Sample records for complex regulatory systems
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Complex systems dynamics in aging: new evidence, continuing questions.
Cohen, Alan A
2016-02-01
There have long been suggestions that aging is tightly linked to the complex dynamics of the physiological systems that maintain homeostasis, and in particular to dysregulation of regulatory networks of molecules. This review synthesizes recent work that is starting to provide evidence for the importance of such complex systems dynamics in aging. There is now clear evidence that physiological dysregulation--the gradual breakdown in the capacity of complex regulatory networks to maintain homeostasis--is an emergent property of these regulatory networks, and that it plays an important role in aging. It can be measured simply using small numbers of biomarkers. Additionally, there are indications of the importance during aging of emergent physiological processes, functional processes that cannot be easily understood through clear metabolic pathways, but can nonetheless be precisely quantified and studied. The overall role of such complex systems dynamics in aging remains an important open question, and to understand it future studies will need to distinguish and integrate related aspects of aging research, including multi-factorial theories of aging, systems biology, bioinformatics, network approaches, robustness, and loss of complexity.
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Deconstructing the core dynamics from a complex time-lagged regulatory biological circuit.
Eriksson, O; Brinne, B; Zhou, Y; Björkegren, J; Tegnér, J
2009-03-01
Complex regulatory dynamics is ubiquitous in molecular networks composed of genes and proteins. Recent progress in computational biology and its application to molecular data generate a growing number of complex networks. Yet, it has been difficult to understand the governing principles of these networks beyond graphical analysis or extensive numerical simulations. Here the authors exploit several simplifying biological circumstances which thereby enable to directly detect the underlying dynamical regularities driving periodic oscillations in a dynamical nonlinear computational model of a protein-protein network. System analysis is performed using the cell cycle, a mathematically well-described complex regulatory circuit driven by external signals. By introducing an explicit time delay and using a 'tearing-and-zooming' approach the authors reduce the system to a piecewise linear system with two variables that capture the dynamics of this complex network. A key step in the analysis is the identification of functional subsystems by identifying the relations between state-variables within the model. These functional subsystems are referred to as dynamical modules operating as sensitive switches in the original complex model. By using reduced mathematical representations of the subsystems the authors derive explicit conditions on how the cell cycle dynamics depends on system parameters, and can, for the first time, analyse and prove global conditions for system stability. The approach which includes utilising biological simplifying conditions, identification of dynamical modules and mathematical reduction of the model complexity may be applicable to other well-characterised biological regulatory circuits. [Includes supplementary material].
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-14
... complex order auction (COA) and book (COB) rule. The COA system facilitates the handling and execution of complex orders by allowing for complex orders to rest in the system and allowing for inbound complex... order), and the stock component of a stock-option complex order handled by the system is executed on...
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Egri-Nagy, Attila; Nehaniv, Chrystopher L
2008-01-01
Beyond complexity measures, sometimes it is worthwhile in addition to investigate how complexity changes structurally, especially in artificial systems where we have complete knowledge about the evolutionary process. Hierarchical decomposition is a useful way of assessing structural complexity changes of organisms modeled as automata, and we show how recently developed computational tools can be used for this purpose, by computing holonomy decompositions and holonomy complexity. To gain insight into the evolution of complexity, we investigate the smoothness of the landscape structure of complexity under minimal transitions. As a proof of concept, we illustrate how the hierarchical complexity analysis reveals symmetries and irreversible structure in biological networks by applying the methods to the lac operon mechanism in the genetic regulatory network of Escherichia coli.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-17
... System (a) Definition: No change. (b) Types of Complex Orders: No change. (c) Complex Order Book (i)-(iii..., the System will evaluate the COB when a complex order enters the COB, when the Exchange BBO changes... System may generate leg orders for the remaining size of the complex order in accordance with...
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Regulatory Compliance in Multi-Tier Supplier Networks
NASA Technical Reports Server (NTRS)
Goossen, Emray R.; Buster, Duke A.
2014-01-01
Over the years, avionics systems have increased in complexity to the point where 1st tier suppliers to an aircraft OEM find it financially beneficial to outsource designs of subsystems to 2nd tier and at times to 3rd tier suppliers. Combined with challenging schedule and budgetary pressures, the environment in which safety-critical systems are being developed introduces new hurdles for regulatory agencies and industry. This new environment of both complex systems and tiered development has raised concerns in the ability of the designers to ensure safety considerations are fully addressed throughout the tier levels. This has also raised questions about the sufficiency of current regulatory guidance to ensure: proper flow down of safety awareness, avionics application understanding at the lower tiers, OEM and 1st tier oversight practices, and capabilities of lower tier suppliers. Therefore, NASA established a research project to address Regulatory Compliance in a Multi-tier Supplier Network. This research was divided into three major study efforts: 1. Describe Modern Multi-tier Avionics Development 2. Identify Current Issues in Achieving Safety and Regulatory Compliance 3. Short-term/Long-term Recommendations Toward Higher Assurance Confidence This report presents our findings of the risks, weaknesses, and our recommendations. It also includes a collection of industry-identified risks, an assessment of guideline weaknesses related to multi-tier development of complex avionics systems, and a postulation of potential modifications to guidelines to close the identified risks and weaknesses.
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Zylberberg, Claudia; Matosevic, Sandro
2016-11-01
Liposomes were the first nanoscale drug to be approved for clinical use in 1995. Since then, the technology has grown considerably, and pioneering recent work in liposome-based delivery systems has brought about remarkable developments with significant clinical implications. This includes long-circulating liposomes, stimuli-responsive liposomes, nebulized liposomes, elastic liposomes for topical, oral and transdermal delivery and covalent lipid-drug complexes for improved drug plasma membrane crossing and targeting to specific organelles. While the regulatory bodies' opinion on liposomes is well-documented, current guidance that address new delivery systems are not. This review describes, in depth, the current state-of-the-art of these new liposomal delivery systems and provides a critical overview of the current regulatory landscape surrounding commercialization efforts of higher-level complexity systems, the expected requirements and the hurdles faced by companies seeking to bring novel liposome-based systems for clinical use to market.
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Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars.
Mühlebach, Stefan; Borchard, Gerrit; Yildiz, Selcan
2015-03-01
Nanomedicines are highly complex products and are the result of difficult to control manufacturing processes. Nonbiological complex drugs and their biological counterparts can comprise nanoparticles and therefore show nanomedicine characteristics. They consist of not fully known nonhomomolecular structures, and can therefore not be characterized by physicochemical means only. Also, intended copies of nanomedicines (follow-on similars) may have clinically meaningful differences, creating the regulatory challenge of how to grant a high degree of assurance for patients' benefit and safety. As an example, the current regulatory approach for marketing authorization of intended copies of nonbiological complex drugs appears inappropriate; also, a valid strategy incorporating the complexity of such systems is undefined. To demonstrate sufficient similarity and comparability, a stepwise quality, nonclinical and clinical approach is necessary to obtain market authorization for follow-on products as therapeutic alternatives, substitution and/or interchangeable products. To fill the regulatory gap, harmonized and science-based standards are needed.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-05-16
... every executed contract for complex orders routed to CBOE through their system. The purpose of this... that offer complex order execution systems in order for the Participant to qualify to participate in... complex order execution systems as of May 6, 2013. \\4\\ SR-CBOE-2013-032, pp. 5-7. The primary functional...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-01-12
... Electronic Complex Orders entered to the NYSE Arca System must comply with the order exposure requirements of... Complex Order, a Stock/ Option Order, or a Stock/Complex Order must be entered into the NYSE Arca System... Change Amending NYSE Arca Options Rule 6.62(h) to Define Stock/Complex Orders, Amending NYSE Arca Options...
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The complexity of gene expression dynamics revealed by permutation entropy
2010-01-01
Background High complexity is considered a hallmark of living systems. Here we investigate the complexity of temporal gene expression patterns using the concept of Permutation Entropy (PE) first introduced in dynamical systems theory. The analysis of gene expression data has so far focused primarily on the identification of differentially expressed genes, or on the elucidation of pathway and regulatory relationships. We aim to study gene expression time series data from the viewpoint of complexity. Results Applying the PE complexity metric to abiotic stress response time series data in Arabidopsis thaliana, genes involved in stress response and signaling were found to be associated with the highest complexity not only under stress, but surprisingly, also under reference, non-stress conditions. Genes with house-keeping functions exhibited lower PE complexity. Compared to reference conditions, the PE of temporal gene expression patterns generally increased upon stress exposure. High-complexity genes were found to have longer upstream intergenic regions and more cis-regulatory motifs in their promoter regions indicative of a more complex regulatory apparatus needed to orchestrate their expression, and to be associated with higher correlation network connectivity degree. Arabidopsis genes also present in other plant species were observed to exhibit decreased PE complexity compared to Arabidopsis specific genes. Conclusions We show that Permutation Entropy is a simple yet robust and powerful approach to identify temporal gene expression profiles of varying complexity that is equally applicable to other types of molecular profile data. PMID:21176199
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-02
... basis. NYSE Amex represents that any Customer Electronic Complex Orders entered to the NYSE Amex System..., or a Stock/Complex Order must be entered into the NYSE Amex System and displayed at a total or net...) To Define Stock/ Complex Orders, Rule 963NY(d) To Update and Clarify the Priority of Complex Orders...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-15
... to use their existing quotation systems to enter quotes for complex order strategies rather than... posted on the complex order book are not firm, nor included in the national market system. The Exchange... Complex Orders July 11, 2011. Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934 (the...
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Tandem Affinity Purification of Protein Complexes from Eukaryotic Cells.
Ma, Zheng; Fung, Victor; D'Orso, Iván
2017-01-26
The purification of active protein-protein and protein-nucleic acid complexes is crucial for the characterization of enzymatic activities and de novo identification of novel subunits and post-translational modifications. Bacterial systems allow for the expression and purification of a wide variety of single polypeptides and protein complexes. However, this system does not enable the purification of protein subunits that contain post-translational modifications (e.g., phosphorylation and acetylation), and the identification of novel regulatory subunits that are only present/expressed in the eukaryotic system. Here, we provide a detailed description of a novel, robust, and efficient tandem affinity purification (TAP) method using STREP- and FLAG-tagged proteins that facilitates the purification of protein complexes with transiently or stably expressed epitope-tagged proteins from eukaryotic cells. This protocol can be applied to characterize protein complex functionality, to discover post-translational modifications on complex subunits, and to identify novel regulatory complex components by mass spectrometry. Notably, this TAP method can be applied to study protein complexes formed by eukaryotic or pathogenic (viral and bacterial) components, thus yielding a wide array of downstream experimental opportunities. We propose that researchers working with protein complexes could utilize this approach in many different ways.
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Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.
Moreno-Moral, Aida; Pesce, Francesco; Behmoaras, Jacques; Petretto, Enrico
2017-01-01
Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.
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Wang, Jiguang; Sun, Yidan; Zheng, Si; Zhang, Xiang-Sun; Zhou, Huarong; Chen, Luonan
2013-01-01
Synergistic interactions among transcription factors (TFs) and their cofactors collectively determine gene expression in complex biological systems. In this work, we develop a novel graphical model, called Active Protein-Gene (APG) network model, to quantify regulatory signals of transcription in complex biomolecular networks through integrating both TF upstream-regulation and downstream-regulation high-throughput data. Firstly, we theoretically and computationally demonstrate the effectiveness of APG by comparing with the traditional strategy based only on TF downstream-regulation information. We then apply this model to study spontaneous type 2 diabetic Goto-Kakizaki (GK) and Wistar control rats. Our biological experiments validate the theoretical results. In particular, SP1 is found to be a hidden TF with changed regulatory activity, and the loss of SP1 activity contributes to the increased glucose production during diabetes development. APG model provides theoretical basis to quantitatively elucidate transcriptional regulation by modelling TF combinatorial interactions and exploiting multilevel high-throughput information.
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Wang, Jiguang; Sun, Yidan; Zheng, Si; Zhang, Xiang-Sun; Zhou, Huarong; Chen, Luonan
2013-01-01
Synergistic interactions among transcription factors (TFs) and their cofactors collectively determine gene expression in complex biological systems. In this work, we develop a novel graphical model, called Active Protein-Gene (APG) network model, to quantify regulatory signals of transcription in complex biomolecular networks through integrating both TF upstream-regulation and downstream-regulation high-throughput data. Firstly, we theoretically and computationally demonstrate the effectiveness of APG by comparing with the traditional strategy based only on TF downstream-regulation information. We then apply this model to study spontaneous type 2 diabetic Goto-Kakizaki (GK) and Wistar control rats. Our biological experiments validate the theoretical results. In particular, SP1 is found to be a hidden TF with changed regulatory activity, and the loss of SP1 activity contributes to the increased glucose production during diabetes development. APG model provides theoretical basis to quantitatively elucidate transcriptional regulation by modelling TF combinatorial interactions and exploiting multilevel high-throughput information. PMID:23346354
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Wang, Xia; Yang, Jian-Guo; Chen, Li; Wang, Ji-Long; Cheng, Qi; Dixon, Ray; Wang, Yi-Ping
2013-01-01
Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ∼100% activity of native K. pneumoniae system. Based on the expression levels of these BioBrick parts, a T7 RNA polymerase–LacI expression system was used to replace the σ54-dependent promoters located upstream of nif operons. Expression patterns of nif operons were critical for the maximum activity of the recombinant system. By mimicking these expression levels with variable-strength T7-dependent promoters, ∼42% of the nitrogenase activity of the σ54-dependent nif system was achieved in E. coli. When the newly constructed T7-dependent nif system was challenged with different genetic and physiological conditions, it bypassed the original complex regulatory circuits, with minor physiological limitations. Therefore, we have successfully replaced the nif regulatory elements with a simple expression system that may provide the first step for further research of introducing nif genes into eukaryotic organelles, which has considerable potentials in agro-biotechnology. PMID:23935879
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2011-01-01
Background Green plant leaves have always fascinated biologists as hosts for photosynthesis and providers of basic energy to many food webs. Today, comprehensive databases of gene expression data enable us to apply increasingly more advanced computational methods for reverse-engineering the regulatory network of leaves, and to begin to understand the gene interactions underlying complex emergent properties related to stress-response and development. These new systems biology methods are now also being applied to organisms such as Populus, a woody perennial tree, in order to understand the specific characteristics of these species. Results We present a systems biology model of the regulatory network of Populus leaves. The network is reverse-engineered from promoter information and expression profiles of leaf-specific genes measured over a large set of conditions related to stress and developmental. The network model incorporates interactions between regulators, such as synergistic and competitive relationships, by evaluating increasingly more complex regulatory mechanisms, and is therefore able to identify new regulators of leaf development not found by traditional genomics methods based on pair-wise expression similarity. The approach is shown to explain available gene function information and to provide robust prediction of expression levels in new data. We also use the predictive capability of the model to identify condition-specific regulation as well as conserved regulation between Populus and Arabidopsis. Conclusions We outline a computationally inferred model of the regulatory network of Populus leaves, and show how treating genes as interacting, rather than individual, entities identifies new regulators compared to traditional genomics analysis. Although systems biology models should be used with care considering the complexity of regulatory programs and the limitations of current genomics data, methods describing interactions can provide hypotheses about the underlying cause of emergent properties and are needed if we are to identify target genes other than those constituting the "low hanging fruit" of genomic analysis. PMID:21232107
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Gaiti, Federico; Jindrich, Katia; Fernandez-Valverde, Selene L; Roper, Kathrein E; Degnan, Bernard M; Tanurdžić, Miloš
2017-01-01
Combinatorial patterns of histone modifications regulate developmental and cell type-specific gene expression and underpin animal complexity, but it is unclear when this regulatory system evolved. By analysing histone modifications in a morphologically-simple, early branching animal, the sponge Amphimedonqueenslandica, we show that the regulatory landscape used by complex bilaterians was already in place at the dawn of animal multicellularity. This includes distal enhancers, repressive chromatin and transcriptional units marked by H3K4me3 that vary with levels of developmental regulation. Strikingly, Amphimedon enhancers are enriched in metazoan-specific microsyntenic units, suggesting that their genomic location is extremely ancient and likely to place constraints on the evolution of surrounding genes. These results suggest that the regulatory foundation for spatiotemporal gene expression evolved prior to the divergence of sponges and eumetazoans, and was necessary for the evolution of animal multicellularity. DOI: http://dx.doi.org/10.7554/eLife.22194.001 PMID:28395144
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-11-29
... orders.\\10\\ In addition, because CBOE's electronic complex order execution systems, the Complex Order..., ``Minimum Increments for Bids and Offers,'' to establish a minimum quoting increment for complex orders. The... 6.42(4) provides that bids and offers on complex orders may be expressed in any increment regardless...
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Mern, Demissew S; Ha, Seung-Wook; Khodaverdi, Viola; Gliese, Nicole; Görisch, Helmut
2010-05-01
In addition to the known response regulator ErbR (former AgmR) and the two-component regulatory system EraSR (former ExaDE), three additional regulatory proteins have been identified as being involved in controlling transcription of the aerobic ethanol oxidation system in Pseudomonas aeruginosa. Two putative sensor kinases, ErcS and ErcS', and a response regulator, ErdR, were found, all of which show significant similarity to the two-component flhSR system that controls methanol and formaldehyde metabolism in Paracoccus denitrificans. All three identified response regulators, EraR (formerly ExaE), ErbR (formerly AgmR) and ErdR, are members of the luxR family. The three sensor kinases EraS (formerly ExaD), ErcS and ErcS' do not contain a membrane domain. Apparently, they are localized in the cytoplasm and recognize cytoplasmic signals. Inactivation of gene ercS caused an extended lag phase on ethanol. Inactivation of both genes, ercS and ercS', resulted in no growth at all on ethanol, as did inactivation of erdR. Of the three sensor kinases and three response regulators identified thus far, only the EraSR (formerly ExaDE) system forms a corresponding kinase/regulator pair. Using reporter gene constructs of all identified regulatory genes in different mutants allowed the hierarchy of a hypothetical complex regulatory network to be established. Probably, two additional sensor kinases and two additional response regulators, which are hidden among the numerous regulatory genes annotated in the genome of P. aeruginosa, remain to be identified.
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The Yeast Nuclear Pore Complex and Transport Through It
Aitchison, John D.; Rout, Michael P.
2012-01-01
Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell’s genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or “Nups”), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC’s role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins. PMID:22419078
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Using DCOM to support interoperability in forest ecosystem management decision support systems
W.D. Potter; S. Liu; X. Deng; H.M. Rauscher
2000-01-01
Forest ecosystems exhibit complex dynamics over time and space. Management of forest ecosystems involves the need to forecast future states of complex systems that are often undergoing structural changes. This in turn requires integration of quantitative science and engineering components with sociopolitical, regulatory, and economic considerations. The amount of data...
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Licensing of future mobile satellite systems
NASA Technical Reports Server (NTRS)
Lepkowski, Ronald J.
1990-01-01
The regulatory process for licensing mobile satellite systems is complex and can require many years to complete. This process involves frequency allocations, national licensing, and frequency coordination. The regulatory process that resulted in the establishment of the radiodetermination satellite service (RDSS) between 1983 and 1987 is described. In contrast, each of these steps in the licensing of the mobile satellite service (MSS) is taking a significantly longer period of time to complete.
