Hasil untuk "q-bio.SC"

Christof A. Bertram, Taryn A. Donovan, Alexander Bartel

Increased proliferation is a key driver of tumorigenesis, and quantification of mitotic activity is a standard task for prognostication. The goal of this systematic review is scholarly analysis of all available references on mitotic activity in feline tumors, and to provide an overview of the measuring methods and prognostic value. A systematic literature search in PubMed and Scopus and a manual search in Google Scholar was conducted. All articles on feline tumors that correlated mitotic activity with patient outcome were identified. Data analysis revealed that of the eligible 42 articles, the mitotic count (MC, mitotic figures per tumor area) was evaluated in 39 instances and the mitotic index (MI, mitotic figures per tumor cells) in three instances. The risk of bias was considered high for most studies (26/42, 62%) based on small study populations, insufficient details of the MC/MI methods, and lack of statistical measures for diagnostic accuracy or effect on outcome. The MC/MI methods varied markedly between studies. A significant association of the MC with survival was determined in 21/29 (72%) studies, while one study found an inverse effect. There were three tumor types with at least four studies and a prognostic association was found in 5/6 studies on mast cell tumors, 5/5 on mammary tumors and 3/4 on soft tissue sarcomas. The MI was shown to correlate with survival by two research groups, however a comparison to the MC was not conducted. An updated systematic review will be needed with of new literature for different tumor types.

Utkarsh Upadhyay, Chandrima Barua, Shivani Devi et al.

Unfolded protein aggregation in cellular system is a problem causing various types of diseases depending on which type unfolded proteins aggregate. This phenomenon of aggregation may take place during production, storage, shipment or delivery in the cellular medium. In the present work, we studied a simplified and extended version of unfolded protein aggregation model by Lumry and Eyring using stochastic approach. We solved analytically the Master equation of the model for the probability distribution $P(x,t)$ of the unfolded protein population and the solution was found to be time dependent complex binomial distribution. In the large population limit $P(x,t)\sim Λ(x,t)\times Pois(x,t)$. Further, the distribution became Normal distribution at large population and mean of the distribution limit: $P(x,t)\simΛ(x,t)\times N(\langle qx\rangle,\langle qx\rangle)$. The fluctuations inherent in the dynamics measured by Fano factor can have sub-Poisson, Poisson and super-Poisson at different situations.

Cheng Wang, Mian Zhang, M. Lonvcar

Lithium niobate (LN) is an excellent nonlinear optical and electro-optic material that has found many applications in classical nonlinear optics, optical fiber communications and quantum photonics. Here we review the recent development of thin-film LN technology that has allowed the miniaturization of LN photonic devices and microcavities with ultrahigh quality factors. We discuss the design principle of LN devices that makes use of the largest nonlinear coefficients, various device fabrication approaches and resulting device performances, and the current and potential applications of LN microcavities.

Joseph J. Klobusicky, John Fricks, Peter R. Kramer

Analytical formulas for effective drift, diffusivity, run times, and run lengths are derived for an intracellular transport system consisting of a cargo attached to two cooperative but not identical molecular motors (for example, kinesin-1 and kinesin-2) which can each attach and detach from a microtubule. The dynamics of the motor and cargo in each phase are governed by stochastic differential equations, and the switching rates depend on the spatial configuration of the motor and cargo. This system is analyzed in a limit where the detached motors have faster dynamics than the cargo, which in turn has faster dynamics than the attached motors. The attachment and detachment rates are also taken to be slow relative to the spatial dynamics. Through an application of iterated stochastic averaging to this system, and the use of renewal-reward theory to stitch together the progress within each switching phase, we obtain explicit analytical expressions for the effective drift, diffusivity, and processivity of the motor-cargo system. Our approach accounts in particular for jumps in motor-cargo position that occur during attachment and detachment events, as the cargo tracking variable makes a rapid adjustment due to the averaged fast scales. The asymptotic formulas are in generally good agreement with direct stochastic simulations of the detailed model based on experimental parameters for various pairings of kinesin-1 and kinesin-2 under assisting, hindering, or no load.

