Synthetic tetracycline-inducible regulatory networks: computer-aided design of dynamic phenotypes

<p>Abstract</p> <p>Background</p> <p>Tightly regulated gene networks, precisely controlling the expression of protein molecules, have received considerable interest by the biomedical community due to their promising applications. Among the most well studied inducible transcription systems are the tetracycline regulatory expression systems based on the tetracycline resistance operon of Escherichia coli, Tet-Off (tTA) and Tet-On (rtTA). Despite their initial success and improved designs, limitations still persist, such as low inducer sensitivity. Instead of looking at these networks statically, and simply changing or mutating the promoter and operator regions with trial and error, a systematic investigation of the dynamic behavior of the network can result in rational design of regulatory gene expression systems. Sophisticated algorithms can accurately capture the dynamical behavior of gene networks. With computer aided design, we aim to improve the synthesis of regulatory networks and propose new designs that enable tighter control of expression.</p> <p>Results</p> <p>In this paper we engineer novel networks by recombining existing genes or part of genes. We synthesize four novel regulatory networks based on the Tet-Off and Tet-On systems. We model all the known individual biomolecular interactions involved in transcription, translation, regulation and induction. With multiple time-scale stochastic-discrete and stochastic-continuous models we accurately capture the transient and steady state dynamics of these networks. Important biomolecular interactions are identified and the strength of the interactions engineered to satisfy design criteria. A set of clear design rules is developed and appropriate mutants of regulatory proteins and operator sites are proposed.</p> <p>Conclusion</p> <p>The complexity of biomolecular interactions is accurately captured through computer simulations. Computer simulations allow us to look into the molecular level, portray the dynamic behavior of gene regulatory networks and rationally engineer novel ones with useful applications. We are able to propose, test and accept or reject design principles for each network. Guided by simulations, we develop a set of design principles for novel tetracycline-inducible networks.</p

On the effect of receiver impairments on incoherent QAM systems

Incoherent QAM is a differentially detected, multilevel modulation format that can improve spectral efficiency in optical communication systems. The effect of three receiver impairments on the performance of an incoherent QAM system is assessed in this paper for the first time. Specifically, the impairments studied are an unbalanced Mach-Zehnder Interferometer (MZI,), the phase detuning of the MZI and the amplitude imbalance of the Balanced Photodetectors (BPD). Extensive simulations were carried out and results indicate that incoherent QAM is quite robust in respect to the aforementioned impairments, with the phase detuning being the most critical parameter leading to peiformance degradatio

Energy considerations regarding next generation passive optical networks

The increasing demand for faster broadband access requires the development of next-generation Passive Optical Networks (PONs) operating at very high bit rates (e.g. 40 Gb/s). On the same time, energy efficiency in Information and Communication Technology (ICT) infrastructure has become a very important topic. In this paper, several proposed solutions for future high-speed PONs, such as coherent and incoherent multilevel signaling, wavelength-multiplexed On-Off Keying (OOK) and Orthogonal Frequency Division Multiplexing (OFDM), are examined with regards to the energy consumption of the system, with results indicating that the necessary bit rates can be provided without sacrificing energy efficiency

Multi-level modulation formats for optical access networks

There is growing demand for higher bit rates at the access domain. The most promising and future-proof technology for providing end users with high bandwidth is Passive Optical Networks (PON). In order to provide these higher bit rates, the use of multi-level modulation has been proposed. By moving to multi-level signals, low speed electronics can be used, with some added complexity to the optical part. This paper investigates the performance of incoherent multi-level modulation formats (in particular QAM and DQPSK) in bidirectional PONs. The simulation results indicate that incoherent QAM is a strong candidate for future PONs

Multiscale Hy3S: Hybrid stochastic simulation for supercomputers

BACKGROUND: Stochastic simulation has become a useful tool to both study natural biological systems and design new synthetic ones. By capturing the intrinsic molecular fluctuations of "small" systems, these simulations produce a more accurate picture of single cell dynamics, including interesting phenomena missed by deterministic methods, such as noise-induced oscillations and transitions between stable states. However, the computational cost of the original stochastic simulation algorithm can be high, motivating the use of hybrid stochastic methods. Hybrid stochastic methods partition the system into multiple subsets and describe each subset as a different representation, such as a jump Markov, Poisson, continuous Markov, or deterministic process. By applying valid approximations and self-consistently merging disparate descriptions, a method can be considerably faster, while retaining accuracy. In this paper, we describe Hy3S, a collection of multiscale simulation programs. RESULTS: Building on our previous work on developing novel hybrid stochastic algorithms, we have created the Hy3S software package to enable scientists and engineers to both study and design extremely large well-mixed biological systems with many thousands of reactions and chemical species. We have added adaptive stochastic numerical integrators to permit the robust simulation of dynamically stiff biological systems. In addition, Hy3S has many useful features, including embarrassingly parallelized simulations with MPI; special discrete events, such as transcriptional and translation elongation and cell division; mid-simulation perturbations in both the number of molecules of species and reaction kinetic parameters; combinatorial variation of both initial conditions and kinetic parameters to enable sensitivity analysis; use of NetCDF optimized binary format to quickly read and write large datasets; and a simple graphical user interface, written in Matlab, to help users create biological systems and analyze data. We demonstrate the accuracy and efficiency of Hy3S with examples, including a large-scale system benchmark and a complex bistable biochemical network with positive feedback. The software itself is open-sourced under the GPL license and is modular, allowing users to modify it for their own purposes. CONCLUSION: Hy3S is a powerful suite of simulation programs for simulating the stochastic dynamics of networks of biochemical reactions. Its first public version enables computational biologists to more efficiently investigate the dynamics of realistic biological systems