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Renn, Jürgen
2015-01-01
ABSTRACT This paper introduces a conceptual framework for the evolution of complex systems based on the integration of regulatory network and niche construction theories. It is designed to apply equally to cases of biological, social and cultural evolution. Within the conceptual framework we focus especially on the transformation of complex networks through the linked processes of externalization and internalization of causal factors between regulatory networks and their corresponding niches and argue that these are an important part of evolutionary explanations. This conceptual framework extends previous evolutionary models and focuses on several challenges, such as the path‐dependent nature of evolutionary change, the dynamics of evolutionary innovation and the expansion of inheritance systems. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 565–577, 2015. © 2015 The Authors. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution published by Wiley Periodicals, Inc. PMID:26097188
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Stochastic model simulation using Kronecker product analysis and Zassenhaus formula approximation.
Caglar, Mehmet Umut; Pal, Ranadip
2013-01-01
Probabilistic Models are regularly applied in Genetic Regulatory Network modeling to capture the stochastic behavior observed in the generation of biological entities such as mRNA or proteins. Several approaches including Stochastic Master Equations and Probabilistic Boolean Networks have been proposed to model the stochastic behavior in genetic regulatory networks. It is generally accepted that Stochastic Master Equation is a fundamental model that can describe the system being investigated in fine detail, but the application of this model is computationally enormously expensive. On the other hand, Probabilistic Boolean Network captures only the coarse-scale stochastic properties of the system without modeling the detailed interactions. We propose a new approximation of the stochastic master equation model that is able to capture the finer details of the modeled system including bistabilities and oscillatory behavior, and yet has a significantly lower computational complexity. In this new method, we represent the system using tensors and derive an identity to exploit the sparse connectivity of regulatory targets for complexity reduction. The algorithm involves an approximation based on Zassenhaus formula to represent the exponential of a sum of matrices as product of matrices. We derive upper bounds on the expected error of the proposed model distribution as compared to the stochastic master equation model distribution. Simulation results of the application of the model to four different biological benchmark systems illustrate performance comparable to detailed stochastic master equation models but with considerably lower computational complexity. The results also demonstrate the reduced complexity of the new approach as compared to commonly used Stochastic Simulation Algorithm for equivalent accuracy.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-08
... SQF 6.0 for convenience purposes so that market participants utilizing SQF 6.0 have an additional... provided on SQF 5.0); (3) System Event Messages (e.g., start of messages, start of system hours, start of quoting, start of opening); (4) Complex Order Strategy Auction Notifications (COLA); (5) Complex Order...
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Clinical trials bureaucracy: unintended consequences of well-intentioned policy.
Califf, Robert M
2006-01-01
As randomized controlled trials have become the 'gold standard' for medical research, a complex regulatory structure for the conduct of clinical trials has emerged. However, this structure has not been adequately assessed to ensure that regulations governing human subjects research actually produce the desired effects. Our purpose is to identify some of the major shortcomings in the current regulatory system of human clinical trials oversight, and to propose some potential solutions to these problems. We discuss the evolution of the current US regulatory environment and its application in the context of several widely-used drug therapies. Despite numerous randomized controlled trials, performed within a structure of extensive documentation and data collection, serious shortcomings in a number of pharmaceutical therapies were not detected until after the drugs were approved and widely adopted by clinicians. The current system of regulatory bureaucracy in clinical trials has led to an extremely expensive research paradigm that, in spite of complex systems of oversight and exhaustive data collection, cannot be shown to adequately ensure the integrity of the research process and the protection of human research subjects. Some parts of the system, including Research Ethics Review Boards, may not be well-suited to carrying out their core mission of overseeing research conduct, and other aspects of clinical trials regulatory structure, such as monitoring/auditing review and adverse event reporting, may constitute a waste of money and resources. Misdirected data collection and adverse events reporting divert valuable resources and hamper development of large, simple clinical trials powered to definitively answer important research questions. Careful scrutiny of the utility of current or proposed regulatory schemes is required to ensure the integrity of human subjects research and to enhance the effectiveness of research dollars.
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Ibarra-Arellano, Miguel A.; Campos-González, Adrián I.; Treviño-Quintanilla, Luis G.; Tauch, Andreas; Freyre-González, Julio A.
2016-01-01
The availability of databases electronically encoding curated regulatory networks and of high-throughput technologies and methods to discover regulatory interactions provides an invaluable source of data to understand the principles underpinning the organization and evolution of these networks responsible for cellular regulation. Nevertheless, data on these sources never goes beyond the regulon level despite the fact that regulatory networks are complex hierarchical-modular structures still challenging our understanding. This brings the necessity for an inventory of systems across a large range of organisms, a key step to rendering feasible comparative systems biology approaches. In this work, we take the first step towards a global understanding of the regulatory networks organization by making a cartography of the functional architectures of diverse bacteria. Abasy (Across-bacteria systems) Atlas provides a comprehensive inventory of annotated functional systems, global network properties and systems-level elements (global regulators, modular genes shaping functional systems, basal machinery genes and intermodular genes) predicted by the natural decomposition approach for reconstructed and meta-curated regulatory networks across a large range of bacteria, including pathogenically and biotechnologically relevant organisms. The meta-curation of regulatory datasets provides the most complete and reliable set of regulatory interactions currently available, which can even be projected into subsets by considering the force or weight of evidence supporting them or the systems that they belong to. Besides, Abasy Atlas provides data enabling large-scale comparative systems biology studies aimed at understanding the common principles and particular lifestyle adaptions of systems across bacteria. Abasy Atlas contains systems and system-level elements for 50 regulatory networks comprising 78 649 regulatory interactions covering 42 bacteria in nine taxa, containing 3708 regulons and 1776 systems. All this brings together a large corpus of data that will surely inspire studies to generate hypothesis regarding the principles governing the evolution and organization of systems and the functional architectures controlling them. Database URL: http://abasy.ccg.unam.mx PMID:27242034
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A Telecommunications Industry Primer: A Systems Model.
ERIC Educational Resources Information Center
Obermier, Timothy R.; Tuttle, Ronald H.
2003-01-01
Describes the Telecommunications Systems Model to help technical educators and students understand the increasingly complex telecommunications infrastructure. Specifically looks at ownership and regulatory status, service providers, transport medium, network protocols, and end-user services. (JOW)
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Shaffer, Fred
2015-01-01
Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self-regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems. PMID:25694852
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McCraty, Rollin; Shaffer, Fred
2015-01-01
Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self-regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems.
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Dissecting innate immune responses with the tools of systems biology.
Smith, Kelly D; Bolouri, Hamid
2005-02-01
Systems biology strives to derive accurate predictive descriptions of complex systems such as innate immunity. The innate immune system is essential for host defense, yet the resulting inflammatory response must be tightly regulated. Current understanding indicates that this system is controlled by complex regulatory networks, which maintain homoeostasis while accurately distinguishing pathogenic infections from harmless exposures. Recent studies have used high throughput technologies and computational techniques that presage predictive models and will be the foundation of a systems level understanding of innate immunity.
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Establishing an unusual cell type: How to make a dikaryon
Kruzel, Emilia K.; Hull, Christina M.
2010-01-01
Summary The dikaryons of basidiomycete fungi represent an unusual cell type required for complete sexual development. Dikaryon formation occurs via the activities of cell type-specific homeodomain transcription factors, which form regulatory complexes to establish the dikaryotic state. Decades of classical genetic and cell biological studies in mushrooms have provided a foundation for more recent molecular studies in the pathogenic species Ustilago maydis and Cryptococcus neoformans. Studies in these systems have revealed novel mechanisms of regulation that function downstream of classic homeodomain complexes to ensure that dikaryons are established and propagated. Comparisons of these dikaryon-specific networks promise to reveal the nature of regulatory network evolution and the adaptations responsible for driving complex eukaryotic development. PMID:21036099
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Beaver, Julia A.; Tzou, Abraham; Blumenthal, Gideon M.; McKee, Amy E.; Kim, Geoffrey; Pazdur, Richard; Philip, Reena
2016-01-01
As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges including analytical performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the U.S. Food and Drug Administration (FDA). These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. PMID:27993967
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Straube, Ronny
2017-12-01
Much of the complexity of regulatory networks derives from the necessity to integrate multiple signals and to avoid malfunction due to cross-talk or harmful perturbations. Hence, one may expect that the input-output behavior of larger networks is not necessarily more complex than that of smaller network motifs which suggests that both can, under certain conditions, be described by similar equations. In this review, we illustrate this approach by discussing the similarities that exist in the steady state descriptions of a simple bimolecular reaction, covalent modification cycles and bacterial two-component systems. Interestingly, in all three systems fundamental input-output characteristics such as thresholds, ultrasensitivity or concentration robustness are described by structurally similar equations. Depending on the system the meaning of the parameters can differ ranging from protein concentrations and affinity constants to complex parameter combinations which allows for a quantitative understanding of signal integration in these systems. We argue that this approach may also be extended to larger regulatory networks. Copyright © 2017 Elsevier B.V. All rights reserved.
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Beal, Jacob; Lu, Ting; Weiss, Ron
2011-01-01
Background The field of synthetic biology promises to revolutionize our ability to engineer biological systems, providing important benefits for a variety of applications. Recent advances in DNA synthesis and automated DNA assembly technologies suggest that it is now possible to construct synthetic systems of significant complexity. However, while a variety of novel genetic devices and small engineered gene networks have been successfully demonstrated, the regulatory complexity of synthetic systems that have been reported recently has somewhat plateaued due to a variety of factors, including the complexity of biology itself and the lag in our ability to design and optimize sophisticated biological circuitry. Methodology/Principal Findings To address the gap between DNA synthesis and circuit design capabilities, we present a platform that enables synthetic biologists to express desired behavior using a convenient high-level biologically-oriented programming language, Proto. The high level specification is compiled, using a regulatory motif based mechanism, to a gene network, optimized, and then converted to a computational simulation for numerical verification. Through several example programs we illustrate the automated process of biological system design with our platform, and show that our compiler optimizations can yield significant reductions in the number of genes () and latency of the optimized engineered gene networks. Conclusions/Significance Our platform provides a convenient and accessible tool for the automated design of sophisticated synthetic biological systems, bridging an important gap between DNA synthesis and circuit design capabilities. Our platform is user-friendly and features biologically relevant compiler optimizations, providing an important foundation for the development of sophisticated biological systems. PMID:21850228
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Beal, Jacob; Lu, Ting; Weiss, Ron
2011-01-01
The field of synthetic biology promises to revolutionize our ability to engineer biological systems, providing important benefits for a variety of applications. Recent advances in DNA synthesis and automated DNA assembly technologies suggest that it is now possible to construct synthetic systems of significant complexity. However, while a variety of novel genetic devices and small engineered gene networks have been successfully demonstrated, the regulatory complexity of synthetic systems that have been reported recently has somewhat plateaued due to a variety of factors, including the complexity of biology itself and the lag in our ability to design and optimize sophisticated biological circuitry. To address the gap between DNA synthesis and circuit design capabilities, we present a platform that enables synthetic biologists to express desired behavior using a convenient high-level biologically-oriented programming language, Proto. The high level specification is compiled, using a regulatory motif based mechanism, to a gene network, optimized, and then converted to a computational simulation for numerical verification. Through several example programs we illustrate the automated process of biological system design with our platform, and show that our compiler optimizations can yield significant reductions in the number of genes (~ 50%) and latency of the optimized engineered gene networks. Our platform provides a convenient and accessible tool for the automated design of sophisticated synthetic biological systems, bridging an important gap between DNA synthesis and circuit design capabilities. Our platform is user-friendly and features biologically relevant compiler optimizations, providing an important foundation for the development of sophisticated biological systems.
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The ribonucleoprotein Csr network.
Seyll, Ethel; Van Melderen, Laurence
2013-11-08
Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA binds to mRNA targets and regulates translation either negatively or positively. Binding to small non-coding RNAs controls activity of this protein. Expression of these regulators is tightly regulated at the level of transcription and stability by various global regulators (RNAses, two-component systems, alarmone). We discuss the implications of these complex regulations in bacterial adaptation.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-06-05
... systems to execute Stock/Option Orders,\\7\\ Stock/Complex Orders,\\8\\ and the option components of such... Change Amending Exchange Rule 6.91 To Remove Provisions Governing How the Complex Matching Engine Handles Electronic Complex Orders That Contain a Stock Leg May 30, 2013. Pursuant to Section 19(b)(1) \\1\\ of the...
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Integrative FourD omics approach profiles the target network of the carbon storage regulatory system
Sowa, Steven W.; Gelderman, Grant; Leistra, Abigail N.; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A.; Romeo, Tony; Baldea, Michael
2017-01-01
Abstract Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. PMID:28126921
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Rosen, C J; Glowacki, J; Craig, W
1998-01-01
Aging is associated with profound changes in the growth hormone/insulin-like growth factor (IGF) regulatory system. These include reductions in growth hormone, IGF-I, IGFBP3, and IGFBP-5 and an increase in IGFBP-4. These changes, coupled with rather marked declines in sex steroid production from both the ovary and adrenals may combine to have very deleterious effects on several organ systems in the postmenopausal woman. In particular, the prevalence of two very common diseases, osteoporosis and coronary artery disease, increase dramatically after the cessation of gonadal steroid production. The complex interrelationship between the IGF regulatory system and estrogens/androgens in the postmenopausal period may provide important clues as to the pathophysiology of both these disorders. In this paper, we begin to define the role of IGF-I (and its constituent IGF binding proteins) in skeletal and vascular tissue. Recent experimental data show the effects of estrogen on circulating and tissue IGFs in older individuals. Finally, estrogen replacement therapy affects the IGF regulatory system in postmenopausal women. Although conclusions from early studies remain somewhat preliminary, it is likely that the IGF regulatory system will be a prime target for future studies into the pathogenesis of several age and sex hormone related degenerative disorders.
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Ibarra-Arellano, Miguel A; Campos-González, Adrián I; Treviño-Quintanilla, Luis G; Tauch, Andreas; Freyre-González, Julio A
2016-01-01
The availability of databases electronically encoding curated regulatory networks and of high-throughput technologies and methods to discover regulatory interactions provides an invaluable source of data to understand the principles underpinning the organization and evolution of these networks responsible for cellular regulation. Nevertheless, data on these sources never goes beyond the regulon level despite the fact that regulatory networks are complex hierarchical-modular structures still challenging our understanding. This brings the necessity for an inventory of systems across a large range of organisms, a key step to rendering feasible comparative systems biology approaches. In this work, we take the first step towards a global understanding of the regulatory networks organization by making a cartography of the functional architectures of diverse bacteria. Abasy ( A: cross- BA: cteria SY: stems) Atlas provides a comprehensive inventory of annotated functional systems, global network properties and systems-level elements (global regulators, modular genes shaping functional systems, basal machinery genes and intermodular genes) predicted by the natural decomposition approach for reconstructed and meta-curated regulatory networks across a large range of bacteria, including pathogenically and biotechnologically relevant organisms. The meta-curation of regulatory datasets provides the most complete and reliable set of regulatory interactions currently available, which can even be projected into subsets by considering the force or weight of evidence supporting them or the systems that they belong to. Besides, Abasy Atlas provides data enabling large-scale comparative systems biology studies aimed at understanding the common principles and particular lifestyle adaptions of systems across bacteria. Abasy Atlas contains systems and system-level elements for 50 regulatory networks comprising 78 649 regulatory interactions covering 42 bacteria in nine taxa, containing 3708 regulons and 1776 systems. All this brings together a large corpus of data that will surely inspire studies to generate hypothesis regarding the principles governing the evolution and organization of systems and the functional architectures controlling them.Database URL: http://abasy.ccg.unam.mx. © The Author(s) 2016. Published by Oxford University Press.
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Decoding the complex genetic causes of heart diseases using systems biology.
Djordjevic, Djordje; Deshpande, Vinita; Szczesnik, Tomasz; Yang, Andrian; Humphreys, David T; Giannoulatou, Eleni; Ho, Joshua W K
2015-03-01
The pace of disease gene discovery is still much slower than expected, even with the use of cost-effective DNA sequencing and genotyping technologies. It is increasingly clear that many inherited heart diseases have a more complex polygenic aetiology than previously thought. Understanding the role of gene-gene interactions, epigenetics, and non-coding regulatory regions is becoming increasingly critical in predicting the functional consequences of genetic mutations identified by genome-wide association studies and whole-genome or exome sequencing. A systems biology approach is now being widely employed to systematically discover genes that are involved in heart diseases in humans or relevant animal models through bioinformatics. The overarching premise is that the integration of high-quality causal gene regulatory networks (GRNs), genomics, epigenomics, transcriptomics and other genome-wide data will greatly accelerate the discovery of the complex genetic causes of congenital and complex heart diseases. This review summarises state-of-the-art genomic and bioinformatics techniques that are used in accelerating the pace of disease gene discovery in heart diseases. Accompanying this review, we provide an interactive web-resource for systems biology analysis of mammalian heart development and diseases, CardiacCode ( http://CardiacCode.victorchang.edu.au/ ). CardiacCode features a dataset of over 700 pieces of manually curated genetic or molecular perturbation data, which enables the inference of a cardiac-specific GRN of 280 regulatory relationships between 33 regulator genes and 129 target genes. We believe this growing resource will fill an urgent unmet need to fully realise the true potential of predictive and personalised genomic medicine in tackling human heart disease.
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Hill, Kristine; Porco, Silvana; Lobet, Guillaume; Zappala, Susan; Mooney, Sacha; Draye, Xavier; Bennett, Malcolm J.
2013-01-01
Genetic and genomic approaches in model organisms have advanced our understanding of root biology over the last decade. Recently, however, systems biology and modeling have emerged as important approaches, as our understanding of root regulatory pathways has become more complex and interpreting pathway outputs has become less intuitive. To relate root genotype to phenotype, we must move beyond the examination of interactions at the genetic network scale and employ multiscale modeling approaches to predict emergent properties at the tissue, organ, organism, and rhizosphere scales. Understanding the underlying biological mechanisms and the complex interplay between systems at these different scales requires an integrative approach. Here, we describe examples of such approaches and discuss the merits of developing models to span multiple scales, from network to population levels, and to address dynamic interactions between plants and their environment. PMID:24143806
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Xiao, Yi; Jiang, Wen; Zhang, Fuzhong
2017-10-20
Responding to nitrogen status is essential for all living organisms. Bacteria have evolved various complex and exquisite regulatory systems to control nitrogen metabolism. However, natural nitrogen regulatory systems, owing to their complexity, often function only in their original hosts and do not respond properly when transferred to another species. By harnessing the Lactococcus GlnRA system, we developed a genetically encoded, cross-species ammonium biosensor that displays a dynamic range up to 9-fold upon detection of ammonium ion. We demonstrated applications of this ammonium biosensor in three different species (Escherichia coli, Pseudomonas putida, and Synechocystis sp.) to detect different nitrogen sources. This ammonium sensor was further used to regulate the biosynthesis of a nitrogen-rich polymer, cyanophycin, based on ammonium concentration. Given the importance of nitrogen responses, the developed biosensor should be broadly applicable to synthetic biology and bioengineering.
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Models-3 is a flexible software system designed to simplify the development and use of environmental assessment and other decision support tools. It is designed for applications ranging from regulatory and policy analysis to understanding the complex interactions of atmospheri...
