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At least 307 records · Page 17Linked to original sources

arXiv2016

Natural site-directed mutagenesis might exist in eukaryotic cells

Site-directed mutagenesis refers to a man-made molecular biology method that is used to make genetic alterations in the DNA sequence of a gene of interest. But based on our recently published experimental findings, we propose that natural site-directed mutagenesis might exist in the eukaryotic cells, which is triggered by harmful agents and co-directed by special transcription hotspots and mutation-contained intranuclear primers.

q-bio.SC↗

arXiv2016

Perspective: Speculative role of Tmp21 mediated protein secretory pathway during endoplasmic reticulum (ER) stress induced chronic inflammation

By deploying myelofibrosis as the disease context, I wish to propose that increased availability of Tmp21 (an NFAT gene target) induces aberrant protein secretion from the ER contributing to pathological consequences, which has not been elucidated before. Primary myelofibrosis is now mainly considered as an advanced stage of BCR-ABL1 negative myeloproliferative neoplasms (MPN), which otherwise include polycythemia vera and essential thrombocythemia. Myelofibrosis is defined by an increased insoluble collagen fiber deposition in the bone marrow2 and harbors chronic inflammation as an important component in disease progression.

q-bio.SC↗

arXiv2016

Emergent Transport Properties of Molecular Motor Ensemble Affected by Single Motor Mutations

Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - proteins converting chemical energy into kinetic energy. It is known that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of the underlying transport mechanisms, often caused by mutations that alter single motor characteristics, are known to cause neurodegenerative diseases. For example, phosphorylation of kinesin motor domain at the serine residue is implicated in Huntington's disease, with a recent study of phosphorylated and phosphomimetic serine residues indicating lowered single motor stalling forces. In this article we report the effects of mutations of this nature on transport properties of cargo carried by multiple wild-type and mutant motors. Results indicate that mutants with altered stall forces might determine the average velocity and run-length even when they are outnumbered by wild type motors in the ensemble. It is shown that mutants gain a competitive advantage and lead to an increase in expected run-length when load on the cargo is in the vicinity of the mutant's stalling force or a multiple of its stalling force. A separate contribution of this article is the development of a semi-analytic method to analyze transport of cargo by multiple motors of multiple types. The technique determines transition rates between various relative configurations of motors carrying the cargo using the transition rates between various absolute configurations. This enables exact computation of average velocity and run-length. It can also be used to introduce alterations of various single motor parameters to model a mutation and to deduce effects of such alterations on the transport of a common cargo by multiple motors. Our method is easily implementable and we provide a software package for general use.

q-bio.SC↗

arXiv2018

DNA to DNA transcription might exist in eukaryotic cells

Till now, in biological sciences, the term, transcription, mainly refers to DNA to RNA transcription. But our recently published experimental findings obtained from Plasmodium falciparum strongly suggest the existence of DNA to DNA transcription in the genome of eukaryotic cells, which could shed some light on the functions of certain noncoding DNA in the human and other eukaryotic genomes.

q-bio.SC↗

arXiv2016

Chromosome-wide simulations uncover folding pathway and 3D organization of interphase chromosomes

Three-dimensional interphase organization of metazoan genomes has been linked to cellular identity. However, the principles governing 3D interphase genome architecture and its faithful transmission through disruptive events of cell-cycle, like mitosis, are not fully understood. By using Brownian dynamics simulations of Drosophila chromosome 3R up to time-scales of minutes, we show that chromatin binding profile of Polycomb-repressive-complex-1 robustly predicts a sub-set of topologically associated domains (TADs), and inclusion of other factors recapitulates the profile of all TADs, as observed experimentally. Our simulations show that chromosome 3R attains interphase organization from mitotic state by a two-step process in which formation of local TADs is followed by long-range interactions. Our model also explains statistical features and tracks the assembly kinetics of polycomb subnuclear clusters. In conclusion, our approach can be used to predict structural and kinetic features of 3D chromosome folding and its associated proteins in biological relevant genomic and time scales.

q-bio.SC↗

arXiv2016

Effect of hypertension on low-density lipoprotein transport within a multi-layered arterial wall: modelling consistent with experiments

The influence of hypertension on low-density lipoproteins intake into the arterial wall is an important factor for understanding mechanisms of atherosclerosis. It has been experimentally observed that the increased pressure leads to the higher level of the LDL inside the wall. In this paper we attempt to construct a model of the LDL transport which reproduces quantitatively experimental outcomes. We supplement the well known four-layer arterial wall model to include two pressure induced effects: the compression of the intima tissue and the increase of the fraction of leaky junctions. We demonstrate that such model can reach the very good agreement with experimental data.

physics.bio-ph↗

arXiv2016

Nanodomains in biomembranes with recycling

Cell membranes are out of thermodynamic equilibrium notably because of membrane recycling, i.e. active exchange of material with the cytosol. We propose an analytically tractable model of biomembrane predicting the effects of recycling on the size of protein nanodomains. It includes a short-range attraction between proteins and a weaker long-range repulsion which ensures the existence of so-called cluster phases at equilibrium, where monomeric proteins coexist with finite-size domains. Our main finding is that when taking recycling into account, the typical cluster size increases logarithmically with the recycling rate. Using physically realistic model parameters, the predicted two-fold increase due to recycling in living cells is very likely experimentally measurable with the help of super-resolution microscopy.