Geological solutions concluded by petroleum geochemical data in Western Greece

Τα προηγούμενα χρόνια έχει πραγματοποιηθεί μια λεπτομερής γεωχημική μελέτη πετρελαίου στη Δυτική Ελλάδα. Εντοπίστηκαν αρκετοί ορίζοντες πιθανών μητρικών πετρωμάτων πετρελαίου, προσδιορίστηκε το παράθυρο πετρελαίου στις πιο σημαντικές υπολεκάνες, ενώ από τη μελέτη συσχετισμού πετρελαίων προσδιορίστηκαν οι διαφορετικές ομάδες πετρελαίου της περιοχής, που έχουν παραχθεί από τα διαφορετικά μητρικά πετρώματα υδρογονανθράκων. Τα αποτελέσματα αυτά είναι πολύ σημαντικά και απαραίτητα για την έρευνα πετρελαίου στην περιοχή. Όμως, εκτός από αυτά τα δεδομένα, κάποιες επιπλέον γεωχημικές παρατηρήσεις μπορεί να αποβούν εξίσου σημαντικές στην επίλυση ορισμένων γεωλογικών προβλημάτων της Δυτικής Ελλάδας.- Ένα πολύ σημαντικό πρόβλημα είναι η απόθεση και διατήρηση του οργανικού υλικού στις λεκάνες της Δυτικής Ελλάδας.- Η δολομιτίωση σε συνάρτηση με τη γένεση πετρελαίου είναι ένα πρόβλημα.- Ένα άλλο θέμα είναι ο υπολογισμός του πάχους που διαβρώθηκε από τους υπερκείμενους σχηματισμούς.- Ο προσδιορισμός της παλαιογεωθερμικής βαθμίδας είναι επίσης πολύ σημαντικός.Οι δύο τελευταίοι παράμετροι είναι απόλυτα απαραίτητοι για τον προσδιορισμό της ωριμότητας του οργανικού υλικού.Η μελέτη όλων των παραπάνω παραμέτρων συμπληρώνει τη γεωχημική μελέτη της Δυτικής Ελλάδας, και σε συνδυασμό με άλλες γεωλογικές μελέτες μπορεί να δώσει λύσεις σε προβλήματα που σχετίζονται με την έρευνα υδρογονανθράκων στην περιοχή.A detailed petroleum geochemical study has been performed in the previous years in the Western Greece. Several source rock horizons have been identified, the oil window has been calculated for the most significant sub-basins and the oil correlation study has distinguished the different oil groups of the area, generated from different hydrocarbon sources. These results are very significant and useful for the oil exploration. But, further to these, some more geochemical observations can also be very important on solving some geological problems of the area.- A major problem is the deposition and preservation of the organic matter in the Western Greece.- The dolomitization in relation with the oil generation is also an issue.- Another issue is the calculation of the eroded overburden formations thickness.- The Paleogeothermal gradient determination is also very important.The last two parameters are absolutely necessary for organic matter maturity calculations.The study of all the above parameters completes the geochemical study of the Western Greece, and in relation with other geological studies can provide solutions in the petroleum exploration of the area

Extracting the Groupwise Core Structural Connectivity Network: Bridging Statistical and Graph-Theoretical Approaches

Finding the common structural brain connectivity network for a given population is an open problem, crucial for current neuro-science. Recent evidence suggests there's a tightly connected network shared between humans. Obtaining this network will, among many advantages , allow us to focus cognitive and clinical analyses on common connections, thus increasing their statistical power. In turn, knowledge about the common network will facilitate novel analyses to understand the structure-function relationship in the brain. In this work, we present a new algorithm for computing the core structural connectivity network of a subject sample combining graph theory and statistics. Our algorithm works in accordance with novel evidence on brain topology. We analyze the problem theoretically and prove its complexity. Using 309 subjects, we show its advantages when used as a feature selection for connectivity analysis on populations, outperforming the current approaches