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Kristie, T M; LeBowitz, J H; Sharp, P A
1989-01-01
The herpes simplex virus transactivator, alpha TIF, stimulates transcription of the alpha/immediate early genes via a cis-acting site containing an octamer element and a conserved flanking sequence. The alpha TIF protein, produced in a baculovirus expression system, nucleates the formation of at least two DNA--protein complexes on this regulatory element. Both of these complexes contain the ubiquitous Oct-1 protein, whose POU domain alone is sufficient to allow assembly of the alpha TIF-dependent complexes. A second member of the POU domain family, the lymphoid specific Oct-2 protein, can also be assembled into similar complexes at high concentrations of alpha TIF protein. These complexes contain at least two cellular proteins in addition to Oct-1. One of these proteins is present in both insect and HeLa cells and probably recognizes sequences in the cis element. The second cellular protein, only present in HeLa cells, probably binds by protein-protein interactions. Images PMID:2556266
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Kristie, T M; LeBowitz, J H; Sharp, P A
1989-12-20
The herpes simplex virus transactivator, alpha TIF, stimulates transcription of the alpha/immediate early genes via a cis-acting site containing an octamer element and a conserved flanking sequence. The alpha TIF protein, produced in a baculovirus expression system, nucleates the formation of at least two DNA--protein complexes on this regulatory element. Both of these complexes contain the ubiquitous Oct-1 protein, whose POU domain alone is sufficient to allow assembly of the alpha TIF-dependent complexes. A second member of the POU domain family, the lymphoid specific Oct-2 protein, can also be assembled into similar complexes at high concentrations of alpha TIF protein. These complexes contain at least two cellular proteins in addition to Oct-1. One of these proteins is present in both insect and HeLa cells and probably recognizes sequences in the cis element. The second cellular protein, only present in HeLa cells, probably binds by protein-protein interactions.
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Cellular and molecular specificity of pituitary gland physiology.
Perez-Castro, Carolina; Renner, Ulrich; Haedo, Mariana R; Stalla, Gunter K; Arzt, Eduardo
2012-01-01
The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.
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Molecular mechanisms of system responses to novel stimuli are predictable from public data
Danziger, Samuel A.; Ratushny, Alexander V.; Smith, Jennifer J.; Saleem, Ramsey A.; Wan, Yakun; Arens, Christina E.; Armstrong, Abraham M.; Sitko, Katherine; Chen, Wei-Ming; Chiang, Jung-Hsien; Reiss, David J.; Baliga, Nitin S.; Aitchison, John D.
2014-01-01
Systems scale models provide the foundation for an effective iterative cycle between hypothesis generation, experiment and model refinement. Such models also enable predictions facilitating the understanding of biological complexity and the control of biological systems. Here, we demonstrate the reconstruction of a globally predictive gene regulatory model from public data: a model that can drive rational experiment design and reveal new regulatory mechanisms underlying responses to novel environments. Specifically, using ∼1500 publically available genome-wide transcriptome data sets from Saccharomyces cerevisiae, we have reconstructed an environment and gene regulatory influence network that accurately predicts regulatory mechanisms and gene expression changes on exposure of cells to completely novel environments. Focusing on transcriptional networks that induce peroxisomes biogenesis, the model-guided experiments allow us to expand a core regulatory network to include novel transcriptional influences and linkage across signaling and transcription. Thus, the approach and model provides a multi-scalar picture of gene dynamics and are powerful resources for exploiting extant data to rationally guide experimentation. The techniques outlined here are generally applicable to any biological system, which is especially important when experimental systems are challenging and samples are difficult and expensive to obtain—a common problem in laboratory animal and human studies. PMID:24185701
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Tsou, Ann-Ping; Sun, Yi-Ming; Liu, Chia-Lin; Huang, Hsien-Da; Horng, Jorng-Tzong; Tsai, Meng-Feng; Liu, Baw-Juine
2006-07-01
Identification of transcriptional regulatory sites plays an important role in the investigation of gene regulation. For this propose, we designed and implemented a data warehouse to integrate multiple heterogeneous biological data sources with data types such as text-file, XML, image, MySQL database model, and Oracle database model. The utility of the biological data warehouse in predicting transcriptional regulatory sites of coregulated genes was explored using a synexpression group derived from a microarray study. Both of the binding sites of known transcription factors and predicted over-represented (OR) oligonucleotides were demonstrated for the gene group. The potential biological roles of both known nucleotides and one OR nucleotide were demonstrated using bioassays. Therefore, the results from the wet-lab experiments reinforce the power and utility of the data warehouse as an approach to the genome-wide search for important transcription regulatory elements that are the key to many complex biological systems.
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Yin, Weiwei; Garimalla, Swetha; Moreno, Alberto; Galinski, Mary R; Styczynski, Mark P
2015-08-28
There are increasing efforts to bring high-throughput systems biology techniques to bear on complex animal model systems, often with a goal of learning about underlying regulatory network structures (e.g., gene regulatory networks). However, complex animal model systems typically have significant limitations on cohort sizes, number of samples, and the ability to perform follow-up and validation experiments. These constraints are particularly problematic for many current network learning approaches, which require large numbers of samples and may predict many more regulatory relationships than actually exist. Here, we test the idea that by leveraging the accuracy and efficiency of classifiers, we can construct high-quality networks that capture important interactions between variables in datasets with few samples. We start from a previously-developed tree-like Bayesian classifier and generalize its network learning approach to allow for arbitrary depth and complexity of tree-like networks. Using four diverse sample networks, we demonstrate that this approach performs consistently better at low sample sizes than the Sparse Candidate Algorithm, a representative approach for comparison because it is known to generate Bayesian networks with high positive predictive value. We develop and demonstrate a resampling-based approach to enable the identification of a viable root for the learned tree-like network, important for cases where the root of a network is not known a priori. We also develop and demonstrate an integrated resampling-based approach to the reduction of variable space for the learning of the network. Finally, we demonstrate the utility of this approach via the analysis of a transcriptional dataset of a malaria challenge in a non-human primate model system, Macaca mulatta, suggesting the potential to capture indicators of the earliest stages of cellular differentiation during leukopoiesis. We demonstrate that by starting from effective and efficient approaches for creating classifiers, we can identify interesting tree-like network structures with significant ability to capture the relationships in the training data. This approach represents a promising strategy for inferring networks with high positive predictive value under the constraint of small numbers of samples, meeting a need that will only continue to grow as more high-throughput studies are applied to complex model systems.
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Sowa, Steven W; Gelderman, Grant; Leistra, Abigail N; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A; Romeo, Tony; Baldea, Michael; Contreras, Lydia M
2017-02-28
Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-25
... proposed rule change to amend the rules governing the trading of Complex Orders on BOX Market LLC (``BOX... particular investment strategy.\\4\\ BOX notes that its proposed definition of Complex Order is consistent with.../Crossed National Market System Plan.\\5\\ BOX also proposes to delete references to Stock-Option Orders and...
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Analysis of a Plant Transcriptional Regulatory Network Using Transient Expression Systems.
Díaz-Triviño, Sara; Long, Yuchen; Scheres, Ben; Blilou, Ikram
2017-01-01
In plant biology, transient expression systems have become valuable approaches used routinely to rapidly study protein expression, subcellular localization, protein-protein interactions, and transcriptional activity prior to in vivo studies. When studying transcriptional regulation, luciferase reporter assays offer a sensitive readout for assaying promoter behavior in response to different regulators or environmental contexts and to confirm and assess the functional relevance of predicted binding sites in target promoters. This chapter aims to provide detailed methods for using luciferase reporter system as a rapid, efficient, and versatile assay to analyze transcriptional regulation of target genes by transcriptional regulators. We describe a series of optimized transient expression systems consisting of Arabidopsis thaliana protoplasts, infiltrated Nicotiana benthamiana leaves, and human HeLa cells to study the transcriptional regulations of two well-characterized transcriptional regulators SCARECROW (SCR) and SHORT-ROOT (SHR) on one of their targets, CYCLIN D6 (CYCD6).Here, we illustrate similarities and differences in outcomes when using different systems. The plant-based systems revealed that the SCR-SHR complex enhances CYCD6 transcription, while analysis in HeLa cells showed that the complex is not sufficient to strongly induce CYCD6 transcription, suggesting that additional, plant-specific regulators are required for full activation. These results highlight the importance of the system and suggest that including heterologous systems, such as HeLa cells, can provide a more comprehensive analysis of a complex gene regulatory network.
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Biomechanical cell regulatory networks as complex adaptive systems in relation to cancer.
Feller, Liviu; Khammissa, Razia Abdool Gafaar; Lemmer, Johan
2017-01-01
Physiological structure and function of cells are maintained by ongoing complex dynamic adaptive processes in the intracellular molecular pathways controlling the overall profile of gene expression, and by genes in cellular gene regulatory circuits. Cytogenetic mutations and non-genetic factors such as chronic inflammation or repetitive trauma, intrinsic mechanical stresses within extracellular matrix may induce redirection of gene regulatory circuits with abnormal reactivation of embryonic developmental programmes which can now drive cell transformation and cancer initiation, and later cancer progression and metastasis. Some of the non-genetic factors that may also favour cancerization are dysregulation in epithelial-mesenchymal interactions, in cell-to-cell communication, in extracellular matrix turnover, in extracellular matrix-to-cell interactions and in mechanotransduction pathways. Persistent increase in extracellular matrix stiffness, for whatever reason, has been shown to play an important role in cell transformation, and later in cancer cell invasion. In this article we review certain cell regulatory networks driving carcinogenesis, focussing on the role of mechanical stresses modulating structure and function of cells and their extracellular matrices.
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Activity-Based Protein Profiling of Microbes
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sadler, Natalie C.; Wright, Aaron T.
Activity-Based Protein Profiling (ABPP) in conjunction with multimodal characterization techniques has yielded impactful findings in microbiology, particularly in pathogen, bioenergy, drug discovery, and environmental research. Using small molecule chemical probes that react irreversibly with specific proteins or protein families in complex systems has provided insights in enzyme functions in central metabolic pathways, drug-protein interactions, and regulatory protein redox, for systems ranging from photoautotrophic cyanobacteria to mycobacteria, and combining live cell or cell extract ABPP with proteomics, molecular biology, modeling, and other techniques has greatly expanded our understanding of these systems. New opportunities for application of ABPP to microbial systems include:more » enhancing protein annotation, characterizing protein activities in myriad environments, and reveal signal transduction and regulatory mechanisms in microbial systems.« less
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USER MANUAL FOR THE EPA THIRD-GENERATION AIR QUALITY MODELING SYSTEM (MODELS-3 VERSION 3.0)
Models-3 is a flexible software system designed to simplify the development and use of environmental assessment and other decision support tools. It is designed for applications ranging from regulatory and policy analysis to understanding the complex interactions of atmospheri...
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MODELS-3 INSTALLATION PROCEDURES FOR A PC WITH AN NT OPERATING SYSTEM (MODELS-3 VERSION 4.0)
Models-3 is a flexible software system designed to simplify the development and use of air quality models and other environmental decision support tools. It is designed for applications ranging from regulatory and policy analysis to understanding the complex interactions of at...
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Models-3 is a flexible system designed to simplify the development and use of air quality models and other environmental decision support tools. It is designed for applications ranging from regulatory and policy analysis to understanding the complex interactions of atmospheric...
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A systems approach for management of pests and pathogens of nursery crops
Jennifer L. Parke; Niklaus J. Grünwald
2012-01-01
Horticultural nurseries are heterogeneous and spatially complex agricultural systems, which present formidable challenges to management of diseases and pests. Moreover, nursery plants shipped interstate and internationally can serve as important vectors for pathogens and pests that threaten both agriculture and forestry. Current regulatory strategies to prevent this...
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Modelling and analysis of gene regulatory network using feedback control theory
NASA Astrophysics Data System (ADS)
El-Samad, H.; Khammash, M.
2010-01-01
Molecular pathways are a part of a remarkable hierarchy of regulatory networks that operate at all levels of organisation. These regulatory networks are responsible for much of the biological complexity within the cell. The dynamic character of these pathways and the prevalence of feedback regulation strategies in their operation make them amenable to systematic mathematical analysis using the same tools that have been used with success in analysing and designing engineering control systems. In this article, we aim at establishing this strong connection through various examples where the behaviour exhibited by gene networks is explained in terms of their underlying control strategies. We complement our analysis by a survey of mathematical techniques commonly used to model gene regulatory networks and analyse their dynamic behaviour.
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Hourd, Paul; Medcalf, Nicholas; Segal, Joel; Williams, David J
2015-01-01
Computer-aided 3D printing approaches to the industrial production of customized 3D functional living constructs for restoration of tissue and organ function face significant regulatory challenges. Using the manufacture of a customized, 3D-bioprinted nasal implant as a well-informed but hypothetical exemplar, we examine how these products might be regulated. Existing EU and USA regulatory frameworks do not account for the differences between 3D printing and conventional manufacturing methods or the ability to create individual customized products using mechanized rather than craft approaches. Already subject to extensive regulatory control, issues related to control of the computer-aided design to manufacture process and the associated software system chain present additional scientific and regulatory challenges for manufacturers of these complex 3D-bioprinted advanced combination products.
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Large Scale Comparative Visualisation of Regulatory Networks with TRNDiff
Chua, Xin-Yi; Buckingham, Lawrence; Hogan, James M.; ...
2015-06-01
The advent of Next Generation Sequencing (NGS) technologies has seen explosive growth in genomic datasets, and dense coverage of related organisms, supporting study of subtle, strain-specific variations as a determinant of function. Such data collections present fresh and complex challenges for bioinformatics, those of comparing models of complex relationships across hundreds and even thousands of sequences. Transcriptional Regulatory Network (TRN) structures document the influence of regulatory proteins called Transcription Factors (TFs) on associated Target Genes (TGs). TRNs are routinely inferred from model systems or iterative search, and analysis at these scales requires simultaneous displays of multiple networks well beyond thosemore » of existing network visualisation tools [1]. In this paper we describe TRNDiff, an open source system supporting the comparative analysis and visualization of TRNs (and similarly structured data) from many genomes, allowing rapid identification of functional variations within species. The approach is demonstrated through a small scale multiple TRN analysis of the Fur iron-uptake system of Yersinia, suggesting a number of candidate virulence factors; and through a larger study exploiting integration with the RegPrecise database (http://regprecise.lbl.gov; [2]) - a collection of hundreds of manually curated and predicted transcription factor regulons drawn from across the entire spectrum of prokaryotic organisms.« less
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Löffler, Michael; Simen, Joana Danica; Müller, Jan; Jäger, Günter; Laghrami, Salaheddine; Schäferhoff, Karin; Freund, Andreas; Takors, Ralf
2017-09-20
Transcriptional control under nitrogen and carbon-limitation conditions have been well analyzed for Escherichia coli. However, the transcriptional dynamics that underlie the shift in regulatory programs from nitrogen to carbon limitation is not well studied. In the present study, cells were cultivated at steady state under nitrogen (ammonia)-limited conditions then shifted to carbon (glucose) limitation to monitor changes in transcriptional dynamics. Nitrogen limitation was found to be dominated by sigma 54 (RpoN) and sigma 38 (RpoS), whereas the "housekeeping" sigma factor 70 (RpoD) and sigma 38 regulate cellular status under glucose limitation. During the transition, nitrogen-mediated control was rapidly redeemed and mRNAs that encode active uptake systems, such as ptsG and manXYZ, were quickly amplified. Next, genes encoding facilitators such as lamB were overexpressed, followed by high affinity uptake systems such as mglABC and non-specific porins such as ompF. These regulatory programs are complex and require well-equilibrated and superior control. At the metabolome level, 2-oxoglutarate is the likely component that links carbon- and nitrogen-mediated regulation by interacting with major regulatory elements. In the case of dual glucose and ammonia limitation, sigma 24 (RpoE) appears to play a key role in orchestrating these complex regulatory networks. Copyright © 2017 Elsevier B.V. All rights reserved.
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CHEMICAL PROCESSES AND MODELING IN ECOSYSTEMS
Trends in regulatory strategies require EPA to understand better chemical behavior in natural and impacted ecosystems and in biological systems to carry out the increasingly complex array of exposure and risk assessments needed to develop scientifically defensible regulations (GP...
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Estimation of Dynamic Systems for Gene Regulatory Networks from Dependent Time-Course Data.
Kim, Yoonji; Kim, Jaejik
2018-06-15
Dynamic system consisting of ordinary differential equations (ODEs) is a well-known tool for describing dynamic nature of gene regulatory networks (GRNs), and the dynamic features of GRNs are usually captured through time-course gene expression data. Owing to high-throughput technologies, time-course gene expression data have complex structures such as heteroscedasticity, correlations between genes, and time dependence. Since gene experiments typically yield highly noisy data with small sample size, for a more accurate prediction of the dynamics, the complex structures should be taken into account in ODE models. Hence, this study proposes an ODE model considering such data structures and a fast and stable estimation method for the ODE parameters based on the generalized profiling approach with data smoothing techniques. The proposed method also provides statistical inference for the ODE estimator and it is applied to a zebrafish retina cell network.
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A systematic analysis of a mi-RNA inter-pathway regulatory motif
2013-01-01
Background The continuing discovery of new types and functions of small non-coding RNAs is suggesting the presence of regulatory mechanisms far more complex than the ones currently used to study and design Gene Regulatory Networks. Just focusing on the roles of micro RNAs (miRNAs), they have been found to be part of several intra-pathway regulatory motifs. However, inter-pathway regulatory mechanisms have been often neglected and require further investigation. Results In this paper we present the result of a systems biology study aimed at analyzing a high-level inter-pathway regulatory motif called Pathway Protection Loop, not previously described, in which miRNAs seem to play a crucial role in the successful behavior and activation of a pathway. Through the automatic analysis of a large set of public available databases, we found statistical evidence that this inter-pathway regulatory motif is very common in several classes of KEGG Homo Sapiens pathways and concurs in creating a complex regulatory network involving several pathways connected by this specific motif. The role of this motif seems also confirmed by a deeper review of other research activities on selected representative pathways. Conclusions Although previous studies suggested transcriptional regulation mechanism at the pathway level such as the Pathway Protection Loop, a high-level analysis like the one proposed in this paper is still missing. The understanding of higher-level regulatory motifs could, as instance, lead to new approaches in the identification of therapeutic targets because it could unveil new and “indirect” paths to activate or silence a target pathway. However, a lot of work still needs to be done to better uncover this high-level inter-pathway regulation including enlarging the analysis to other small non-coding RNA molecules. PMID:24152805
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Tomicic, Alemka; Martínez, Claudio; Pérez, J Carola; Hollenstein, Tom; Angulo, Salvador; Gerstmann, Adam; Barroux, Isabelle; Krause, Mariane
2015-01-01
This study seeks to provide evidence of the dynamics associated with the configurations of discourse-voice regulatory strategies in patient-therapist interactions in relevant episodes within psychotherapeutic sessions. Its central assumption is that discourses manifest themselves differently in terms of their prosodic characteristics according to their regulatory functions in a system of interactions. The association between discourse and vocal quality in patients and therapists was analyzed in a sample of 153 relevant episodes taken from 164 sessions of five psychotherapies using the state space grid (SSG) method, a graphical tool based on the dynamic systems theory (DST). The results showed eight recurrent and stable discourse-voice regulatory strategies of the patients and three of the therapists. Also, four specific groups of these discourse-voice strategies were identified. The latter were interpreted as regulatory configurations, that is to say, as emergent self-organized groups of discourse-voice regulatory strategies constituting specific interactional systems. Both regulatory strategies and their configurations differed between two types of relevant episodes: Change Episodes and Rupture Episodes. As a whole, these results support the assumption that speaking and listening, as dimensions of the interaction that takes place during therapeutic conversation, occur at different levels. The study not only shows that these dimensions are dependent on each other, but also that they function as a complex and dynamic whole in therapeutic dialog, generating relational offers which allow the patient and the therapist to regulate each other and shape the psychotherapeutic process that characterizes each type of relevant episode.
