pepducins may act as allosteric agonists of NTS1. Additionally, we used surface plasmon resonance (SPR) as a label-free assay to monitor pepducin-induced responses in CHO-K1 cells stably expressing hNTS1. This whole-cell integrated assay enabled us to subdivide our pepducin series into three profile response groups. In order to determine the pepducins' antinociceptive potential, we then screened the series in an acute pain model (tail-flick test) by measuring tail withdrawal latencies to a thermal nociceptive stimulus, following intrathecal pepducin administration (275 nmol/kg). We further evaluated promising pepducins in a tonic pain model (formalin test), as well as in neuropathic (Chronic Constriction Injury) and inflammatory (Complete Freund's Adjuvant) chronic pain models. We report one pepducin, PP-001, that consistently reduced rat nociceptive behaviors, even in chronic pain paradigm. Altogether, these results suggest that NTS1-derived pepducins may represent a promising strategy in pain-relief.
A Thermodynamic Model for Active Ion Transport
Authors: Xiang Zou
Date: 2020-02-09 00:00:00
Tasks: model

Active ion transport is very critical for living cells to maintain and regular internal and external environment. It is known that adenosine 5'-triphosphate (ATP) is a general energy source that applies bond energy for pumps to overcome ion concentration gradient. In this study, we introduce a novel thermodynamic model for active ion transport, which allows the pump to act as a 'Maxwell's demon', and also conforms to the second law of thermodynamics. Transport against the gradient is caused by the thermodynamic fluctuation with information recording in ATP stream. Besides, exhaustive experiments about Na-K ATPase performed in the red cell ghost system are reviewed to verify this model, and all the results can support the solvable theory about the working mechanism of demon pumps. Our findings indicate the possible role of ATP as an information carrier but not energy currency. The high-energy phosphate bonds can improve the efficiency of information recording in relevance to ion transport and may mainly convert to heat.
On the validation of Newcomb-Benford law and Weibull distribution in neuromuscular transmission
Authors: A. J. da Silva, S. Floquet, D. O. C. Santos, R. F. Lima
Date: 2020-02-05 00:00:00

The neuromuscular junction represents a relevant substrate for revealing important biophysical mechanisms of synaptic transmission. In this context, calcium ions are important in the synapse machinery, providing the nervous impulse transmission to the muscle fiber. In this work, we carefully investigated whether intervals of spontaneous electrical activity, recorded in seven different calcium concentrations, conform Newcomb-Benford law. Our analysis revealed that electrical discharge of neuromuscular junction obeys the expected values for Newcomb-Benford law for first and second digits, while first-two digits do not perfectly follows the law. We next examined previous theoretical studies, establishing a relation between the law and lognormal and Weibull distributions. We showed that Weibull distribution is more appropriate to fit the intervals as compared to lognormal distribution. Altogether, the present findings strongly suggest that spontaneous activity is a base-scale invariant phenomenon.
Modeling transport and mean age of dense core vesicles in large axonal arbors
Authors: Ivan A. Kuznetsov, Andrey V. Kuznetsov
Date: 2019-03-25 00:00:00

A model simulating transport of dense core vesicles (DCVs) in type II axonal terminals of Drosophila motoneurons has been developed. The morphology of type II terminals is characterized by the large number of en passant boutons. The lack of both scaled up DCV transport and scaled down DCV capture in boutons results in a less efficient supply of DCVs to distal boutons. Furthermore, the large number of boutons that DCVs pass as they move anterogradely, until they reach the most distal bouton, may lead to the capture of a majority of DCVs before they turn around in the most distal bouton to move in the retrograde direction. This may lead to a reduced retrograde flux of DCVs and a lack of DCV circulation in type II terminals. The developed model simulates DCV concentrations in boutons, DCV fluxes between the boutons, age density distributions of DCVs, and the mean age of DCVs in various boutons. Unlike published experimental observations, our model predicts DCV circulation in type II terminals after these terminals are filled to saturation. This disagreement is likely because experimentally observed terminals were not at steady-state, but rather were accumulating DCVs for later release. Our estimates show that the number of DCVs in the transiting state is much smaller than that in the resident state. DCVs traveling in the axon, rather than DCVs transiting in the terminal, may provide a reserve of DCVs for replenishing boutons after a release. The techniques for modeling transport of DCVs developed in our paper can be used to model the transport of other organelles in axons.
A probabilistic approach to extreme statistics of Brownian escape times in dimensions 1, 2, and 3
Authors: Sean D. Lawley, Jacob B. Madrid
Date: 2019-07-17 00:00:00