Ashutosh Gupta, Somya Mani, Ankit Shukla

Vesicle Traffic Systems (VTSs) are the material transport mechanisms among the compartments inside the biological cells. The compartments are viewed as nodes that are labeled with the containing chemicals and the transport channels are similarly viewed as labeled edges between the nodes. Understanding VTSs is an ongoing area of research and for many cells they are partially known. For example, there may be undiscovered edges, nodes, or their labels in a VTS of a cell. It has been speculated that there are properties that the VTSs must satisfy. For example, stability, i.e., every chemical that is leaving a compartment comes back. Many synthesis questions may arise in this scenario, where we want to complete a partially known VTS under a given property. In the paper, we present novel encodings of the above questions into the QBF (quantified Boolean formula) satisfiability problems. We have implemented the encodings in a highly configurable tool and applied to a couple of found-in-nature VTSs and several synthetic graphs. Our results demonstrate that our method can scale up to the graphs of interest.

Davide Michieletto, Marina Lusic, Davide Marenduzzo et al.

Certain retroviruses, including HIV, insert their DNA in a non-random fraction of the host genome via poorly understood selection mechanisms. Here, we develop a biophysical model for retroviral integrations as stochastic and quasi-equilibrium topological reconnections between polymers. We discover that physical effects, such as DNA accessibility and elasticity, play important and universal roles in this process. Our simulations predict that integration is favoured within nucleosomal and flexible DNA, in line with experiments, and that these biases arise due to competing energy barriers associated with DNA deformations. By considering a long chromosomal region in human T-cells during interphase, we discover that at these larger scales integration sites are predominantly determined by chromatin accessibility. Finally, we propose and solve a reaction-diffusion problem that recapitulates the distribution of HIV hot-spots within T-cells. With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection.

Kelath Murali Manoj, Abhinav Parashar

Mitochondrial oxidative phosphorylation (mOxPhos) makes ATP, the energy currency of life. Chemiosmosis, a proton centric mechanism, advocates that Complex V harnesses a transmembrane potential (TMP) for ATP synthesis. This perception of cellular respiration requires oxygen to stay tethered at Complex IV (an association inhibited by cyanide) and diffusible reactive oxygen species (DROS) are considered wasteful and toxic products. With new mechanistic insights on heme and flavin enzymes, an oxygen or DROS centric explanation (called murburn concept) was recently proposed for mOxPhos. In the new mechanism, TMP is not directly harnessed, protons are a rate limiting reactant and DROS within matrix serve as the chemical coupling agents that directly link NADH oxidation with ATP synthesis. Herein, we report multiple ADP binding sites and solvent accessible DROS channels in respiratory proteins, which validate the oxygen or DROS centric power generation (ATP synthesis) system in mOxPhos. Since cyanide's heme binding Kd is high (mM), low doses (uM) of cyanide is lethal because cyanide disrupts DROS dynamics in mOxPhos. The critical study also provides comprehensive arguments against Mitchell's and Boyer's explanations and extensive support for murburn concept based holistic perspectives for mOxPhos.

Serge Feyder, Johan-Owen De Craene, Séverine Bär et al.

The yeast Saccharomyces cerevisiae is one of the best characterized eukaryotic models. The secretory pathway was the first trafficking pathway clearly understood mainly thanks to the work done in the laboratory of Randy Schekman in the 1980s. They have isolated yeast sec mutants unable to secrete an extracellular enzyme and these SEC genes were identified as encoding key effectors of the secretory machinery. For this work, the 2013 Nobel Prize in Physiology and Medicine has been awarded to Randy Schekman; the prize is shared with James Rothman and Thomas S{ü}dhof. Here, we present the different trafficking pathways of yeast S. cerevisiae. At the Golgi apparatus newly synthesized proteins are sorted between those transported to the plasma membrane (PM), or the external medium, via the exocytosis or secretory pathway (SEC), and those targeted to the vacuole either through endosomes (vacuolar protein sorting or VPS pathway) or directly (alkaline phosphatase or ALP pathway). Plasma membrane proteins can be internalized by endocytosis (END) and transported to endosomes where they are sorted between those targeted for vacuolar degradation and those redirected to the Golgi (recycling or RCY pathway). Studies in yeast S. cerevisiae allowed the identification of most of the known effectors, protein complexes, and trafficking pathways in eukaryotic cells, and most of them are conserved among eukaryotes.