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Healthcare software assurance.
Cooper, Jason G; Pauley, Keith A
2006-01-01
Software assurance is a rigorous, lifecycle phase-independent set of activities which ensure completeness, safety, and reliability of software processes and products. This is accomplished by guaranteeing conformance to all requirements, standards, procedures, and regulations. These assurance processes are even more important when coupled with healthcare software systems, embedded software in medical instrumentation, and other healthcare-oriented life-critical systems. The current Food and Drug Administration (FDA) regulatory requirements and guidance documentation do not address certain aspects of complete software assurance activities. In addition, the FDA's software oversight processes require enhancement to include increasingly complex healthcare systems such as Hospital Information Systems (HIS). The importance of complete software assurance is introduced, current regulatory requirements and guidance discussed, and the necessity for enhancements to the current processes shall be highlighted.
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Cooper, Jason G.; Pauley, Keith A.
2006-01-01
Software assurance is a rigorous, lifecycle phase-independent set of activities which ensure completeness, safety, and reliability of software processes and products. This is accomplished by guaranteeing conformance to all requirements, standards, procedures, and regulations. These assurance processes are even more important when coupled with healthcare software systems, embedded software in medical instrumentation, and other healthcare-oriented life-critical systems. The current Food and Drug Administration (FDA) regulatory requirements and guidance documentation do not address certain aspects of complete software assurance activities. In addition, the FDA’s software oversight processes require enhancement to include increasingly complex healthcare systems such as Hospital Information Systems (HIS). The importance of complete software assurance is introduced, current regulatory requirements and guidance discussed, and the necessity for enhancements to the current processes shall be highlighted. PMID:17238324
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Strengthening health professions regulation in Cambodia: a rapid assessment.
Clarke, David; Duke, Jan; Wuliji, Tana; Smith, Alyson; Phuong, Keat; San, Un
2016-03-10
This paper describes a rapid assessment of Cambodia's current system for regulating its health professions. The assessment forms part of a co-design process to set strategic priorities for strengthening health profession regulation to improve the quality and safety of health services. A health system approach for strengthening health professions' regulation is underway and aims to support the Government of Cambodia's plans for scaling up its health workforce, improving health services' safety and quality, and meeting its Association of South East Asian Nations (ASEAN) obligations to facilitate trade in health care services. The assessment used a mixed methods approach including: A desktop review of key laws, plans, reports and other documents relating to the regulation of the health professions in Cambodia (medicine, dentistry, midwifery, nursing and pharmacy); Key informant interviews with stakeholders in Cambodia (The term "stakeholders" refers to government officials, people working on health professional regulation, people working for the various health worker training institutions and health workers at the national and provincial level); Surveys and questionnaires to assess Cambodian stakeholder knowledge of regulation; Self-assessments by members of the five Cambodian regulatory councils regarding key capacities and activities of high-performing regulatory bodies; and A rapid literature review to identify: The key functions of health professional regulation; The key issues affecting the Cambodian health sector (including relevant developments in the wider ASEAN region); and "Smart" health profession regulation practices of possible relevance to Cambodia. We found that the current regulatory system only partially meets Cambodia's needs. A number of key regulatory functions are being performed, but overall, the current system was not designed with Cambodia's specific needs in mind. The existing system is also overly complex, with considerable duplication and overlap between governance and regulatory arrangements for the five regulated professions. There is considerable scope for reform to the current regulatory system to better align the system to Cambodia's: Current needs and circumstances; Health system strategic priorities; and International obligations. Cambodia is also well placed to base its reformed regulatory system on recent developments of "smart regulatory practices" for health professionals.
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Coordination of frontline defense mechanisms under severe oxidative stress.
Kaur, Amardeep; Van, Phu T; Busch, Courtney R; Robinson, Courtney K; Pan, Min; Pang, Wyming Lee; Reiss, David J; DiRuggiero, Jocelyne; Baliga, Nitin S
2010-07-01
Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations--this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of gamma rays.
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Models-3 is a flexible system designed to simplify the development and use of air quality models and other environmental decision support tools. It is designed for applications ranging from regulatory and policy analysis to understanding the complex interactions of atmospheric...
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Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation.
Manteiga, Sara; Choi, Kyungoh; Jayaraman, Arul; Lee, Kyongbum
2013-01-01
Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co-ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over-nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro-inflammatory phenotype drives a self-reinforcing cycle of pro-inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity-related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.
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Mammalian synthetic biology for studying the cell
Mathur, Melina; Xiang, Joy S.
2017-01-01
Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. PMID:27932576
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Gene Regulation, Two Component Regulatory Systems, and Adaptive Responses in Treponema Denticola.
Marconi, Richard T
2017-10-13
The oral microbiome consists of a remarkably diverse group of 500-700 bacterial species. The microbial etiology of periodontal disease is similarly complex. Of the ~400 bacterial species identified in subgingival plaque, at least 50 belong to the genus Treponema. As periodontal disease develops and progresses, T. denticola transitions from a low to high abundance species in the subgingival crevice. Changes in the overall composition of the bacterial population trigger significant changes in the local physical, immunological and physiochemical conditions. For T. denticola to thrive in periodontal pockets, it must be nimble and adapt to rapidly changing environmental conditions. The purpose of this chapter is to review the current understanding of the molecular basis of these essential adaptive responses, with a focus on the role of two component regulatory systems with global regulatory potential.
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Cross-border healthcare: Directive 2011/24 and the Greek law.
Vidalis, Takis; Kyriakaki, Irini
2014-03-01
The Greek legal framework on healthcare is characterized by the complexity of an immense number of laws and regulatory acts, particularly regarding the national health system. In the face front of that problem, the Directive stands as an effort (and an opportunity) to achieve a regulatory rationalization. The Law 3918/2011 established the National Organisation for Healthcare (EOPYY). EOPYY is the unique national contact point in the country for the purposes of the Directive, having a responsibility to ensure that the services provided by its affiliated healthcare providers meet certain quality and safety standards. Furthermore, the Greek legal system encompasses an integrated body of legislation on informed consent, privacy, and data protection, as well as an explicit reference to the 'quality, safety and efficiency' of medical services, and provisions related to reimbursement issues that need further regulatory specification.
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Hyytiäinen, H; Montesano, M; Palva, E T
2001-08-01
The production of the main virulence determinants, the extracellular plant cell wall-degrading enzymes, and hence virulence of Erwinia carotovora subsp. carotovora is controlled by a complex regulatory network. One of the global regulators, the response regulator ExpA, a GacA homolog, is required for transcriptional activation of the extracellular enzyme genes of this soft-rot pathogen. To elucidate the mechanism of ExpA control as well as interactions with other regulatory systems, we isolated second-site transposon mutants that would suppress the enzyme-negative phenotype of an expA (gacA) mutant. Inactivation of kdgR resulted in partial restoration of extracellular enzyme production and virulence to the expA mutant, suggesting an interaction between the two regulatory pathways. This interaction was mediated by the RsmA-rsmB system. Northern analysis was used to show that the regulatory rsmB RNA was under positive control of ExpA. Conversely, the expression of rsmA encoding a global repressor was under negative control of ExpA and positive control of KdgR. This study indicates a central role for the RsmA-rsmB regulatory system during pathogenesis, integrating signals from the ExpA (GacA) and KdgR global regulators of extracellular enzyme production in E. carotovora subsp. carotovora.
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Regulatory logic of pan-neuronal gene expression in C. elegans
Stefanakis, Nikolaos; Carrera, Ines; Hobert, Oliver
2015-01-01
While neuronal cell types display an astounding degree of phenotypic diversity, most if not all neuron types share a core panel of terminal features. However, little is known about how pan-neuronal expression patterns are genetically programmed. Through an extensive analysis of the cis-regulatory control regions of a battery of pan-neuronal C.elegans genes, including genes involved in synaptic vesicle biology and neuropeptide signaling, we define a common organizational principle in the regulation of pan-neuronal genes in the form of a surprisingly complex array of seemingly redundant, parallel-acting cis-regulatory modules that direct expression to broad, overlapping domains throughout the nervous system. These parallel-acting cis-regulatory modules are responsive to a multitude of distinct trans-acting factors. Neuronal gene expression programs therefore fall into two fundamentally distinct classes. Neuron type-specific genes are generally controlled by discrete and non-redundantly acting regulatory inputs, while pan-neuronal gene expression is controlled by diverse, coincident and seemingly redundant regulatory inputs. PMID:26291158
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Identification and role of regulatory non-coding RNAs in Listeria monocytogenes.
Izar, Benjamin; Mraheil, Mobarak Abu; Hain, Torsten
2011-01-01
Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes.
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Buyel, Johannes Felix; Fischer, Rainer
2014-01-31
Plants provide multiple benefits for the production of biopharmaceuticals including low costs, scalability, and safety. Transient expression offers the additional advantage of short development and production times, but expression levels can vary significantly between batches thus giving rise to regulatory concerns in the context of good manufacturing practice. We used a design of experiments (DoE) approach to determine the impact of major factors such as regulatory elements in the expression construct, plant growth and development parameters, and the incubation conditions during expression, on the variability of expression between batches. We tested plants expressing a model anti-HIV monoclonal antibody (2G12) and a fluorescent marker protein (DsRed). We discuss the rationale for selecting certain properties of the model and identify its potential limitations. The general approach can easily be transferred to other problems because the principles of the model are broadly applicable: knowledge-based parameter selection, complexity reduction by splitting the initial problem into smaller modules, software-guided setup of optimal experiment combinations and step-wise design augmentation. Therefore, the methodology is not only useful for characterizing protein expression in plants but also for the investigation of other complex systems lacking a mechanistic description. The predictive equations describing the interconnectivity between parameters can be used to establish mechanistic models for other complex systems.
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Novel excipients - Regulatory challenges and perspectives - The EU insight.
Kozarewicz, Piotr; Loftsson, Thorsteinn
2018-05-21
Novel excipients are indispensable in development of modern, advanced drug delivery systems and biotechnology-derived drugs. Although numerous novel excipients are developed for pharmaceutical use, they are not frequently seen in medicinal products due to the strict regulatory requirements and perception that their use makes new product evaluation more complex with risk of delays in the approval process. Regulators regard novel excipients as new substances and whenever new excipient is used in a formulation it must be subjected to full evaluation, similarly to the one required for new active substance. Consequently, the amount of information required in support of the regulatory approval (i.e. marketing authorization) is much more complex and comprehensive than for established excipients. This short review provides an insight into the use of novel excipients in medicinal products approved in the European Union. In addition, barriers and challenges in development of novel excipients are being discussed as well as means to overcome those barriers. Copyright © 2018 Elsevier B.V. All rights reserved.
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Ondondo, Beatrice Omusiro
2014-01-01
Excessive immune responses directed against foreign pathogens, self-antigens, or commensal microflora can cause cancer establishment and progression if the execution of tight immuno-regulatory mechanisms fails. On the other hand, induction of potent tumor antigen-specific immune responses together with stimulation of the innate immune system is a pre-requisite for effective anti-tumor immunity, and if suppressed by the strong immuno-regulatory mechanisms can lead to cancer progression. Therefore, it is crucial that the inevitable co-existence of these fundamental, yet conflicting roles of immune-regulatory cells is carefully streamlined as imbalances can be detrimental to the host. Infection with chronic persistent viruses is characterized by severe immune dysfunction resulting in T cell exhaustion and sometimes deletion of antigen-specific T cells. More often, this is due to increased immuno-regulatory processes, which are triggered to down-regulate immune responses and limit immunopathology. However, such heightened levels of immune disruption cause a concomitant loss of tumor immune-surveillance and create a permissive microenvironment for cancer establishment and progression, as demonstrated by increased incidences of cancer in immunosuppressed hosts. Paradoxically, while some cancers arise as a consequence of increased immuno-regulatory mechanisms that inhibit protective immune responses and impinge on tumor surveillance, other cancers arise due to impaired immuno-regulatory mechanisms and failure to limit pathogenic inflammatory responses. This intricate complexity, where immuno-regulatory cells can be beneficial in certain immune settings but detrimental in other settings underscores the need for carefully formulated interventions to equilibrate the balance between immuno-stimulatory and immuno-regulatory processes. PMID:24639678
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Steering healthcare service delivery: a regulatory perspective.
Prakash, Gyan
2015-01-01
The purpose of this paper is to explore regulation in India's healthcare sector and makes recommendations needed for enhancing the healthcare service. The literature was reviewed to understand healthcare's regulatory context. To understand the current healthcare system, qualitative data were collected from state-level officials, public and private hospital staff. A patient survey was performed to assess service quality (QoS). Regulation plays a central role in driving healthcare QoS. India needs to strengthen market and institutional co-production based approaches for steering its healthcare in which delivery processes are complex and pose different challenges. This study assesses current healthcare regulation in an Indian state and presents a framework for studying and strengthening regulation. Agile regulation should be based on service delivery issues (pull approach) rather than monitoring and sanctions based regulatory environment (push approach). Healthcare pitfalls across the world seem to follow similar follies. India's complexity and experience is useful for emerging and developed economies. The author reviewed around 70 publications and synthesised them in healthcare regulatory contexts. Patient's perception of private providers could be a key input towards steering regulation. Identifying gaps across QoS dimensions would be useful in taking corrective measures.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-18
... contains regulatory documents #0;having general applicability and legal effect, most of which are keyed #0... structures, propulsion methods, and systems technologies, the 6,000-pound demarcation is no longer justified... F & R flight testing regardless of the airplane's systems complexity or level of automation. After...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-09
..., the Exchange has designated this proposal to be operative for trades settling on or after February 1... system receives a Complex Order that improves the cPBBO. See Exchange Rule 1080. \\17\\ Market Exhaust... circumstance, the Phlx XL II system, using Market Exhaust, will initiate a Market Exhaust auction for the...
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Control systems and coordination protocols of the secretory pathway.
Luini, Alberto; Mavelli, Gabriella; Jung, Juan; Cancino, Jorge
2014-01-01
Like other cellular modules, the secretory pathway and the Golgi complex are likely to be supervised by control systems that support homeostasis and optimal functionality under all conditions, including external and internal perturbations. Moreover, the secretory apparatus must be functionally connected with other cellular modules, such as energy metabolism and protein degradation, via specific rules of interaction, or "coordination protocols". These regulatory devices are of fundamental importance for optimal function; however, they are generally "hidden" at steady state. The molecular components and the architecture of the control systems and coordination protocols of the secretory pathway are beginning to emerge through studies based on the use of controlled transport-specific perturbations aimed specifically at the detection and analysis of these internal regulatory devices.
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Tomicic, Alemka; Martínez, Claudio; Pérez, J. Carola; Hollenstein, Tom; Angulo, Salvador; Gerstmann, Adam; Barroux, Isabelle; Krause, Mariane
2015-01-01
This study seeks to provide evidence of the dynamics associated with the configurations of discourse-voice regulatory strategies in patient–therapist interactions in relevant episodes within psychotherapeutic sessions. Its central assumption is that discourses manifest themselves differently in terms of their prosodic characteristics according to their regulatory functions in a system of interactions. The association between discourse and vocal quality in patients and therapists was analyzed in a sample of 153 relevant episodes taken from 164 sessions of five psychotherapies using the state space grid (SSG) method, a graphical tool based on the dynamic systems theory (DST). The results showed eight recurrent and stable discourse-voice regulatory strategies of the patients and three of the therapists. Also, four specific groups of these discourse-voice strategies were identified. The latter were interpreted as regulatory configurations, that is to say, as emergent self-organized groups of discourse-voice regulatory strategies constituting specific interactional systems. Both regulatory strategies and their configurations differed between two types of relevant episodes: Change Episodes and Rupture Episodes. As a whole, these results support the assumption that speaking and listening, as dimensions of the interaction that takes place during therapeutic conversation, occur at different levels. The study not only shows that these dimensions are dependent on each other, but also that they function as a complex and dynamic whole in therapeutic dialog, generating relational offers which allow the patient and the therapist to regulate each other and shape the psychotherapeutic process that characterizes each type of relevant episode. PMID:25932014
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Howard, Thomas P; Lloyd, Julie C; Raines, Christine A
2011-07-01
In darkened leaves the Calvin cycle enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK) form a regulatory multi-enzyme complex with the small chloroplast protein CP12. GAPDH also forms a high molecular weight regulatory mono-enzyme complex. Given that there are different reports as to the number and subunit composition of these complexes and that enzyme regulatory mechanisms are known to vary between species, it was reasoned that protein-protein interactions may also vary between species. Here, this variation is investigated. This study shows that two different tetramers of GAPDH (an A2B2 heterotetramer and an A4 homotetramer) have the capacity to form part of the PRK/GAPDH/CP12 complex. The role of the PRK/GAPDH/CP12 complex is not simply to regulate the 'non-regulatory' A4 GAPDH tetramer. This study also demonstrates that the abundance and nature of PRK/GAPDH/CP12 interactions are not equal in all species and that whilst NAD enhances complex formation in some species, this is not sufficient for complex formation in others. Furthermore, it is shown that the GAPDH mono-enzyme complex is more abundant as a 2(A2B2) complex, rather than the larger 4(A2B2) complex. This smaller complex is sensitive to cellular metabolites indicating that it is an important regulatory isoform of GAPDH. This comparative study has highlighted considerable heterogeneity in PRK and GAPDH protein interactions between closely related species and the possible underlying physiological basis for this is discussed.
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Lobo, Daniel; Levin, Michael
2015-01-01
Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self-regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating in silico the rich dataset of morphological phenotypes resulting from genetic, surgical, and pharmacological experiments. We demonstrated our approach by inferring complete regulatory networks explaining the outcomes of the main functional regeneration experiments in the planarian literature; By analyzing all the datasets together, our system inferred the first systems-biology comprehensive dynamical model explaining patterning in planarian regeneration. This method provides an automated, highly generalizable framework for identifying the underlying control mechanisms responsible for the dynamic regulation of growth and form. PMID:26042810
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2005-07-01
vehicles to deliver mail or packages across town, in a large indoor complex or building, or even to deliver...drugs, marihuana , depressants or stimulants.330 Further, current licenses and certified personnel may have their
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-08-13
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-69829A; File No. SR-PHLX-2013-65] Self-Regulatory Organizations; Notice of Filing of Proposed Rule Change Relating To Which Complex Orders Can... Complex Orders Can Initiate a Complex Order Live Auction. The document was dated incorrectly. FOR FURTHER...