First passage time (FPT) theory is often used to estimate timescales in cellular and molecular biology. While the overwhelming majority of studies have focused on the time it takes a given single Brownian searcher to reach a target, cellular processes are instead often triggered by the arrival of the first molecule out of many molecules. In these scenarios, the more relevant timescale is the FPT of the first Brownian searcher to reach a target from a large group of independent and identical Brownian searchers. Though the searchers are identically distributed, one searcher will reach the target before the others and will thus have the fastest FPT. This fastest FPT depends on extremely rare events and its mean can be orders of magnitude faster than the mean FPT of a given single searcher. In this paper, we use rigorous probabilistic methods to study this fastest FPT. We determine the asymptotic behavior of all the moments of this fastest FPT in the limit of many searchers in a general class of two- and three-dimensional domains. We establish these results by proving that the fastest searcher takes an almost direct path to the target.
Biochemically altered human erythrocytes as a carrier for targeted delivery of primaquine: an in vitro study
Authors: Fars K. Alanazi, Gamal El-Din I. Harisa, Ahmad Maqboul, Magdi Abdel-Hamid, Steven H. Neau, Ibrahim A. Alsarra
Date: 2019-12-09 00:00:00

The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies.
Sphingolipid biosynthesis modulates plasmodesmal ultrastructure and phloem unloading
Authors: Dawei Yan, Shri Yadav, Andrea Paterlini, William Nicolas, Ilya Belevich, Magali Grison, Anne Vaten, Leila Karami, Sedeer El-Showk, Jung-Youn Lee, Gosia Murawska, Jenny Mortimer, Michael Knoblauch, Eija Jokitalo, Jonathan Markham, Emmanuelle Bayer, Ykä Helariutta
Date: 2019-12-09 00:00:00

During phloem unloading, multiple cell-to-cell transport events move organic substances to the root meristem. Although the primary unloading event from the sieve elements to the phloem pole pericycle has been characterized to some extent, little is known about post-sieve element unloading. Here, we report a novel gene, PHLOEM UNLOADING MODULATOR (PLM), in the absence of which plasmodesmata-mediated symplastic transport through the phloem pole pericycle--endodermis interface is specifically enhanced. Increased unloading is attributable to a defect in the formation of the endoplasmic reticulum--plasma membrane tethers during plasmodesmal morphogenesis, resulting in the majority of pores lacking a visible cytoplasmic sleeve. PLM encodes a putative enzyme required for the biosynthesis of sphingolipids with very-long-chain fatty acid. Taken together, our results indicate that post-sieve element unloading involves sphingolipid metabolism, which affects plasmodesmal ultrastructure. They also raise the question of how and why plasmodesmata with no cytoplasmic sleeve facilitate molecular trafficking.
Channel Modeling for Synaptic Molecular Communication With Re-uptake and Reversible Receptor Binding
Authors: Sebastian Lotter, Arman Ahmadzadeh, Robert Schober
Date: 2019-12-02 00:00:00

In Diffusive Molecular Communication (DMC), information is transmitted by diffusing molecules. Synaptic signaling is a natural implementation of this paradigm. It is responsible for relaying information from one neuron to another, but also provides support for complex functionalities, such as learning and memory. Many of its features are not yet understood, some are, however, known to be critical for robust, reliable neural communication. In particular, some synapses feature a re-uptake mechanism at the presynaptic neuron, which provides a means for removing neurotransmitters from the synaptic cleft and for recycling them for future reuse. In this paper, we develop a comprehensive channel model for synaptic DMC encompassing a spatial model of the synaptic cleft, molecule re-uptake at the presynaptic neuron, and reversible binding to individual receptors at the postsynaptic neuron. Based on this model, we derive an analytical time domain expression for the channel impulse response (CIR) of the synaptic DMC system. Our model explicitly incorporates macroscopic physical channel parameters and can be used to evaluate the impact of re-uptake, receptor density, and channel width on the CIR of the synaptic DMC system. Furthermore, we provide results from particlebased computer simulation, which validate the analytical model. The proposed comprehensive channel model for synaptic DMC systems can be exploited for the investigation of challenging problems, like the quantification of the inter-symbol interference between successive synaptic signals and the design of synthetic neural communication systems.
Quadruplex detection in human cells
Authors: David Monchaud
Date: 2019-10-08 00:00:00