Zeev Schuss, Kimsy Tor, David Holcman

Do biological cells sense time by the number of their divisions, a process that ends at senescence? We consider the question "can the cell's perception of time be expressed through the length of the shortest telomere?" The answer is that the absolute time before senescence cannot be expressed by the telomere's length and that a cell can survive many more divisions than intuitively expected. This apparent paradox is due to shortening and elongation of the telomere, which suggests a random walk model of the telomere's length. The model indicates two phases, first, a determinist drift of the length toward a quasi-equilibrium state, and second, persistence of the length near an attracting state for the majority of divisions prior to senescence. The measure of stability of the latter phase is the expected number of divisions at the attractor ("lifetime") prior to crossing a threshold to senescence. The telomerase regulates stability by creating an effective potential barrier that separates statistically the shortest lifetime from the next shortest. The random walk has to overcome the barrier in order to extend the range of the first regime. The model explains how random telomere dynamics underlies the extension of cell survival time.

M. Reza Shaebani, Aravind Pasula, Albrecht Ott et al.

Many cellular processes are tightly connected to the dynamics of microtubules (MTs). While in neuronal axons MTs mainly regulate intracellular trafficking, they participate in cytoskeleton reorganization in many other eukaryotic cells, enabling the cell to efficiently adapt to changes in the environment. We show that the functional differences of MTs in different cell types and regions is reflected in the dynamic properties of MT tips. Using plus-end tracking proteins EB1 to monitor growing MT plus-ends, we show that MT dynamics and life cycle in axons of human neurons significantly differ from that of fibroblast cells. The density of plus-ends, as well as the rescue and catastrophe frequencies increase while the growth rate decreases toward the fibroblast cell margin. This results in a rather stable filamentous network structure and maintains the connection between nucleus and membrane. In contrast, plus-ends are uniformly distributed along the axons and exhibit diverse polymerization run times and spatially homogeneous rescue and catastrophe frequencies, leading to MT segments of various lengths. The probability distributions of the excursion length of polymerization and the MT length both follow nearly exponential tails, in agreement with the analytical predictions of a two-state model of MT dynamics.

Khem Raj Ghusinga, Abhyudai Singh

Gene expression is inherently a noisy process which manifests as cell-to-cell variability in time evolution of proteins. Consequently, events that trigger at critical threshold levels of regulatory proteins exhibit stochasticity in their timing. An important contributor to the noise in gene expression is translation bursts which correspond to randomness in number of proteins produced in a single mRNA lifetime. Modeling timing of an event as a first-passage time (FPT) problem, we explore the effect of burst size distribution on event timing. Towards this end, the probability density function of FPT is computed for a gene expression model with burst size drawn from a generic non-negative distribution. Analytical formulas for FPT moments are provided in terms of known vectors and inverse of a matrix. The effect of burst size distribution is investigated by looking at how the feedback regulation strategy that minimizes noise in timing around a given time deviates from the case when burst is deterministic. Interestingly, results show that the feedback strategy for deterministic burst case is quite robust to change in burst size distribution, and deviations from it are confined to about 20% of the optimal value. These findings facilitate an improved understanding of noise regulation in event timing.

Timothy R. Peterson, Mathieu Laplante, Ed Van Veen et al.