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Paital, Biswaranjan
2014-01-01
Responses of redox regulatory system to long-term survival (>18 h) of the catfish Heteropneustes fossilis in air are not yet understood. Lipid and protein oxidation level, oxidant (H2O2) generation, antioxidative status (levels of superoxide dismutase, catalase, glutathione peroxidase and reductase, ascorbic acid and non-protein sulfhydryl) and activities of respiratory complexes (I, II, III and IV) in mitochondria were investigated in muscle of H. fossilis under air exposure condition (0, 3, 6, 12 and 18 h at 25 °C). The increased levels of both H2O2 and tissue oxidation were observed due to the decreased activities of antioxidant enzymes in muscle under water deprivation condition. However, ascorbic acid and non-protein thiol groups were the highest at 18 h air exposure time. A linear increase in complex II activity with air exposure time and an increase up to 12 h followed by a decrease in activity of complex I at 18 h were observed. Negative correlation was observed for complex III and V activity with exposure time. Critical time to modulate the above parameters was found to be 3 h air exposure. Dehydration induced oxidative stress due to modulation of electron transport chain and redox metabolizing enzymes in muscle of H. fossilis was clearly observed. Possible contribution of redox regulatory system in muscle tissue of the fish for long-term survival in air is elucidated. Results of the present study may be useful to understand the redox metabolism in muscle of fishes those are exposed to air in general and air breathing fishes in particular.
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Mammalian synthetic biology for studying the cell.
Mathur, Melina; Xiang, Joy S; Smolke, Christina D
2017-01-02
Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. © 2017 Mathur et al.
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Evolutionary rewiring of bacterial regulatory networks
Taylor, Tiffany B.; Mulley, Geraldine; McGuffin, Liam J.; Johnson, Louise J.; Brockhurst, Michael A.; Arseneault, Tanya; Silby, Mark W.; Jackson, Robert W.
2015-01-01
Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks - homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor, et al. Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs. PMID:28357301
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Role of antisense RNAs in evolution of yeast regulatory complexity.
Lin, Chih-Hsu; Tsai, Zing Tsung-Yeh; Wang, Daryi
2013-01-01
Antisense RNAs (asRNAs) are known to regulate gene expression. However, a genome-wide mechanism of asRNA regulation is unclear, and there is no good explanation why partial asRNAs are not functional. To explore its regulatory role, we investigated asRNAs using an evolutionary approach, as genome-wide experimental data are limited. We found that the percentage of genes coupling with asRNAs in Saccharomyces cerevisiae is negatively associated with regulatory complexity and evolutionary age. Nevertheless, asRNAs evolve more slowly when their sense genes are under more complex regulation. Older genes coupling with asRNAs are more likely to demonstrate inverse expression, reflecting the role of these asRNAs as repressors. Our analyses provide novel evidence, suggesting a minor contribution of asRNAs in developing regulatory complexity. Although our results support the leaky hypothesis for asRNA transcription, our evidence also suggests that partial asRNAs may have evolved as repressors. Our study deepens the understanding of asRNA regulatory evolution. Copyright © 2013 Elsevier Inc. All rights reserved.
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Dintner, Sebastian; Heermann, Ralf; Fang, Chong; Jung, Kirsten; Gebhard, Susanne
2014-10-03
Resistance against antimicrobial peptides in many Firmicutes bacteria is mediated by detoxification systems that are composed of a two-component regulatory system (TCS) and an ATP-binding cassette (ABC) transporter. The histidine kinases of these systems depend entirely on the transporter for sensing of antimicrobial peptides, suggesting a novel mode of signal transduction where the transporter constitutes the actual sensor. The aim of this study was to investigate the molecular mechanisms of this unusual signaling pathway in more detail, using the bacitracin resistance system BceRS-BceAB of Bacillus subtilis as an example. To analyze the proposed communication between TCS and the ABC transporter, we characterized their interactions by bacterial two-hybrid analyses and could show that the permease BceB and the histidine kinase BceS interact directly. In vitro pulldown assays confirmed this interaction, which was found to be independent of bacitracin. Because it was unknown whether BceAB-type transporters could detect their substrate peptides directly or instead recognized the peptide-target complex in the cell envelope, we next analyzed substrate binding by the transport permease, BceB. Direct and specific binding of bacitracin by BceB was demonstrated by surface plasmon resonance spectroscopy. Finally, in vitro signal transduction assays indicated that complex formation with the transporter influenced the autophosphorylation activity of the histidine kinase. Taken together, our findings clearly show the existence of a sensory complex composed of TCS and ABC transporters and provide the first functional insights into the mechanisms of stimulus perception, signal transduction, and antimicrobial resistance employed by Bce-like detoxification systems. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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Dintner, Sebastian; Heermann, Ralf; Fang, Chong; Jung, Kirsten; Gebhard, Susanne
2014-01-01
Resistance against antimicrobial peptides in many Firmicutes bacteria is mediated by detoxification systems that are composed of a two-component regulatory system (TCS) and an ATP-binding cassette (ABC) transporter. The histidine kinases of these systems depend entirely on the transporter for sensing of antimicrobial peptides, suggesting a novel mode of signal transduction where the transporter constitutes the actual sensor. The aim of this study was to investigate the molecular mechanisms of this unusual signaling pathway in more detail, using the bacitracin resistance system BceRS-BceAB of Bacillus subtilis as an example. To analyze the proposed communication between TCS and the ABC transporter, we characterized their interactions by bacterial two-hybrid analyses and could show that the permease BceB and the histidine kinase BceS interact directly. In vitro pulldown assays confirmed this interaction, which was found to be independent of bacitracin. Because it was unknown whether BceAB-type transporters could detect their substrate peptides directly or instead recognized the peptide-target complex in the cell envelope, we next analyzed substrate binding by the transport permease, BceB. Direct and specific binding of bacitracin by BceB was demonstrated by surface plasmon resonance spectroscopy. Finally, in vitro signal transduction assays indicated that complex formation with the transporter influenced the autophosphorylation activity of the histidine kinase. Taken together, our findings clearly show the existence of a sensory complex composed of TCS and ABC transporters and provide the first functional insights into the mechanisms of stimulus perception, signal transduction, and antimicrobial resistance employed by Bce-like detoxification systems. PMID:25118291
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Fish pigmentation and the melanocortin system.
Cal, Laura; Suarez-Bregua, Paula; Cerdá-Reverter, José Miguel; Braasch, Ingo; Rotllant, Josep
2017-09-01
The melanocortin system is a complex neuroendocrine signaling mechanism involved in numerous physiological processes in vertebrates, including pigmentation, steroidogenesis and metabolic control. This review focuses at one of its most fascinating function in fish, its regulatory role in the control of pigmentation, in which the melanocortin 1 receptor (Mc1r), its agonist α-melanocyte stimulating hormone (α-Msh), and the endogenous antagonist agouti signaling protein (Asip1) are the main players. Functional control of Mc1r, which is highly expressed in fish skin and whose activation stimulates melanin production and melanosome dispersion in fish melanophores, is considered a key mechanism for vertebrate pigment phenotypes. The α-Msh peptide, the most documented Mc1r agonist involved in pigmentation, is produced in the pituitary gland, activating melanin synthesis by binding to Mc1r in fish melanophores. Finally, Asip1 is the putative factor for establishing the evolutionarily conserved dorso-ventral pigment pattern found across vertebrates. However, we are just starting to understand how other melanocortin system components are acting in this complex regulatory network. Copyright © 2017 Elsevier Inc. All rights reserved.
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Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment.
Yao, Yao; Storme, Veronique; Marchal, Kathleen; Van de Peer, Yves
2016-01-01
We developed a bio-inspired robot controller combining an artificial genome with an agent-based control system. The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent-based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems. Using such a design that separates the static from the conditionally active part of the gene regulatory network contributes to a better general adaptive behaviour. Here, we have explored the potential of our platform with respect to the evolution of adaptive behaviour, such as preying when food becomes scarce, in a complex and changing environment and show through simulations of swarm robots in an A-life environment that evolution of collective behaviour likely can be attributed to bio-inspired evolutionary processes acting at different levels, from the gene and the genome to the individual robot and robot population.
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Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment
Yao, Yao; Storme, Veronique; Marchal, Kathleen
2016-01-01
We developed a bio-inspired robot controller combining an artificial genome with an agent-based control system. The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent-based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems. Using such a design that separates the static from the conditionally active part of the gene regulatory network contributes to a better general adaptive behaviour. Here, we have explored the potential of our platform with respect to the evolution of adaptive behaviour, such as preying when food becomes scarce, in a complex and changing environment and show through simulations of swarm robots in an A-life environment that evolution of collective behaviour likely can be attributed to bio-inspired evolutionary processes acting at different levels, from the gene and the genome to the individual robot and robot population. PMID:28028477
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USDA-ARS?s Scientific Manuscript database
Serine acetyltransferase (SAT) catalyzes the limiting reaction in plant and microbial biosynthesis of cysteine. In addition to its enzymatic function, SAT forms a macromolecular complex with O-acetylserine sulfhydrylase (OASS). Formation of the cysteine regulatory complex (CRC) is a critical biochem...
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Coordination of frontline defense mechanisms under severe oxidative stress
Kaur, Amardeep; Van, Phu T; Busch, Courtney R; Robinson, Courtney K; Pan, Min; Pang, Wyming Lee; Reiss, David J; DiRuggiero, Jocelyne; Baliga, Nitin S
2010-01-01
Complexity of cellular response to oxidative stress (OS) stems from its wide-ranging damage to nucleic acids, proteins, carbohydrates, and lipids. We have constructed a systems model of OS response (OSR) for Halobacterium salinarum NRC-1 in an attempt to understand the architecture of its regulatory network that coordinates this complex response. This has revealed a multi-tiered OS-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism. Through experimental validation of interactions within the OSR regulatory network, we show that despite their inability to directly sense reactive oxygen species, general transcription factors have an important function in coordinating this response. Remarkably, a significant fraction of this OSR was accurately recapitulated by a model that was earlier constructed from cellular responses to diverse environmental perturbations—this constitutes the general stress response component. Notwithstanding this observation, comparison of the two models has identified the coordination of frontline defense and repair systems by regulatory mechanisms that are triggered uniquely by severe OS and not by other environmental stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of γ rays. PMID:20664639
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McBride, David J.; Buckle, Adam; van Heyningen, Veronica; Kleinjan, Dirk A.
2011-01-01
The PAX6 gene plays a crucial role in development of the eye, brain, olfactory system and endocrine pancreas. Consistent with its pleiotropic role the gene exhibits a complex developmental expression pattern which is subject to strict spatial, temporal and quantitative regulation. Control of expression depends on a large array of cis-elements residing in an extended genomic domain around the coding region of the gene. The minimal essential region required for proper regulation of this complex locus has been defined through analysis of human aniridia-associated breakpoints and YAC transgenic rescue studies of the mouse smalleye mutant. We have carried out a systematic DNase I hypersensitive site (HS) analysis across 200 kb of this critical region of mouse chromosome 2E3 to identify putative regulatory elements. Mapping the identified HSs onto a percent identity plot (PIP) shows many HSs correspond to recognisable genomic features such as evolutionarily conserved sequences, CpG islands and retrotransposon derived repeats. We then focussed on a region previously shown to contain essential long range cis-regulatory information, the Pax6 downstream regulatory region (DRR), allowing comparison of mouse HS data with previous human HS data for this region. Reporter transgenic mice for two of the HS sites, HS5 and HS6, show that they function as tissue specific regulatory elements. In addition we have characterised enhancer activity of an ultra-conserved cis-regulatory region located near Pax6, termed E60. All three cis-elements exhibit multiple spatio-temporal activities in the embryo that overlap between themselves and other elements in the locus. Using a deletion set of YAC reporter transgenic mice we demonstrate functional interdependence of the elements. Finally, we use the HS6 enhancer as a marker for the migration of precerebellar neuro-epithelium cells to the hindbrain precerebellar nuclei along the posterior and anterior extramural streams allowing visualisation of migratory defects in both pathways in Pax6Sey/Sey mice. PMID:22220192
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Programming Morphogenesis through Systems and Synthetic Biology.
Velazquez, Jeremy J; Su, Emily; Cahan, Patrick; Ebrahimkhani, Mo R
2018-04-01
Mammalian tissue development is an intricate, spatiotemporal process of self-organization that emerges from gene regulatory networks of differentiating stem cells. A major goal in stem cell biology is to gain a sufficient understanding of gene regulatory networks and cell-cell interactions to enable the reliable and robust engineering of morphogenesis. Here, we review advances in synthetic biology, single cell genomics, and multiscale modeling, which, when synthesized, provide a framework to achieve the ambitious goal of programming morphogenesis in complex tissues and organoids. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Martínez, Luary C; Yakhnin, Helen; Camacho, Martha I; Georgellis, Dimitris; Babitzke, Paul; Puente, José L; Bustamante, Víctor H
2011-06-01
Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) play key roles in the pathogenesis of Salmonella enterica. Previously, we showed that when Salmonella grows in Luria-Bertani medium, HilD, encoded in SPI-1, first induces the expression of hilA, located in SPI-1, and subsequently of the ssrAB operon, located in SPI-2. These genes code for HilA and the SsrA/B two-component system, the positive regulators of the SPI-1 and SPI-2 regulons respectively. In this study, we demonstrate that CsrA, a global regulatory RNA binding protein, post-transcriptionally regulates hilD expression by directly binding near the Shine-Dalgarno and translation initiation codon sequences of the hilD mRNA, preventing its translation and leading to its accelerated turnover. Negative regulation is counteracted by the global SirA/BarA two-component system, which directly activates the expression of CsrB and CsrC, two non-coding regulatory RNAs that sequester CsrA, thereby preventing it from binding to its target mRNAs. Our results illustrate the integration of global and specific regulators into a multifactorial regulatory cascade controlling the expression of virulence genes acquired by horizontal transfer events. © 2011 Blackwell Publishing Ltd.
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Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.
Hovingh, Elise S; van den Broek, Bryan; Jongerius, Ilse
2016-01-01
The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.
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Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion
Hovingh, Elise S.; van den Broek, Bryan; Jongerius, Ilse
2016-01-01
The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed. PMID:28066340
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-29
... designated this proposal to be operative for trades settling on or after January 4, 2010. The proposed...) during normal trading if the Phlx XL system receives a Complex Order that improves the cPBBO. See... in the series is received. In such a circumstance, the Phlx XL II system, using Market Exhaust, will...
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Fractal dynamics in physiology: Alterations with disease and aging
Goldberger, Ary L.; Amaral, Luis A. N.; Hausdorff, Jeffrey M.; Ivanov, Plamen Ch.; Peng, C.-K.; Stanley, H. Eugene
2002-01-01
According to classical concepts of physiologic control, healthy systems are self-regulated to reduce variability and maintain physiologic constancy. Contrary to the predictions of homeostasis, however, the output of a wide variety of systems, such as the normal human heartbeat, fluctuates in a complex manner, even under resting conditions. Scaling techniques adapted from statistical physics reveal the presence of long-range, power-law correlations, as part of multifractal cascades operating over a wide range of time scales. These scaling properties suggest that the nonlinear regulatory systems are operating far from equilibrium, and that maintaining constancy is not the goal of physiologic control. In contrast, for subjects at high risk of sudden death (including those with heart failure), fractal organization, along with certain nonlinear interactions, breaks down. Application of fractal analysis may provide new approaches to assessing cardiac risk and forecasting sudden cardiac death, as well as to monitoring the aging process. Similar approaches show promise in assessing other regulatory systems, such as human gait control in health and disease. Elucidating the fractal and nonlinear mechanisms involved in physiologic control and complex signaling networks is emerging as a major challenge in the postgenomic era. PMID:11875196
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Monzón-Sandoval, Jimena; Castillo-Morales, Atahualpa; Crampton, Sean; McKelvey, Laura; Nolan, Aoife; O'Keeffe, Gerard; Gutierrez, Humberto
2015-01-01
During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune-related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS. In order to gain insights into the scale and wider functional organization of immune-related genetic networks in the NS, we examined the large scale pattern of expression of these genes in the brain. Our results show a highly significant correlated expression and transcriptional clustering among immune-related genes in the developing and adult brain, and this correlation was the highest in the brain when compared to muscle, liver, kidney and endothelial cells. We experimentally tested the regulatory clustering of immune system (IS) genes by using microarray expression profiling in cultures of dissociated neurons stimulated with the pro-inflammatory cytokine TNF-alpha, and found a highly significant enrichment of immune system-related genes among the resulting differentially expressed genes. Our findings strongly suggest a coherent recruitment of entire immune-related genetic regulatory modules by the neural-specific genetic programme that shapes the NS.
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Smith, Jeffrey K
2013-04-01
Regulatory administrative database systems within the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) are essential to supporting its core mission, as a regulatory agency. Such systems are used within FDA to manage information and processes surrounding the processing, review, and tracking of investigational and marketed product submissions. This is an area of increasing interest in the pharmaceutical industry and has been a topic at trade association conferences (Buckley 2012). Such databases in CBER are complex, not for the type or relevance of the data to any particular scientific discipline but because of the variety of regulatory submission types and processes the systems support using the data. Commonalities among different data domains of CBER's regulatory administrative databases are discussed. These commonalities have evolved enough to constitute real database convergence and provide a valuable asset for business process intelligence. Balancing review workload across staff, exploring areas of risk in review capacity, process improvement, and presenting a clear and comprehensive landscape of review obligations are just some of the opportunities of such intelligence. This convergence has been occurring in the presence of usual forces that tend to drive information technology (IT) systems development toward separate stovepipes and data silos. CBER has achieved a significant level of convergence through a gradual process, using a clear goal, agreed upon development practices, and transparency of database objects, rather than through a single, discrete project or IT vendor solution. This approach offers a path forward for FDA systems toward a unified database.
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Diehl, Adam G
2018-01-01
Abstract The mouse is widely used as system to study human genetic mechanisms. However, extensive rewiring of transcriptional regulatory networks often confounds translation of findings between human and mouse. Site-specific gain and loss of individual transcription factor binding sites (TFBS) has caused functional divergence of orthologous regulatory loci, and so we must look beyond this positional conservation to understand common themes of regulatory control. Fortunately, transcription factor co-binding patterns shared across species often perform conserved regulatory functions. These can be compared to ‘regulatory sentences’ that retain the same meanings regardless of sequence and species context. By analyzing TFBS co-occupancy patterns observed in four human and mouse cell types, we learned a regulatory grammar: the rules by which TFBS are combined into meaningful regulatory sentences. Different parts of this grammar associate with specific sets of functional annotations regardless of sequence conservation and predict functional signatures more accurately than positional conservation. We further show that both species-specific and conserved portions of this grammar are involved in gene expression divergence and human disease risk. These findings expand our understanding of transcriptional regulatory mechanisms, suggesting that phenotypic divergence and disease risk are driven by a complex interplay between deeply conserved and species-specific transcriptional regulatory pathways. PMID:29361190
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Diversified Control Paths: A Significant Way Disease Genes Perturb the Human Regulatory Network
Wang, Bingbo; Gao, Lin; Zhang, Qingfang; Li, Aimin; Deng, Yue; Guo, Xingli
2015-01-01
Background The complexity of biological systems motivates us to use the underlying networks to provide deep understanding of disease etiology and the human diseases are viewed as perturbations of dynamic properties of networks. Control theory that deals with dynamic systems has been successfully used to capture systems-level knowledge in large amount of quantitative biological interactions. But from the perspective of system control, the ways by which multiple genetic factors jointly perturb a disease phenotype still remain. Results In this work, we combine tools from control theory and network science to address the diversified control paths in complex networks. Then the ways by which the disease genes perturb biological systems are identified and quantified by the control paths in a human regulatory network. Furthermore, as an application, prioritization of candidate genes is presented by use of control path analysis and gene ontology annotation for definition of similarities. We use leave-one-out cross-validation to evaluate the ability of finding the gene-disease relationship. Results have shown compatible performance with previous sophisticated works, especially in directed systems. Conclusions Our results inspire a deeper understanding of molecular mechanisms that drive pathological processes. Diversified control paths offer a basis for integrated intervention techniques which will ultimately lead to the development of novel therapeutic strategies. PMID:26284649
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Disentangling the many layers of eukaryotic transcriptional regulation.