cond-mat.soft↗

arXiv2016

Stability of stationary solutions in models of the Calvin cycle

In this paper results are obtained concerning the number of positive stationary solutions in simple models of the Calvin cycle of photosynthesis and the stability of these solutions. It is proved that there are open sets of parameters in a model of Zhu et. al. for which there exist two positive stationary solutions. There are never more than two isolated positive stationary solutions but under certain explicit special conditions on the parameters there is a whole continuum of positive stationary solutions. It is also shown that in the set of parameter values for which two isolated positive stationary solutions exist there is an open subset where one of the solutions is asymptotically stable and the other is unstable. In related models , for which it was known that more that one positive stationary solution exists, it is proved that there are parameter values for which one of these solutions is asymptotically stable and the other unstable. A key technical aspect of the proofs is to exploit the fact that there is a bifurcation where the centre manifold is one-dimensional.

q-bio.SC↗

arXiv2016

Excluded volume effects in on- and off-lattice reaction-diffusion models

Mathematical models are important tools to study the excluded volume effects on reaction-diffusion systems, which are known to play an important role inside living cells. Detailed microscopic simulations with off-lattice Brownian dynamics become computationally expensive in crowded environments. In this paper we therefore investigate to which extent on-lattice approximations, so called Cellular Automata models, can be used to simulate reactions and diffusion in the presence of crowding molecules. We show that the diffusion is most severely slowed down in the off-lattice model, since randomly distributed obstacles effectively exclude more volume than those ordered on an artificial grid. Crowded reaction rates can be both increased and decreased by the grid structure and it proves important to model the molecules with realistic sizes when excluded volume is taken into account. The grid artifacts increase with increasing crowder density and we conclude that the computationally more efficient on-lattice simulations are accurate approximations only for low crowder densities.

q-bio.QM↗

arXiv2016

Kinesin-8 effects on mitotic microtubule dynamics contribute to spindle function in fission yeast

Kinesin-8 motor proteins destabilize microtubules. Their absence during cell division is associated with disorganized mitotic chromosome movements and chromosome loss. Despite recent work studying effects of kinesin 8s on microtubule dynamics, it remains unclear whether the kinesin-8 mitotic phenotypes are consequences of their effect on microtubule dynamics, their well-established motor activity, or additional unknown functions. To better understand the role of kinesin-8 proteins in mitosis, we have studied the effects of deletion of the fission-yeast kinesin-8 proteins Klp5 and Klp6 on chromosome movements and spindle length dynamics. Aberrant microtubule-driven kinetochore pushing movements and tripolar mitotic spindles occurred in cells lacking Klp5 but not Klp6. Kinesin-8 deletion strains showed large fluctuations in metaphase spindle length, suggesting a disruption of spindle length stabilization. Comparison of our results from light microscopy with a mathematical model suggests that kinesin-8 induced effects on microtubule dynamics, kinetochore attachment stability, and sliding force in the spindle can explain the aberrant chromosome movements and spindle length fluctuations seen.

q-bio.SC↗

arXiv2016

A Possible Mechanism of DNA to DNA Transcription in Eukaryotic Cells : Endonuclease Dependent Transcript Cutout

We previously proposed the existence of DNA to DNA transcription in eukaryotic cells, but the mechanism by which single-stranded DNA (ssDNA) transcript is produced and released from the genome remains unknown. We once speculated that the mechanism of DNA to DNA transcription might be similar to that of DNA to RNA transcription, but now we propose that endonuclease dependent transcript cutout may be a possible mechanism of DNA to DNA transcription, in which a copy of ssDNA fragment (transcript) between two nicks produced by nicking endonuclease is released from double-stranded DNA (dsDNA) region in the genome by an unknown ssDNA fragment releasing enzyme. The gap in the dsDNA will be filled through DNA repair mechanism. Occasionally, multiple copies of ssDNA transcripts could be produced through multiple rounds of cutout-repair-cutout cycle.

q-bio.SC↗

arXiv2016

Hybrid Markov-mass action law for cell activation by rare binding events

The binding of molecules, ions or proteins to specific target sites is a generic step for cell activation. However, this step relies on rare events where stochastic particles located in a large bulk are searching for small and often hidden targets and thus remains difficult to study. We present here a hybrid discrete-continuum model where the large ensemble of particles is described by mass-action laws. The rare discrete binding events are modeled by a Markov chain for the encounter of a finite number of small targets by few Brownian particles, for which the arrival time is Poissonian. This model is applied for predicting the time distribution of vesicular release at neuronal synapses that remains elusive. This release is triggered by the binding of few calcium ions that can originate either from the synaptic bulk or from the transient entry through calcium channels. We report that the distribution of release time is bimodal although triggered by a single fast action potential: while the first peak follows a stimulation, the second corresponds to the random arrival over much longer time of ions located in the bulk to small binding targets. To conclude, the present multiscale stochastic chemical reaction modeling allows studying cellular events based on integrating discrete molecular events over various time scales.