Understanding the mechanisms by which cells coordinate their size with their ability to divide has long attracted the interest of biologists. The Target of Rapamycin (TOR) pathway is becoming increasingly recognized as a master regulator of cell size, however less is known how TOR activity might be coupled with the cell cycle. Here, we establish that mTOR complex 1 (mTORC1) promotes cytokinesis through activation of a Rho GTPase-Rho Kinase (ROCK) signaling cascade. Hyperactivation of mTORC1 signaling by depletion of any of its negative regulators: TSC1, TSC2, PTEN, or DEPTOR, induces polyploidy in a rapamycin-sensitive manner. mTORC1 hyperactivation-mediated polyploidization occurs by a prolonged, but ultimately failed attempt at abcission followed by re-fusion. Similar to the effects of ROCK2 overexpression, these mTORC1-driven aberrant cytokinesis events are accompanied by increased Rho-GTP loading, extensive plasma membrane blebbing, and increased actin-myosin contractility, all of which can be rescued by either mTORC1 or ROCK inhibition. These results provide evidence for the existence of a novel mTORC1-Rho-ROCK pathway during cytokinesis and suggest that mTORC1 might play a critical role in setting the size at which a mammalian cell divides.

Ildefonso M. De la Fuente

A large number of studies have shown the existence of metabolic covalent modifications in different molecular structures, able to store biochemical information that is not encoded by the DNA. Some of these covalent mark patterns can be transmitted across generations (epigenetic changes). Recently, the emergence of Hopfield-like attractor dynamics has been observed in the self-organized enzymatic networks, which have the capacity to store functional catalytic patterns that can be correctly recovered by the specific input stimuli. The Hopfield-like metabolic dynamics are stable and can be maintained as a long-term biochemical memory. In addition, specific molecular information can be transferred from the functional dynamics of the metabolic networks to the enzymatic activity involved in the covalent post-translational modulation so that determined functional memory can be embedded in multiple stable molecular marks. Both the metabolic dynamics governed by Hopfield-type attractors (functional processes) and the enzymatic covalent modifications of determined molecules (structural dynamic processes) seem to represent the two stages of the dynamical memory of cellular metabolism (metabolic memory). Epigenetic processes appear to be the structural manifestation of this cellular metabolic memory. Here, a new framework for molecular information storage in the cell is presented, which is characterized by two functionally and molecularly interrelated systems: a dynamic, flexible and adaptive system (metabolic memory) and an essentially conservative system (genetic memory). The molecular information of both systems seems to coordinate the physiological development of the whole cell.

Shantia Yarahmadian, Vineetha Menon, Majid Mahrooghy et al.

Recent studies has revealed that Microtubules (MTs) exhibit three transition states of growth, shrinkage and pause. In this paper, we first introduce a three states random evolution model as a framework for studying MTs dynamics in three transition states of growth, pause and shrinkage. Then, we introduce a non-traditional stack run encoding scheme with 5 symbols for detecting transition states as well as to encode MT experimental data. The peak detection is carried out in the wavelet domain to effectively detect these three transition states. One of the added advantages of including peak information while encoding being that it enables to detect the peaks efficiently and encodes them simultaneously in the wavelet domain without having the need to do further processing after the decoding stage. Experimental results show that using this form of non-traditional stack run encoding has better compression and reconstruction performance as opposed to traditional stack run encoding and run length encoding schemes. Parameters for MTs modeled in the three states are estimated and is shown to closely approximate original MT data for lower compression rates. As the compression rate increases, we may end up throwing away details that are required to detect transition states of MTs. Thus, choosing the right compression rate is a trade-off between admissible level of error in signal reconstruction, its parameter estimation and considerable rate of compression of MT data.