Lelli, Katherine M; Slattery, Matthew; Mann, Richard S
2012-01-01
Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models.
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Who owns Australia's water--elements of an effective regulatory model.
McKay, J
2003-01-01
This paper identifies and describes a number of global trends in regulatory theory and legal scholarship. It points out the huge level of complexity demanded by globalisation and the unfortunate complication of this is that there is legal indeterminacy. The legal indeterminacy springs from the desire to amend and alter existing models. That has been the thrust of the Council of Australian Governments changes to adapt and add huge amounts of complexity to a flawed system. This paper argues that an effective water regulatory model requires a fundamental re-examination of the concept of water ownership and a capturing by the State of the right to allocate rainfall. This foundation is effective and the way forward to deal with the key issues in this transition phase. The second key element to an effective regulatory model is the concept of performance-based assessment. This requires information and schemes to be set up to work out ways to monitor and evaluate the performance of the utility on selected criteria. For Australia at present there is a dire lack of agreed criteria on these key issues and these have the potential to pull apart the whole process. The key issues are indigenous rights, governance issues, public participation, alteration of pre-existing rights and incorporation of environmental requirements.
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Gonçalves, Joana P; Aires, Ricardo S; Francisco, Alexandre P; Madeira, Sara C
2012-01-01
Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched processes related to these biological events were identified. Ranking scores further suggested ability to discern the primary role of a gene (target or regulator). Prototype is available at: http://kdbio.inesc-id.pt/software/regulatorysnapshots.
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Gonçalves, Joana P.; Aires, Ricardo S.; Francisco, Alexandre P.; Madeira, Sara C.
2012-01-01
Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched processes related to these biological events were identified. Ranking scores further suggested ability to discern the primary role of a gene (target or regulator). Prototype is available at: http://kdbio.inesc-id.pt/software/regulatorysnapshots. PMID:22563474
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Osadnik, Hendrik; Schöpfel, Michael; Heidrich, Eyleen; Mehner, Denise; Lilie, Hauke; Parthier, Christoph; Risselada, H Jelger; Grubmüller, Helmut; Stubbs, Milton T; Brüser, Thomas
2015-11-01
Phage shock protein A (PspA) belongs to the highy conserved PspA/IM30 family and is a key component of the stress inducible Psp system in Escherichia coli. One of its central roles is the regulatory interaction with the transcriptional activator of this system, the σ(54) enhancer-binding protein PspF, a member of the AAA+ protein family. The PspA/F regulatory system has been intensively studied and serves as a paradigm for AAA+ enzyme regulation by trans-acting factors. However, the molecular mechanism of how exactly PspA controls the activity of PspF and hence σ(54) -dependent expression of the psp genes is still unclear. To approach this question, we identified the minimal PspF-interacting domain of PspA, solved its structure, determined its affinity to PspF and the dissociation kinetics, identified residues that are potentially important for PspF regulation and analyzed effects of their mutation on PspF in vivo and in vitro. Our data indicate that several characteristics of AAA+ regulation in the PspA·F complex resemble those of the AAA+ unfoldase ClpB, with both proteins being regulated by a structurally highly conserved coiled-coil domain. The convergent evolution of both regulatory domains points to a general mechanism to control AAA+ activity for divergent physiologic tasks via coiled-coil domains. © 2015 John Wiley & Sons Ltd.
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Proteome complexity and the forces that drive proteome imbalance.
Harper, J Wade; Bennett, Eric J
2016-09-15
The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer.
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Revisiting the Issues: The Uniform Adoption Act.
ERIC Educational Resources Information Center
Hollinger, Joan Heifetz
1995-01-01
Discusses how a complex regulatory system, along with a lack of consensus about the functions served by adoption, produces uncertainty on many basic issues, including distinguishing lawful adoption versus illegal "baby-selling." The author recommends passage of more uniform state adoption laws, describes the 1994 Uniform Adoption Act,…
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USDA-ARS?s Scientific Manuscript database
To balance the demand for uptake of essential elements with their potential toxicity living cells have complex regulatory mechanisms. Here, we describe a genome-wide screen to identify genes that impact the elemental composition (‘ionome’) of yeast Saccharomyces cerevisiae. Using inductively coupled...
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Application of SAE ARP4754A to Flight Critical Systems
NASA Technical Reports Server (NTRS)
Peterson, Eric M.
2015-01-01
This report documents applications of ARP4754A to the development of modern computer-based (i.e., digital electronics, software and network-based) aircraft systems. This study is to offer insight and provide educational value relative to the guidelines in ARP4754A and provide an assessment of the current state-of-the- practice within industry and regulatory bodies relative to development assurance for complex and safety-critical computer-based aircraft systems.
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Using trading zones and life cycle analysis to understand nanotechnology regulation.
Wardak, Ahson; Gorman, Michael E
2006-01-01
This article reviews the public health and environmental regulations applicable to nanotechnology using a life cycle model from basic research through end-of-life for products. Given nanotechnology's immense promise and public investment, regulations are important, balancing risk with the public good. Trading zones and earth systems engineering management assist in explaining potential solutions to gaps in an otherwise complex, overlapping regulatory system.
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Artificial intelligence (AI) systems for interpreting complex medical datasets.
Altman, R B
2017-05-01
Advances in machine intelligence have created powerful capabilities in algorithms that find hidden patterns in data, classify objects based on their measured characteristics, and associate similar patients/diseases/drugs based on common features. However, artificial intelligence (AI) applications in medical data have several technical challenges: complex and heterogeneous datasets, noisy medical datasets, and explaining their output to users. There are also social challenges related to intellectual property, data provenance, regulatory issues, economics, and liability. © 2017 ASCPT.
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Gluconacetobacter diazotrophicus PAL5 possesses an active quorum sensing regulatory system.
Bertini, Elisa V; Nieto Peñalver, Carlos G; Leguina, Ana C; Irazusta, Verónica P; de Figueroa, Lucía I C
2014-09-01
The endophytic bacterium Gluconacetobacter diazotrophicus colonizes a broad range of host plants. Its plant growth-promoting capability is related to the capacity to perform biological nitrogen fixation, the biosynthesis of siderophores, antimicrobial substances and the solubilization of mineral nutrients. Colonization of and survival in these endophytic niche requires a complex regulatory network. Among these, quorum sensing systems (QS) are signaling mechanisms involved in the control of several genes related to microbial interactions, host colonization and stress survival. G. diazotrophicus PAL5 possesses a QS composed of a luxR and a luxI homolog, and produces eight molecules from the AHL family as QS signals. In this report data are provided showing that glucose concentration modifies the relative levels of these signal molecules. The activity of G. diazotrophicus PAL5 QS is also altered in presence of other carbon sources and under saline stress conditions. Inactivation of the QS system of G. diazotrophicus PAL5 by means of a quorum quenching strategy allowed the identification of extracellular and intracellular proteins under the control of this regulatory mechanism.
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Ferrucci, Luigi; Ble, Alessandro; Bandinelli, Stefania; Lauretani, Fulvio; Suthers, Kristen; Guralnik, Jack M
2004-06-01
Inflammation is a human being's primary defense against threats to homeostasis that are encountered every day. Especially in old age, when regulatory mechanisms responsible for inflammatory responses may be ineffective or damaged, the result can be adverse pathological conditions, and an increased risk of morbidity and mortality. The inflammation response is a plastic network composed of redundant signaling among several different mediators. These mediators have a reciprocal relationship with other biological sub-systems, including hormone regulation, the autonomic nervous system, and oxidative/anti-oxidant balance. Studying this complex architecture requires parallel and multiple research strategies from epidemiological to biochemical level, from observational studies to innovative intervention approaches. Given that the inflammatory response is a critical age-related process, understanding its regulatory action is essential in avoiding hazardous consequences in old age.
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Multi-agent electricity market modeling with EMCAS.
DOE Office of Scientific and Technical Information (OSTI.GOV)
North, M.; Macal, C.; Conzelmann, G.
2002-09-05
Electricity systems are a central component of modern economies. Many electricity markets are transitioning from centrally regulated systems to decentralized markets. Furthermore, several electricity markets that have recently undergone this transition have exhibited extremely unsatisfactory results, most notably in California. These high stakes transformations require the introduction of largely untested regulatory structures. Suitable tools that can be used to test these regulatory structures before they are applied to real systems are required. Multi-agent models can provide such tools. To better understand the requirements such as tool, a live electricity market simulation was created. This experience helped to shape the developmentmore » of the multi-agent Electricity Market Complex Adaptive Systems (EMCAS) model. To explore EMCAS' potential, several variations of the live simulation were created. These variations probed the possible effects of changing power plant outages and price setting rules on electricity market prices.« less
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An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response
Buckley, Katherine M.; Rast, Jonathan P.
2017-01-01
The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN) approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17), are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism. PMID:29109720
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Heroven, Ann Kathrin; Böhme, Katja; Dersch, Petra
2012-04-01
This review emphasizes the function and regulation of the Csr regulatory system in the human enteropathogen Yersinia pseudotuberculosis and compares its features with the homologous Csr/Rsm systems of related pathogens. The Csr/Rsm systems of eubacteria form a complex regulatory network in which redundant non-translated Csr/Rsm-RNAs bind the RNA-binding protein CsrA/RsmA, thereby preventing its interaction with mRNA targets. The Csr system is controlled by the BarA/UvrY-type of two-component sensor-regulator systems. Apart from that, common or pathogen-specific regulators control the abundance of the Csr components. The coordinate control of virulence factors and infection-linked physiological traits by the Csr/Rsm systems helps the pathogens to adapt individually to rapidly changing conditions to which they are exposed during the different stages of an infection. As Csr/Rsm function is relevant for full virulence, it represents a target suitable for antimicrobial drug development.
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Uhl, Juli D.; Cook, Tiffany A.; Gebelein, Brian
2010-01-01
Hox transcription factors specify numerous cell fates along the anterior-posterior axis by regulating the expression of downstream target genes. While expression analysis has uncovered large numbers of de-regulated genes in cells with altered Hox activity, determining which are direct versus indirect targets has remained a significant challenge. Here, we characterize the DNA binding activity of Hox transcription factor complexes on eight experimentally verified cis-regulatory elements. Hox factors regulate the activity of each element by forming protein complexes with two cofactor proteins, Extradenticle (Exd) and Homothorax (Hth). Using comparative DNA binding assays, we found that a number of flexible arrangements of Hox, Exd, and Hth binding sites mediate cooperative transcription factor complexes. Moreover, analysis of a Distal-less regulatory element (DMXR) that is repressed by abdominal Hox factors revealed that suboptimal binding sites can be combined to form high affinity transcription complexes. Lastly, we determined that the anterior Hox factors are more dependent upon Exd and Hth for complex formation than posterior Hox factors. Based upon these findings, we suggest a general set of guidelines to serve as a basis for designing bioinformatics algorithms aimed at identifying Hox regulatory elements using the wealth of recently sequenced genomes. PMID:20398649
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Manufacturing of biodrugs: need for harmonization in regulatory standards.
Sahoo, Niharika; Choudhury, Koel; Manchikanti, Padmavati
2009-01-01
Biodrugs (biologics) are much more complex than chemically synthesized drugs because of their structural heterogeneity and interactions within a given biologic system. The manufacturing process in the biodrug industry varies with each type of molecule and is far more elaborate and stringent due to the use of living organisms and complex substrates. Product purity and altered structural characteristics leading to potential immunogenicity have often been of concern when establishing quality and safety in the use of biodrugs. Regulatory compliance in manufacturing and commercialization of biodrugs involves quality control, quality assurance, and batch documentation. Many factors such as host cell development, cell bank establishment, cell culture, protein production, purification, analysis, formulation, storage, and handling are critical for ensuring the purity, activity, and safety of the finished product. Good Manufacturing Practice (GMP) for biodrugs has been developed in certain regions such as the EU, US, and Japan. Due to differences in manufacturing methods and systems, product-specific GMP guidelines are evolving. In general, there are variations in GMP guidelines between countries, which lead to difficulty for the manufacturers in conforming to different standards, thus entailing delays in the commercialization of biodrugs. There is a need to develop a unified regulatory guideline for biodrug manufacturing across various countries, which would be helpful in the marketing of products and trade. This review deals with the comparative framework and analysis of GMP regulation of biodrugs.
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Role of transcriptional regulation in the evolution of plant phenotype: A dynamic systems approach.
Rodríguez-Mega, Emiliano; Piñeyro-Nelson, Alma; Gutierrez, Crisanto; García-Ponce, Berenice; Sánchez, María De La Paz; Zluhan-Martínez, Estephania; Álvarez-Buylla, Elena R; Garay-Arroyo, Adriana
2015-03-02
A growing body of evidence suggests that alterations in transcriptional regulation of genes involved in modulating development are an important part of phenotypic evolution, and this can be documented among species and within populations. While the effects of differential transcriptional regulation in organismal development have been preferentially studied in animal systems, this phenomenon has also been addressed in plants. In this review, we summarize evidence for cis-regulatory mutations, trans-regulatory changes and epigenetic modifications as molecular events underlying important phenotypic alterations, and thus shaping the evolution of plant development. We postulate that a mechanistic understanding of why such molecular alterations have a key role in development, morphology and evolution will have to rely on dynamic models of complex regulatory networks that consider the concerted action of genetic and nongenetic components, and that also incorporate the restrictions underlying the genotype to phenotype mapping process. Developmental Dynamics, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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Stability analysis of an autocatalytic protein model
NASA Astrophysics Data System (ADS)
Lee, Julian
2016-05-01
A self-regulatory genetic circuit, where a protein acts as a positive regulator of its own production, is known to be the simplest biological network with a positive feedback loop. Although at least three components—DNA, RNA, and the protein—are required to form such a circuit, stability analysis of the fixed points of this self-regulatory circuit has been performed only after reducing the system to a two-component system, either by assuming a fast equilibration of the DNA component or by removing the RNA component. Here, stability of the fixed points of the three-component positive feedback loop is analyzed by obtaining eigenvalues of the full three-dimensional Hessian matrix. In addition to rigorously identifying the stable fixed points and saddle points, detailed information about the system can be obtained, such as the existence of complex eigenvalues near a fixed point.
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Scientific and Regulatory Considerations for Generic Complex Drug Products Containing Nanomaterials.
Zheng, Nan; Sun, Dajun D; Zou, Peng; Jiang, Wenlei
2017-05-01
In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.
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Cardiac mitochondrial matrix and respiratory complex protein phosphorylation
Covian, Raul
2012-01-01
It has become appreciated over the last several years that protein phosphorylation within the cardiac mitochondrial matrix and respiratory complexes is extensive. Given the importance of oxidative phosphorylation and the balance of energy metabolism in the heart, the potential regulatory effect of these classical signaling events on mitochondrial function is of interest. However, the functional impact of protein phosphorylation and the kinase/phosphatase system responsible for it are relatively unknown. Exceptions include the well-characterized pyruvate dehydrogenase and branched chain α-ketoacid dehydrogenase regulatory system. The first task of this review is to update the current status of protein phosphorylation detection primarily in the matrix and evaluate evidence linking these events with enzymatic function or protein processing. To manage the scope of this effort, we have focused on the pathways involved in energy metabolism. The high sensitivity of modern methods of detecting protein phosphorylation and the low specificity of many kinases suggests that detection of protein phosphorylation sites without information on the mole fraction of phosphorylation is difficult to interpret, especially in metabolic enzymes, and is likely irrelevant to function. However, several systems including protein translocation, adenine nucleotide translocase, cytochrome c, and complex IV protein phosphorylation have been well correlated with enzymatic function along with the classical dehydrogenase systems. The second task is to review the current understanding of the kinase/phosphatase system within the matrix. Though it is clear that protein phosphorylation occurs within the matrix, based on 32P incorporation and quantitative mass spectrometry measures, the kinase/phosphatase system responsible for this process is ill-defined. An argument is presented that remnants of the much more labile bacterial protein phosphoryl transfer system may be present in the matrix and that the evaluation of this possibility will require the application of approaches developed for bacterial cell signaling to the mitochondria. PMID:22886415
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Gene Regulatory Networks in Cardiac Conduction System Development
Munshi, Nikhil V.