DNA and RNA quadruplexes are extensively studied for the key roles they are suspected to play in the cellular regulation networks at both genomic and transcriptomic levels. The reliable detection of quadruplexes in cells was and remains a challenging task. Here, we describe the various strategies that have been implemented over the past years to visualize functionally relevant DNA and RNA quadruplexes in human cells, from immunodetection studies to the design and use of quadruplex-specific turn-on fluorescent probes.
On the Role of Vesicle Transport in Neurite Growth: Modelling and Experiments
Authors: Ina Humpert, Danila Di Meo, Andreas W. Püschel, Jan-Frederik Pietschmann
Date: 2019-08-06 00:00:00

The processes that determine the establishment of the complex morphology of neurons during development are still poorly understood. We present experiments that use live imaging to examine the role of vesicle transport and propose a lattice-based model that shows symmetry breaking features similar to a neuron during its polarization. In a otherwise symmetric situation our model predicts that a difference in neurite length increases the growth potential of the longer neurite indicating that vesicle transport can be regarded as a major factor in neurite growth.
Mitochondrial network state scales mtDNA genetic dynamics
Authors: Juvid Aryaman, Charlotte Bowles, Nick S. Jones, Iain G. Johnston
Date: 2018-09-06 00:00:00

Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.
Comparative approaches to understanding thyroid hormone regulation of neurogenesis
Authors: Jean-David Gothié, Barbara Demeneix, Sylvie Remaud
Date: 2019-05-09 00:00:00

Thyroid hormone (TH) signalling, an evolutionary conserved pathway, is crucial for brain function and cognition throughout life, from early development to ageing. In humans, TH deficiency during pregnancy alters offspring brain development, increasing the risk of cognitive disorders. How TH regulates neurogenesis and subsequent behaviour and cognitive functions remains a major research challenge. Cellular and molecular mechanisms underlying TH signalling on proliferation, survival, determination, migration, differentiation and maturation have been studied in mammalian animal models for over a century. However, recent data show that THs also influence embryonic and adult neurogenesis throughout vertebrates (from mammals to teleosts). These latest observations raise the question of how TH availability is controlled during neurogenesis and particularly in specific neural stem cell populations. This review deals with the role of TH in regulating neurogenesis in the developing and the adult brain across different vertebrate species. Such evo-devo approaches can shed new light on (i) the evolution of the nervous system and (ii) the evolutionary control of neurogenesis by TH across animal phyla. We also discuss the role of thyroid disruptors on brain development in an evolutionary context.
Tuning the Transdermal Transport by Application of External Continuous Electric Field: A Molecular Dynamics Coarse-Grained Study
Authors: Neila Machado, Clarissa Callegaro, Marcelo Augusto Christoffolete, Herculano Martinho
Date: 2019-05-06 00:00:00

Since a long time the application of small electric potentials on biological membranes (iontophoresis) proved enabling control and improvement of transdermal delivery of substances across this barrier. In spite of a large experimental data, the detailed molecular mechanism of iontophoresis is absent. In the present work the interaction among the external continuous electric field with the outermost layer of the skin (\textit{stratum corneum}) was studied by coarse-grained molecular dynamics. Our results pointed out the occurrence of water-rich vesicles formation depending on the field strength. The corresponding phase diagram indicated that the large set of phenomena (vesicle formation, reversibility, phase transition, disruption) could be completely controlled by tuning external continuous electric fields. Interestingly, electric field shielding effects are in the origin of observed effects and followed a general Arrhenius-like time dependence. Direct current (DC) electric field usage would also have booster diffusion effects due to vesicles creation and reincorporation which would have direct beneficial absorption effects on water-soluble topical agents (vitamins) or dermal jet-injection of drugs by fine needles.
Stochastic Dynamics of Nanoparticle and Virus Uptake
Authors: Felix Frey, Falko Ziebert, Ulrich S. Schwarz
Date: 2019-05-03 00:00:00

The cellular uptake of nanoparticles or viruses requires that the gain of adhesion energy overcomes the cost of plasma membrane bending. It is well known that this leads to a minimal particle size for uptake. Using a simple deterministic theory for this process, we first show that, for the same radius and volume, cylindrical particles should be taken up faster than spherical particles, both for normal and parallel orientations. We then address stochastic effects, which are expected to be relevant due to small system size, and show that, now, spherical particles can have a faster uptake, because the mean first passage time profits from the multiplicative noise induced by the spherical geometry. We conclude that stochastic effects are strongly geometry dependent and may favor spherical shapes during adhesion-driven particle uptake.