B. R. Frieden, R. A. Gatenby

Eukaryotic cell development has been optimized by natural selection to obey maximal intracellular flux of messenger proteins. This, in turn, implies maximum Fisher information on angular position about a target nuclear pore complex (NPR). The cell is simply modeled as spherical, with cell membrane (CM) diameter 10 micron and concentric nuclear membrane (NM) diameter 6 micron. The NM contains about 3000 nuclear pore complexes (NPCs). Development requires messenger ligands to travel from the CM-NPC-DNA target binding sites. Ligands acquire negative charge by phosphorylation, passing through the cytoplasm over Newtonian trajectories toward positively charged NPCs (utilizing positive nuclear localization sequences). The CM-NPC channel obeys maximized mean protein flux F and Fisher information I at the NPC, with first-order delta I = 0 and approximate 2nd-order delta I = 0 stability to environmental perturbations. Many of its predictions are confirmed, including the dominance of protein pathways of from 1-4 proteins, a 4nm size for the EGFR protein and the approximate flux value F =10^16 proteins/m2-s. After entering the nucleus, each protein ultimately delivers its ligand information to a DNA target site with maximum probability, i.e. maximum Kullback-Liebler entropy HKL. In a smoothness limit HKL approaches IDNA/2, so that the total CM-NPC-DNA channel obeys maximum Fisher I. Thus maximum information approaches non-equilibrium, one condition for life.

V. Jemseena, Manoj Gopalakrishnan

Several independent observations have suggested that catastrophe transition in microtubules is not a first-order process, as is usually assumed. Recent {\it in vitro} observations by Gardner et al.[ M. K. Gardner et al., Cell {\bf147}, 1092 (2011)] showed that microtubule catastrophe takes place via multiple steps and the frequency increases with the age of the filament. Here, we investigate, via numerical simulations and mathematical calculations, some of the consequences of age dependence of catastrophe on the dynamics of microtubules as a function of the aging rate, for two different models of aging: exponential growth, but saturating asymptotically and purely linear growth. The boundary demarcating the steady state and non-steady state regimes in the dynamics is derived analytically in both cases. Numerical simulations, supported by analytical calculations in the linear model, show that aging leads to non-exponential length distributions in steady state. More importantly, oscillations ensue in microtubule length and velocity. The regularity of oscillations, as characterized by the negative dip in the autocorrelation function, is reduced by increasing the frequency of rescue events. Our study shows that age dependence of catastrophe could function as an intrinsic mechanism to generate oscillatory dynamics in a microtubule population, distinct from hitherto identified ones.

Ajeet K. Sharma, Debashish Chowdhury

A DNA polymerase (DNAP) replicates a template DNA strand. It also exploits the template as the track for its own motor-like mechanical movement. In the polymerase mode it elongates the nascent DNA by one nucleotide in each step. But, whenever it commits an error by misincorporating an incorrect nucleotide, it can switch to an exonuclease mode. In the latter mode it excises the wrong nucleotide before switching back to its polymerase mode. We develop a stochastic kinetic model of DNA replication that mimics an {\it in-vitro} experiment where a single-stranded DNA, subjected to a mechanical tension $F$, is converted to a double-stranded DNA by a single DNAP. The $F$-dependence of the average rate of replication, which depends on the rates of both polymerase and exonuclease activities of the DNAP, is in good qualitative agreement with the corresponding experimental results. We introduce 9 novel distinct {\it conditional dwell times} of a DNAP. Using the methods of first-passage times, we also derive the exact analytical expressions for the probability distributions of these conditional dwell times. The predicted $F$-dependence of these distributions are, in principle, accessible to single-molecule experiments.

Pablo Sartori, Simone Pigolotti

We study stochastic copying schemes in which discrimination between a right and a wrong match is achieved via different kinetic barriers or different binding energies of the two matches. We demonstrate that, in single-step reactions, the two discrimination mechanisms are strictly alternative and can not be mixed to further reduce the error fraction. Close to the lowest error limit, kinetic discrimination results in a diverging copying velocity and dissipation per copied bit. On the opposite, energetic discrimination reaches its lowest error limit in an adiabatic regime where dissipation and velocity vanish. By analyzing experimentally measured kinetic rates of two DNA polymerases, T7 and Polγ, we argue that one of them operates in the kinetic and the other in the energetic regime. Finally, we show how the two mechanisms can be combined in copying schemes implementing error correction through a proofreading pathway

R. Herrmann

L. Sawyer, D. Fishbein, J. McDade