2014-01-01
The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Given its critical role in coordinating cardiac performance, a detailed analysis of the molecular mechanisms underlying conduction system formation should inform our understanding of arrhythmia pathophysiology and affect the development of novel therapeutic strategies. Historically, the ability to distinguish cells of the conduction system from neighboring working myocytes presented a major technical challenge for performing comprehensive mechanistic studies. Early lineage tracing experiments suggested that conduction cells derive from cardiomyocyte precursors, and these claims have been substantiated by using more contemporary approaches. However, regional specialization of conduction cells adds an additional layer of complexity to this system, and it appears that different components of the conduction system utilize unique modes of developmental formation. The identification of numerous transcription factors and their downstream target genes involved in regional differentiation of the conduction system has provided insight into how lineage commitment is achieved. Furthermore, by adopting cutting-edge genetic techniques in combination with sophisticated phenotyping capabilities, investigators have made substantial progress in delineating the regulatory networks that orchestrate conduction system formation and their role in cardiac rhythm and physiology. This review describes the connectivity of these gene regulatory networks in cardiac conduction system development and discusses how they provide a foundation for understanding normal and pathological human cardiac rhythms. PMID:22628576
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Sato, Masanao; Tsuda, Kenichi; Wang, Lin; Coller, John; Watanabe, Yuichiro; Glazebrook, Jane; Katagiri, Fumiaki
2010-01-01
Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. We studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2). This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles for 571 immune response genes of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with Pto DC3000 AvrRpt2. The mRNA profiles were analyzed as detailed descriptions of changes in the network state resulting from the genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting static network model accurately predicted 23 of 25 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i) the components of the network are highly interconnected; and (ii) negative regulatory relationships are common between signaling sectors. Complex regulatory relationships, including a novel negative regulatory relationship between the early microbe-associated molecular pattern-triggered signaling sectors and the salicylic acid sector, were further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a “sector-switching” network, which effectively balances two apparently conflicting demands, robustness against pathogenic perturbations and moderation of negative impacts of immune responses on plant fitness. PMID:20661428
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Modeling gene regulatory network motifs using statecharts
2012-01-01
Background Gene regulatory networks are widely used by biologists to describe the interactions among genes, proteins and other components at the intra-cellular level. Recently, a great effort has been devoted to give gene regulatory networks a formal semantics based on existing computational frameworks. For this purpose, we consider Statecharts, which are a modular, hierarchical and executable formal model widely used to represent software systems. We use Statecharts for modeling small and recurring patterns of interactions in gene regulatory networks, called motifs. Results We present an improved method for modeling gene regulatory network motifs using Statecharts and we describe the successful modeling of several motifs, including those which could not be modeled or whose models could not be distinguished using the method of a previous proposal. We model motifs in an easy and intuitive way by taking advantage of the visual features of Statecharts. Our modeling approach is able to simulate some interesting temporal properties of gene regulatory network motifs: the delay in the activation and the deactivation of the "output" gene in the coherent type-1 feedforward loop, the pulse in the incoherent type-1 feedforward loop, the bistability nature of double positive and double negative feedback loops, the oscillatory behavior of the negative feedback loop, and the "lock-in" effect of positive autoregulation. Conclusions We present a Statecharts-based approach for the modeling of gene regulatory network motifs in biological systems. The basic motifs used to build more complex networks (that is, simple regulation, reciprocal regulation, feedback loop, feedforward loop, and autoregulation) can be faithfully described and their temporal dynamics can be analyzed. PMID:22536967
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Hu, Marian Y; Hwang, Pung-Pung; Tseng, Yung-Che
2015-01-01
Cephalopods have evolved complex sensory systems and an active lifestyle to compete with fish for similar resources in the marine environment. Their highly active lifestyle and their extensive protein metabolism has led to substantial acid-base regulatory abilities enabling these organisms to cope with CO2 induced acid-base disturbances. In convergence to teleost, cephalopods possess an ontogeny-dependent shift in ion-regulatory epithelia with epidermal ionocytes being the major site of embryonic acid-base regulation and ammonia excretion, while gill epithelia take these functions in adults. Although the basic morphology and excretory function of gill epithelia in cephalopods were outlined almost half a century ago, modern immunohistological and molecular techniques are bringing new insights to the mechanistic basis of acid-base regulation and excretion of nitrogenous waste products (e.g. NH3/NH4+) across ion regulatory epithelia of cephalopods. Using cephalopods as an invertebrate model, recent findings reveal partly conserved mechanisms but also novel aspects of acid-base regulation and nitrogen excretion in these exclusively marine animals. Comparative studies using a range of marine invertebrates will create a novel and exciting research direction addressing the evolution of pH regulatory and excretory systems. PMID:26716070
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Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio
2017-01-01
Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung. PMID:28912729
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Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio
2017-01-01
Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.
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Distribution and regulation of stochasticity and plasticity in Saccharomyces cerevisiae
Dar, R. D.; Karig, D. K.; Cooke, J. F.; ...
2010-09-01
Stochasticity is an inherent feature of complex systems with nanoscale structure. In such systems information is represented by small collections of elements (e.g. a few electrons on a quantum dot), and small variations in the populations of these elements may lead to big uncertainties in the information. Unfortunately, little is known about how to work within this inherently noisy environment to design robust functionality into complex nanoscale systems. Here, we look to the biological cell as an intriguing model system where evolution has mediated the trade-offs between fluctuations and function, and in particular we look at the relationships and trade-offsmore » between stochastic and deterministic responses in the gene expression of budding yeast (Saccharomyces cerevisiae). We find gene regulatory arrangements that control the stochastic and deterministic components of expression, and show that genes that have evolved to respond to stimuli (stress) in the most strongly deterministic way exhibit the most noise in the absence of the stimuli. We show that this relationship is consistent with a bursty 2-state model of gene expression, and demonstrate that this regulatory motif generates the most uncertainty in gene expression when there is the greatest uncertainty in the optimal level of gene expression.« less
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In Silico Detection of Sequence Variations Modifying Transcriptional Regulation
Andersen, Malin C; Engström, Pär G; Lithwick, Stuart; Arenillas, David; Eriksson, Per; Lenhard, Boris; Wasserman, Wyeth W; Odeberg, Jacob
2008-01-01
Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation. PMID:18208319
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Automatic Detection of Student Mental Models during Prior Knowledge Activation in MetaTutor
ERIC Educational Resources Information Center
Rus, Vasile; Lintean, Mihai; Azevedo, Roger
2009-01-01
This paper presents several methods to automatically detecting students' mental models in MetaTutor, an intelligent tutoring system that teaches students self-regulatory processes during learning of complex science topics. In particular, we focus on detecting students' mental models based on student-generated paragraphs during prior knowledge…
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USDA-ARS?s Scientific Manuscript database
Polarized growth of pollen tubes is a critical step for successful reproduction in angiosperms and is controlled by ROP GTPases. Spatiotemporal activation of ROP (Rho GTPases of plants) necessitates a complex and sophisticated regulatory system, in which guanine nucleotide exchange factors (RopGEFs)...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-05-08
... countries and jurisdictions regarding entering into an IGA. Under the FATCA Regulations, (A) beginning... correctly under FATCA on payments made to its FFI Members. \\7\\ FFI Members resident in IGA countries, that... jurisdictions. Since the cost of developing and maintaining a complex FATCA Withholding system would be passed...
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Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming
2009-01-01
Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators. PMID:19851479
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Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al-Shyoukh, Ibrahim; Shamma, Jeff; Sun, Ren; Ho, Chih-Ming
2009-01-01
Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators.
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Expression-based clustering of CAZyme-encoding genes of Aspergillus niger.
Gruben, Birgit S; Mäkelä, Miia R; Kowalczyk, Joanna E; Zhou, Miaomiao; Benoit-Gelber, Isabelle; De Vries, Ronald P
2017-11-23
The Aspergillus niger genome contains a large repertoire of genes encoding carbohydrate active enzymes (CAZymes) that are targeted to plant polysaccharide degradation enabling A. niger to grow on a wide range of plant biomass substrates. Which genes need to be activated in certain environmental conditions depends on the composition of the available substrate. Previous studies have demonstrated the involvement of a number of transcriptional regulators in plant biomass degradation and have identified sets of target genes for each regulator. In this study, a broad transcriptional analysis was performed of the A. niger genes encoding (putative) plant polysaccharide degrading enzymes. Microarray data focusing on the initial response of A. niger to the presence of plant biomass related carbon sources were analyzed of a wild-type strain N402 that was grown on a large range of carbon sources and of the regulatory mutant strains ΔxlnR, ΔaraR, ΔamyR, ΔrhaR and ΔgalX that were grown on their specific inducing compounds. The cluster analysis of the expression data revealed several groups of co-regulated genes, which goes beyond the traditionally described co-regulated gene sets. Additional putative target genes of the selected regulators were identified, based on their expression profile. Notably, in several cases the expression profile puts questions on the function assignment of uncharacterized genes that was based on homology searches, highlighting the need for more extensive biochemical studies into the substrate specificity of enzymes encoded by these non-characterized genes. The data also revealed sets of genes that were upregulated in the regulatory mutants, suggesting interaction between the regulatory systems and a therefore even more complex overall regulatory network than has been reported so far. Expression profiling on a large number of substrates provides better insight in the complex regulatory systems that drive the conversion of plant biomass by fungi. In addition, the data provides additional evidence in favor of and against the similarity-based functions assigned to uncharacterized genes.
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Facing regulatory challenges of on-line hemodiafiltration.
Kümmerle, Wolfgang
2011-01-01
On-line hemodiafiltration (on-line HDF) is the result of a vision that triggered multifarious changes in very different areas. Driven by the idea to offer better medical treatment for renal patients, technological innovations were developed and established that also constituted new challenges in the field of regulatory affairs. The existing regulations predominantly addressed the quality and safety of those products needed to perform dialysis treatment which were supplied by industrial manufacturers. However, the complexity of treatment system required for the provision of on-line fluids demanded a holistic approach encompassing all components involved. Hence, focus was placed not only on single products, but much more on their interfacing, and the clinical infrastructure, in particular, had to undergo substantial changes. The overall understanding of the interaction between such factors, quite different in their nature, was crucial to overcome the arising regulatory obstacles. This essay describes the evolution of the on-line HDF procedure from the regulatory point of view. A simplified diagram demonstrates the path taken from the former regulatory understanding to the realization of necessary changes. That achievement was only possible through 'management of preview' and consequent promotion of technical and medical innovations as well as regulatory re-evaluations. Copyright © 2011 S. Karger AG, Basel.
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Regulatory principles governing Salmonella and Yersinia virulence
Erhardt, Marc; Dersch, Petra
2015-01-01
Enteric pathogens such as Salmonella and Yersinia evolved numerous strategies to survive and proliferate in different environmental reservoirs and mammalian hosts. Deciphering common and pathogen-specific principles for how these bacteria adjust and coordinate spatiotemporal expression of virulence determinants, stress adaptation, and metabolic functions is fundamental to understand microbial pathogenesis. In order to manage sudden environmental changes, attacks by the host immune systems and microbial competition, the pathogens employ a plethora of transcriptional and post-transcriptional control elements, including transcription factors, sensory and regulatory RNAs, RNAses, and proteases, to fine-tune and control complex gene regulatory networks. Many of the contributing global regulators and the molecular mechanisms of regulation are frequently conserved between Yersinia and Salmonella. However, the interplay, arrangement, and composition of the control elements vary between these closely related enteric pathogens, which generate phenotypic differences leading to distinct pathogenic properties. In this overview we present common and different regulatory networks used by Salmonella and Yersinia to coordinate the expression of crucial motility, cell adhesion and invasion determinants, immune defense strategies, and metabolic adaptation processes. We highlight evolutionary changes of the gene regulatory circuits that result in different properties of the regulatory elements and how this influences the overall outcome of the infection process. PMID:26441883
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-03-27
... from interested persons. \\1\\ 15 U.S.C. 78s(b)(1). \\2\\ 17 CFR 240.19b-4. I. Self-Regulatory Organization... simple, non-complex orders only. The Exchange now proposes to establish the Complex Order Router Subsidy... simple, non-complex orders under the ORS Program. The Participants would have to agree that they are not...
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2011-01-01
Background In Drosophila, the Enhancer of split complex (E(spl)-C) comprises 11 bHLH and Bearded genes that function during Notch signaling to repress proneural identity in the developing peripheral nervous system. Comparison with other insects indicates that the basal state for Diptera is a single bHLH and Bearded homolog and that the expansion of the gene complex occurred in the lineage leading to Drosophila. However, comparative genomic data from other fly species that would elucidate the origin and sequence of gene duplication for the complex is lacking. Therefore, in order to examine the evolutionary history of the complex within Diptera, we reconstructed, using several fosmid clones, the entire E(spl)-complex in the stalk-eyed fly, Teleopsis dalmanni and collected additional homologs of E(spl)-C genes from searches of dipteran EST databases and the Glossina morsitans genome assembly. Results Comparison of the Teleopsis E(spl)-C gene organization with Drosophila indicates complete conservation in gene number and orientation between the species except that T. dalmanni contains a duplicated copy of E(spl)m5 that is not present in Drosophila. Phylogenetic analysis of E(spl)-complex bHLH and Bearded genes for several dipteran species clearly demonstrates that all members of the complex were present prior to the diversification of schizophoran flies. Comparison of upstream regulatory elements and 3' UTR domains between the species also reveals strong conservation for many of the genes and identifies several novel characteristics of E(spl)-C regulatory evolution including the discovery of a previously unidentified, highly conserved SPS+A domain between E(spl)mγ and E(spl)mβ. Conclusion Identifying the phylogenetic origin of E(spl)-C genes and their associated regulatory DNA is essential to understanding the functional significance of this well-studied gene complex. Results from this study provide numerous insights into the evolutionary history of the complex and will help refine the focus of studies examining the adaptive consequences of this gene expansion. PMID:22151427
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Lloyd, Julie C.; Raines, Christine A.
2011-01-01
In darkened leaves the Calvin cycle enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK) form a regulatory multi-enzyme complex with the small chloroplast protein CP12. GAPDH also forms a high molecular weight regulatory mono-enzyme complex. Given that there are different reports as to the number and subunit composition of these complexes and that enzyme regulatory mechanisms are known to vary between species, it was reasoned that protein–protein interactions may also vary between species. Here, this variation is investigated. This study shows that two different tetramers of GAPDH (an A2B2 heterotetramer and an A4 homotetramer) have the capacity to form part of the PRK/GAPDH/CP12 complex. The role of the PRK/GAPDH/CP12 complex is not simply to regulate the ‘non-regulatory’ A4 GAPDH tetramer. This study also demonstrates that the abundance and nature of PRK/GAPDH/CP12 interactions are not equal in all species and that whilst NAD enhances complex formation in some species, this is not sufficient for complex formation in others. Furthermore, it is shown that the GAPDH mono-enzyme complex is more abundant as a 2(A2B2) complex, rather than the larger 4(A2B2) complex. This smaller complex is sensitive to cellular metabolites indicating that it is an important regulatory isoform of GAPDH. This comparative study has highlighted considerable heterogeneity in PRK and GAPDH protein interactions between closely related species and the possible underlying physiological basis for this is discussed. PMID:21498632
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Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.
Hussaarts, Leonie; Mühlebach, Stefan; Shah, Vinod P; McNeil, Scott; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J A; de Vlieger, Jon S B
2017-11-01
Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.
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Mikulic, Josip; Longet, Stéphanie; Favre, Laurent; Benyacoub, Jalil; Corthesy, Blaise
2017-01-01
The importance of secretory IgA in controlling the microbiota is well known, yet how the antibody affects the perception of the commensals by the local immune system is still poorly defined. We have previously shown that the transport of secretory IgA in complex with bacteria across intestinal microfold cells results in an association with dendritic cells in Peyer’s patches. However, the consequences of such an interaction on dendritic cell conditioning have not been elucidated. In this study, we analyzed the impact of the commensal Lactobacillus rhamnosus, alone or associated with secretory IgA, on the responsiveness of dendritic cells freshly recovered from mouse Peyer’s patches, mesenteric lymph nodes, and spleen. Lactobacillus rhamnosus-conditioned mucosal dendritic cells are characterized by increased expression of Toll-like receptor regulatory proteins [including single immunoglobulin interleukin-1 receptor-related molecule, suppressor of cytokine signaling 1, and Toll-interacting molecule] and retinaldehyde dehydrogenase 2, low surface expression of co-stimulatory markers, high anti- versus pro-inflammatory cytokine production ratios, and induction of T regulatory cells with suppressive function. Association with secretory IgA enhanced the anti-inflammatory/regulatory Lactobacillus rhamnosus-induced conditioning of mucosal dendritic cells, particularly in Peyer’s patches. At the systemic level, activation of splenic dendritic cells exposed to Lactobacillus rhamnosus was partially dampened upon association with secretory IgA. These data suggest that secretory IgA, through coating of commensal bacteria, contributes to the conditioning of mucosal dendritic cells toward tolerogenic profiles essential for the maintenance of intestinal homeostasis. PMID:26972771
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Modularity and evolutionary constraints in a baculovirus gene regulatory network
2013-01-01
Background The structure of regulatory networks remains an open question in our understanding of complex biological systems. Interactions during complete viral life cycles present unique opportunities to understand how host-parasite network take shape and behave. The Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) is a large double-stranded DNA virus, whose genome may encode for 152 open reading frames (ORFs). Here we present the analysis of the ordered cascade of the AgMNPV gene expression. Results We observed an earlier onset of the expression than previously reported for other baculoviruses, especially for genes involved in DNA replication. Most ORFs were expressed at higher levels in a more permissive host cell line. Genes with more than one copy in the genome had distinct expression profiles, which could indicate the acquisition of new functionalities. The transcription gene regulatory network (GRN) for 149 ORFs had a modular topology comprising five communities of highly interconnected nodes that separated key genes that are functionally related on different communities, possibly maximizing redundancy and GRN robustness by compartmentalization of important functions. Core conserved functions showed expression synchronicity, distinct GRN features and significantly less genetic diversity, consistent with evolutionary constraints imposed in key elements of biological systems. This reduced genetic diversity also had a positive correlation with the importance of the gene in our estimated GRN, supporting a relationship between phylogenetic data of baculovirus genes and network features inferred from expression data. We also observed that gene arrangement in overlapping transcripts was conserved among related baculoviruses, suggesting a principle of genome organization. Conclusions Albeit with a reduced number of nodes (149), the AgMNPV GRN had a topology and key characteristics similar to those observed in complex cellular organisms, which indicates that modularity may be a general feature of biological gene regulatory networks. PMID:24006890
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Application of USNRC NUREG/CR-6661 and draft DG-1108 to evolutionary and advanced reactor designs
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chang 'Apollo', Chen
2006-07-01
For the seismic design of evolutionary and advanced nuclear reactor power plants, there are definite financial advantages in the application of USNRC NUREG/CR-6661 and draft Regulatory Guide DG-1108. NUREG/CR-6661, 'Benchmark Program for the Evaluation of Methods to Analyze Non-Classically Damped Coupled Systems', was by Brookhaven National Laboratory (BNL) for the USNRC, and Draft Regulatory Guide DG-1108 is the proposed revision to the current Regulatory Guide (RG) 1.92, Revision 1, 'Combining Modal Responses and Spatial Components in Seismic Response Analysis'. The draft Regulatory Guide DG-1108 is available at http://members.cox.net/apolloconsulting, which also provides a link to the USNRC ADAMS site to searchmore » for NUREG/CR-6661 in text file or image file. The draft Regulatory Guide DG-1108 removes unnecessary conservatism in the modal combinations for closely spaced modes in seismic response spectrum analysis. Its application will be very helpful in coupled seismic analysis for structures and heavy equipment to reduce seismic responses and in piping system seismic design. In the NUREG/CR-6661 benchmark program, which investigated coupled seismic analysis of structures and equipment or piping systems with different damping values, three of the four participants applied the complex mode solution method to handle different damping values for structures, equipment, and piping systems. The fourth participant applied the classical normal mode method with equivalent weighted damping values to handle differences in structural, equipment, and piping system damping values. Coupled analysis will reduce the equipment responses when equipment, or piping system and structure are in or close to resonance. However, this reduction in responses occurs only if the realistic DG-1108 modal response combination method is applied, because closely spaced modes will be produced when structure and equipment or piping systems are in or close to resonance. Otherwise, the conservatism in the current Regulatory Guide 1.92, Revision 1, will overshadow the advantage of coupled analysis. All four participants applied the realistic modal combination method of DG-1108. Consequently, more realistic and reduced responses were obtained. (authors)« less
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Proteome complexity and the forces that drive proteome imbalance
Harper, J. Wade; Bennett, Eric J.