q-bio.SC↗

arXiv2016

Single-molecule observation of DNA replication repair pathways in E. coli

The method of action of many antibiotics is to interfere with DNA replication - quinolones trap DNA gyrase and topoisomerase proteins onto DNA while metronidazole causes single and double stranded breaks in DNA. To understand how bacteria respond to these drugs, it is important to understand the repair processes utilised when DNA replication is blocked. We have used tandem lac operators inserted into the chromosome bound by fluorescently labelled lac repressors as a model protein block to replication in E. coli. We have used dual-colour, alternating-laser, single-molecule narrowfield microscopy to quantify the amount of operator at the block and simultaneously image fluorescently labelled DNA polymerase. We anticipate use of this system as a quantitative platform to study replication stalling and repair proteins.

q-bio.SC↗

arXiv2016

Using Fluorescence Recovery After Photobleaching (FRAP) to study dynamics of the Structural Maintenance of Chromosome (SMC) complex in vivo

The SMC complex, MukBEF, is important for chromosome organization and segregation in Escherichia coli. Fluorescently tagged MukBEF forms distinct spots (or 'foci') in the cell, where it is thought to carry out most of its chromosome associated activities. This chapter outlines the technique of Fluorescence Recovery After Photobleaching (FRAP) as a method to study the properties of YFP-tagged MukB in fluorescent foci. This method can provide important insight into the dynamics of MukB on DNA and be used to study its biochemical properties in vivo.

q-bio.SC↗

arXiv2016

Single molecule narrowfield microscopy of protein-DNA binding dynamics in glucose signal transduction of live yeast cells

Single-molecule narrowfield microscopy is a versatile tool to investigate a diverse range of protein dynamics in live cells and has been extensively used in bacteria. Here, we describe how these methods can be extended to larger eukaryotic, yeast cells, which contain sub-cellular compartments. We describe how to obtain single-molecule microscopy data but also how to analyse these data to track and obtain the stoichiometry of molecular complexes diffusing in the cell. We chose glucose mediated signal transduction of live yeast cells as the system to demonstrate these single-molecule techniques as transcriptional regulation is fundamentally a single molecule problem - a single repressor protein binding a single binding site in the genome can dramatically alter behaviour at the whole cell and population level.

q-bio.SC↗

arXiv2017

Stochastic Model of Maturation and Vesicular Exchange in Cellular Organelles

The dynamical organization of membrane-bound organelles along intracellular transport pathways relies on vesicular exchange between organelles and on biochemical maturation of the organelle content by specific enzymes. The relative importance of each mechanism in controlling organelle dynamics remains controversial, in particular for transport through the Golgi apparatus. Using a stochastic model, we show that full maturation of membrane-bound compartments can be seen as the stochastic escape from a steady-state in which export is dominated by vesicular exchange. We show that full maturation can contribute a significant fraction of the total out-flux for small organelles such as endosomes and Golgi cisternae.

physics.bio-ph↗

arXiv2016

Nonequilibrium mechanisms underlying de novo biogenesis of Golgi cisternae

A central issue in cell biology is the physico-chemical basis of organelle biogenesis in intracellular trafficking pathways, its most impressive manifestation being the biogenesis of Golgi cisternae. At a basic level, such morphologically and chemically distinct compartments should arise from an interplay between the molecular transport and chemical maturation. Here, we formulate analytically tractable, minimalist models, that incorporate this interplay between transport and chemical progression in physical space, and explore the conditions for de novo biogenesis of distinct cisternae. We propose new quantitative measures that can discriminate between the various models of transport in a qualitative manner- this includes measures of the dynamics in steady state and the dynamical response to perturbations of the kind amenable to live-cell imaging.

physics.bio-ph↗

arXiv2016

How does a protein reach its binding locus: sliding along DNA chain or not?

In gene expression, various kinds of proteins need to bind to specific locus of DNA. It is still not clear how these proteins find their target locus. In this study, the mean first-passage time (FPT) of protein binding to its target locus on DNA chain is discussed by a chain-space coupled model. Our results show that the 1-dimensional diffusion constant has a critical value, with which the mean time spent by a protein to find its target locus is almost independent of the binding rate of protein to DNA chain and the detachment rate from DNA chain. Which implies that, the frequency of protein binding to DNA and the sliding time on DNA chain have little influence on the search efficiency, and therefore whether or not the 1-dimensional sliding on DNA chain increases the search efficiency depends on the 1-dimensional diffusion constant of the protein on DNA chain. This study also finds that only protein bindings to DNA loci which are close to the target locus help to increase the search efficiency, while bindings to those loci which are far from the target locus might delay the target binding process. As expected, the mean FPT increases with the distance between the initial position of protein in cell space and its target locus on DNA chain. The direct binding probability, which can be regarded as one index to describe if the 1-dimensional sliding along DNA chain is helpful to increase the search efficiency is calculated. Our results show that the influence of 1-dimensional sliding along DNA chain on the search process depends on both diffusion constants of protein in cell space and on the 1-dimensional DNA chain.

physics.bio-ph↗