2016-01-01
Summary The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer. PMID:27629639
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Pérez-Morales, Deyanira; Bustamante, Víctor H
2016-02-01
A novel connection between two regulatory systems controlling crucial biological processes in bacteria, the carbon storage regulator (Csr) system and the glucose-specific phosphotransferase system (PTS), is reported by Leng et al. in this issue. This involves the interaction of unphosphorylated EIIA(Glc), a component of the glucose-specific PTS, with the CsrD protein, which accelerates the decay of the CsrB and CsrC small RNAs via RNase E in Escherichia coli. As unphosphorylated EIIA(G) (lc) is generated in the presence of glucose, the PTS thus acts as a sensor of glucose for the Csr system. Interestingly, another pathway can operate for communication between the Csr system and the glucose-specific PTS. The absence of glucose generates phosphorylated EIIA(Glc) , which activates the enzyme adenylate cyclase to produce cyclic adenosine monophosphate (cAMP) that, in turn, binds to the regulator cAMP receptor protein (CRP). Leng et al. show that the complex cAMP-CRP modestly reduces CsrB decay independently of CsrD. On the other hand, a previous study indicates that the complex cAMP-CRP positively regulates the transcription of CsrB and CsrC in Salmonella enterica. Therefore, EIIA(G) (lc) could work as a molecular switch that regulates the activity of the Csr system, in response to its phosphorylation state determined by the presence or absence of glucose, in order to control gene expression. © 2015 John Wiley & Sons Ltd.
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Complex and unexpected dynamics in simple genetic regulatory networks
NASA Astrophysics Data System (ADS)
Borg, Yanika; Ullner, Ekkehard; Alagha, Afnan; Alsaedi, Ahmed; Nesbeth, Darren; Zaikin, Alexey
2014-03-01
One aim of synthetic biology is to construct increasingly complex genetic networks from interconnected simpler ones to address challenges in medicine and biotechnology. However, as systems increase in size and complexity, emergent properties lead to unexpected and complex dynamics due to nonlinear and nonequilibrium properties from component interactions. We focus on four different studies of biological systems which exhibit complex and unexpected dynamics. Using simple synthetic genetic networks, small and large populations of phase-coupled quorum sensing repressilators, Goodwin oscillators, and bistable switches, we review how coupled and stochastic components can result in clustering, chaos, noise-induced coherence and speed-dependent decision making. A system of repressilators exhibits oscillations, limit cycles, steady states or chaos depending on the nature and strength of the coupling mechanism. In large repressilator networks, rich dynamics can also be exhibited, such as clustering and chaos. In populations of Goodwin oscillators, noise can induce coherent oscillations. In bistable systems, the speed with which incoming external signals reach steady state can bias the network towards particular attractors. These studies showcase the range of dynamical behavior that simple synthetic genetic networks can exhibit. In addition, they demonstrate the ability of mathematical modeling to analyze nonlinearity and inhomogeneity within these systems.
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Predictive computation of genomic logic processing functions in embryonic development
Peter, Isabelle S.; Faure, Emmanuel; Davidson, Eric H.
2012-01-01
Gene regulatory networks (GRNs) control the dynamic spatial patterns of regulatory gene expression in development. Thus, in principle, GRN models may provide system-level, causal explanations of developmental process. To test this assertion, we have transformed a relatively well-established GRN model into a predictive, dynamic Boolean computational model. This Boolean model computes spatial and temporal gene expression according to the regulatory logic and gene interactions specified in a GRN model for embryonic development in the sea urchin. Additional information input into the model included the progressive embryonic geometry and gene expression kinetics. The resulting model predicted gene expression patterns for a large number of individual regulatory genes each hour up to gastrulation (30 h) in four different spatial domains of the embryo. Direct comparison with experimental observations showed that the model predictively computed these patterns with remarkable spatial and temporal accuracy. In addition, we used this model to carry out in silico perturbations of regulatory functions and of embryonic spatial organization. The model computationally reproduced the altered developmental functions observed experimentally. Two major conclusions are that the starting GRN model contains sufficiently complete regulatory information to permit explanation of a complex developmental process of gene expression solely in terms of genomic regulatory code, and that the Boolean model provides a tool with which to test in silico regulatory circuitry and developmental perturbations. PMID:22927416
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Lucas-Samuel, Sophie; Ferry, Nicolas; Trouvin, Jean-Hugues
2015-01-01
Advanced therapy medicinal products, a new class of products with promising therapeutic effects, have been classified as medicinal products and as such should be developed according to a well-structured development plan, to establish their quality, safety and efficacy profile and conclude, at the time of the marketing authorisation evaluation, on a positive risk/benefit balance for patients. An important part of this development plan is achieved through clinical trials, which have also to be approved according to a well-established regulatory process, prior any initiation. This chapter is dedicated to describe the regulatory pathway to be followed in France, before initiating any clinical trial with those investigational advanced therapy medicinal products. In France, to get the final authorisation to initiate a clinical trial, the legislation imposes to run in parallel two independent but complementary authorisation procedures. The first procedure is aimed at assessing the ethical aspect of the biomedical research, while the second has to review the safety and regulatory aspects. A third procedure has to be envisaged where in case the investigational product consists or contains a genetically modified organism. The French system herein described is in line with the EU regulation on clinical trial and follows the respective deadlines for granting the final approval. The complexity of the procedure is in fact more due to the complexity of the products and protocols to be assessed than to the procedure itself which is now very close to the well-known procedure applied routinely for more conventional chemical or biological candidate medicinal products.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-09-23
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-70425; File No. SR-NYSEArca-2013-90] Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing and Immediate Effectiveness of Proposed Rule... Complex Orders and Complex Order Auction Eligible Orders in Accordance With the Guaranteed Participation...
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Liu, Zhaoqun; Wang, Lingling; Zhou, Zhi; Sun, Ying; Wang, Mengqiang; Wang, Hao; Hou, Zhanhui; Gao, Dahai; Gao, Qiang; Song, Linsheng
2016-05-19
The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of the host. In the present study, the bioinformatical analysis of the transcriptomic data from oyster Crassostrea gigas and further biological validation revealed that oyster TNF (CgTNF-1 CGI_10018786) could activate the transcription factors NF-κB and HSF (heat shock transcription factor) through MAPK signaling pathway, and then regulate apoptosis, redox reaction, neuro-regulation and protein folding in oyster haemocytes. The activated immune cells then released neurotransmitters including acetylcholine, norepinephrine and [Met(5)]-enkephalin to regulate the immune response by arising the expression of three TNF (CGI_10005109, CGI_10005110 and CGI_10006440) and translocating two NF-κB (Cgp65, CGI_10018142 and CgRel, CGI_10021567) between the cytoplasm and nuclei of haemocytes. Neurotransmitters exhibited the immunomodulation effects by influencing apoptosis and phagocytosis of oyster haemocytes. Acetylcholine and norepinephrine could down-regulate the immune response, while [Met(5)]-enkephalin up-regulate the immune response. These results suggested that the simple neuroendocrine-immune regulatory network in oyster might be activated by oyster TNF and then regulate the immune response by virtue of neurotransmitters, cytokines and transcription factors.
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NASA Astrophysics Data System (ADS)
Liu, Zhaoqun; Wang, Lingling; Zhou, Zhi; Sun, Ying; Wang, Mengqiang; Wang, Hao; Hou, Zhanhui; Gao, Dahai; Gao, Qiang; Song, Linsheng
2016-05-01
The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of the host. In the present study, the bioinformatical analysis of the transcriptomic data from oyster Crassostrea gigas and further biological validation revealed that oyster TNF (CgTNF-1 CGI_10018786) could activate the transcription factors NF-κB and HSF (heat shock transcription factor) through MAPK signaling pathway, and then regulate apoptosis, redox reaction, neuro-regulation and protein folding in oyster haemocytes. The activated immune cells then released neurotransmitters including acetylcholine, norepinephrine and [Met5]-enkephalin to regulate the immune response by arising the expression of three TNF (CGI_10005109, CGI_10005110 and CGI_10006440) and translocating two NF-κB (Cgp65, CGI_10018142 and CgRel, CGI_10021567) between the cytoplasm and nuclei of haemocytes. Neurotransmitters exhibited the immunomodulation effects by influencing apoptosis and phagocytosis of oyster haemocytes. Acetylcholine and norepinephrine could down-regulate the immune response, while [Met5]-enkephalin up-regulate the immune response. These results suggested that the simple neuroendocrine-immune regulatory network in oyster might be activated by oyster TNF and then regulate the immune response by virtue of neurotransmitters, cytokines and transcription factors.
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Petrovskaya, Olga V; Petrovskiy, Evgeny D; Lavrik, Inna N; Ivanisenko, Vladimir A
2017-04-01
Gene network modeling is one of the widely used approaches in systems biology. It allows for the study of complex genetic systems function, including so-called mosaic gene networks, which consist of functionally interacting subnetworks. We conducted a study of a mosaic gene networks modeling method based on integration of models of gene subnetworks by linear control functionals. An automatic modeling of 10,000 synthetic mosaic gene regulatory networks was carried out using computer experiments on gene knockdowns/knockouts. Structural analysis of graphs of generated mosaic gene regulatory networks has revealed that the most important factor for building accurate integrated mathematical models, among those analyzed in the study, is data on expression of genes corresponding to the vertices with high properties of centrality.
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Posttranscriptional regulation on a global scale: Form and function of Csr/Rsm systems
Romeo, Tony; Vakulskas, Christopher A.; Babitzke, Paul
2012-01-01
Summary Originally described as a repressor of gene expression in the stationary phase of growth, CsrA (RsmA) regulates primary and secondary metabolic pathways, biofilm formation, motility, virulence circuitry of pathogens, quorum sensing, and stress response systems by binding to conserved sequences in its target mRNAs and altering their translation and/or turnover. While the binding of CsrA to RNA is understood at an atomic level, new mechanisms of gene activation and repression by this protein are still emerging. In the γ-proteobacteria, small noncoding RNAs (sRNAs) use molecular mimicry to sequester multiple CsrA dimers away from mRNA. In contrast, the FliW protein of Bacillus subtilis inhibits CsrA activity by binding to this protein, thereby establishing a checkpoint in flagellum morphogenesis. Turnover of CsrB and CsrC sRNAs in Escherichia coli requires a specificity protein of the GGDEF-EAL domain superfamily, CsrD, in addition to the housekeeping nucleases RNase E and PNPase. The Csr system of E. coli contains extensive autoregulatory circuitry, which governs the expression and activity of CsrA. Interaction of the Csr system with transcriptional regulatory networks results in a variety of complex response patterns. This minireview will highlight basic principles and new insights into the workings of these complex eubacterial regulatory systems. PMID:22672726
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Post-transcriptional regulation on a global scale: form and function of Csr/Rsm systems.
Romeo, Tony; Vakulskas, Christopher A; Babitzke, Paul
2013-02-01
Originally described as a repressor of gene expression in the stationary phase of growth, CsrA (RsmA) regulates primary and secondary metabolic pathways, biofilm formation, motility, virulence circuitry of pathogens, quorum sensing and stress response systems by binding to conserved sequences in its target mRNAs and altering their translation and/or turnover. While the binding of CsrA to RNA is understood at an atomic level, new mechanisms of gene activation and repression by this protein are still emerging. In the γ-proteobacteria, small non-coding RNAs (sRNAs) use molecular mimicry to sequester multiple CsrA dimers away from mRNA. In contrast, the FliW protein of Bacillus subtilis inhibits CsrA activity by binding to this protein, thereby establishing a checkpoint in flagellum morphogenesis. Turnover of CsrB and CsrC sRNAs in Escherichia coli requires a specificity protein of the GGDEF-EAL domain superfamily, CsrD, in addition to the housekeeping nucleases RNase E and PNPase. The Csr system of E. coli contains extensive autoregulatory circuitry, which governs the expression and activity of CsrA. Interaction of the Csr system with transcriptional regulatory networks results in a variety of complex response patterns. This minireview will highlight basic principles and new insights into the workings of these complex eubacterial regulatory systems. © 2012 Society for Applied Microbiology and Blackwell Publishing Ltd.
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Core regulatory network motif underlies the ocellar complex patterning in Drosophila melanogaster
NASA Astrophysics Data System (ADS)
Aguilar-Hidalgo, D.; Lemos, M. C.; Córdoba, A.
2015-03-01
During organogenesis, developmental programs governed by Gene Regulatory Networks (GRN) define the functionality, size and shape of the different constituents of living organisms. Robustness, thus, is an essential characteristic that GRNs need to fulfill in order to maintain viability and reproducibility in a species. In the present work we analyze the robustness of the patterning for the ocellar complex formation in Drosophila melanogaster fly. We have systematically pruned the GRN that drives the development of this visual system to obtain the minimum pathway able to satisfy this pattern. We found that the mechanism underlying the patterning obeys to the dynamics of a 3-nodes network motif with a double negative feedback loop fed by a morphogenetic gradient that triggers the inhibition in a French flag problem fashion. A Boolean modeling of the GRN confirms robustness in the patterning mechanism showing the same result for different network complexity levels. Interestingly, the network provides a steady state solution in the interocellar part of the patterning and an oscillatory regime in the ocelli. This theoretical result predicts that the ocellar pattern may underlie oscillatory dynamics in its genetic regulation.
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Hormiga, J A; Vera, J; Frías, I; Torres Darias, N V
2008-10-10
The well-documented ability to degrade lignin and a variety of complex chemicals showed by the white-rot fungus Phanerochaete chrysosporium has made it the subject of many studies in areas of environmental concern, including pulp bioleaching and bioremediation technologies. However, until now, most of the work in this field has been focused on the ligninolytic sub-system but, due to the great complexity of the involved processes, less progress has been made in understanding the biochemical regulatory structure that could explain growth dynamics, the substrate utilization and the ligninolytic system production itself. In this work we want to tackle this problem from the perspectives and approaches of systems biology, which have been shown to be effective in the case of complex systems. We will use a top-down approach to the construction of this model aiming to identify the cellular sub-systems that play a major role in the whole process. We have investigated growth dynamics, substrate consumption and lignin peroxidase production of the P. chrysosporium wild type under a set of definite culture conditions. Based on data gathered from different authors and in our own experimental determinations, we built a model using a GMA power-law representation, which was used as platform to make predictive simulations. Thereby, we could assess the consistency of some current assumptions about the regulatory structure of the overall process. The model parameters were estimated from a time series experimental measurements by means of an algorithm previously adapted and optimized for power-law models. The model was subsequently checked for quality by comparing its predictions with the experimental behavior observed in new, different experimental settings and through perturbation analysis aimed to test the robustness of the model. Hence, the model showed to be able to predict the dynamics of two critical variables such as biomass and lignin peroxidase activity when in conditions of nutrient deprivation and after pulses of veratryl alcohol. Moreover, it successfully predicts the evolution of the variables during both, the active growth phase and after the deprivation shock. The close agreement between the predicted and observed behavior and the advanced understanding of its kinetic structure and regulatory features provides the necessary background for the design of a biotechnological set-up designed for the continuous production of the ligninolityc system and its optimization.
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Gelderman, Grant; Sivakumar, Anusha; Lipp, Sarah; Contreras, Lydia
2015-02-01
sRNAs play a significant role in controlling and regulating cellular metabolism. One of the more interesting aspects of certain sRNAs is their ability to make global changes in the cell by interacting with regulatory proteins. In this work, we demonstrate the use of an in vivo Tri-molecular Fluorescence Complementation assay to detect and visualize the central regulatory sRNA-protein interaction of the Carbon Storage Regulatory system in E. coli. The Carbon Storage Regulator consists primarily of an RNA binding protein, CsrA, that alters the activity of mRNA targets and of an sRNA, CsrB, that modulates the activity of CsrA. We describe the construction of a fluorescence complementation system that detects the interactions between CsrB and CsrA. Additionally, we demonstrate that the intensity of the fluorescence of this system is able to detect changes in the affinity of the CsrB-CsrA interaction, as caused by mutations in the protein sequence of CsrA. While previous methods have adopted this technique to study mRNA or RNA localization, this is the first attempt to use this technique to study the sRNA-protein interaction directly in bacteria. This method presents a potentially powerful tool to study complex bacterial RNA protein interactions in vivo. © 2014 Wiley Periodicals, Inc.
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An, Shi-Qi; Febrer, Melanie; McCarthy, Yvonne; Tang, Dong-Jie; Clissold, Leah; Kaithakottil, Gemy; Swarbreck, David; Tang, Ji-Liang; Rogers, Jane; Dow, J Maxwell; Ryan, Robert P
2013-01-01
The bacterium Xanthomonas campestris is an economically important pathogen of many crop species and a model for the study of bacterial phytopathogenesis. In X. campestris, a regulatory system mediated by the signal molecule DSF controls virulence to plants. The synthesis and recognition of the DSF signal depends upon different Rpf proteins. DSF signal generation requires RpfF whereas signal perception and transduction depends upon a system comprising the sensor RpfC and regulator RpfG. Here we have addressed the action and role of Rpf/DSF signalling in phytopathogenesis by high-resolution transcriptional analysis coupled to functional genomics. We detected transcripts for many genes that were unidentified by previous computational analysis of the genome sequence. Novel transcribed regions included intergenic transcripts predicted as coding or non-coding as well as those that were antisense to coding sequences. In total, mutation of rpfF, rpfG and rpfC led to alteration in transcript levels (more than fourfold) of approximately 480 genes. The regulatory influence of RpfF and RpfC demonstrated considerable overlap. Contrary to expectation, the regulatory influence of RpfC and RpfG had limited overlap, indicating complexities of the Rpf signalling system. Importantly, functional analysis revealed over 160 new virulence factors within the group of Rpf-regulated genes. PMID:23617851
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Functions of MicroRNAs in Cardiovascular Biology and Disease
Hata, Akiko
2015-01-01
In 1993, lin-4 was discovered as a critical modulator of temporal development in Caenorhabditis elegans and, most notably, as the first in the class of small, single-stranded noncoding RNAs now defined as microRNAs (miRNAs). Another eight years elapsed before miRNA expression was detected in mammalian cells. Since then, explosive advancements in the field of miRNA biology have elucidated the basic mechanism of miRNA biogenesis, regulation, and gene-regulatory function. The discovery of this new class of small RNAs has augmented the complexity of gene-regulatory programs as well as the understanding of developmental and pathological processes in the cardiovascular system. Indeed, the contributions of miRNAs in cardiovascular development and function have been widely explored, revealing the extensive role of these small regulatory RNAs in cardiovascular physiology. PMID:23157557
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Settling into the midstream? Lessons for governance from the decade of nanotechnology
NASA Astrophysics Data System (ADS)
Bosso, Christopher
2016-06-01
This paper analyzes scholarly papers published from 2003 through 2013 on the general theme of nanotechnology and governance. It considers three general points: (1) the "problem" of nanotechnology; (2) general lessons for governance obtained; and (3) prospects for aligning the US regulatory system to the next generation of complex engineered nano-materials. It argues that engineered nano-materials and products are coming to market within an already mature regulatory framework of decade-old statutes, long-standing bureaucratic rules and routines, narrowly directive judicial decisions, and embedded institutional norms. That extant regulatory regime shapes how policymakers perceive, define, and address the relative benefits and risks of both proximate and yet-to-be idealized nano-materials and applications. The paper concludes that fundamental reforms in the extant regime are unlikely short of a perceived crisis.
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Chappell, James; Freemont, Paul
2013-01-01
The characterization of DNA regulatory elements such as ribosome binding sites and transcriptional promoters is a fundamental aim of synthetic biology. Characterization of such DNA regulatory elements by monitoring the synthesis of fluorescent proteins is a commonly used technique to resolve the relative or absolute strengths. These measurements can be used in combination with mathematical models and computer simulation to rapidly assess performance of DNA regulatory elements both in isolation and in combination, to assist predictable and efficient engineering of complex novel biological devices and systems. Here we describe the construction and relative characterization of Escherichia coli (E. coli) σ(70) transcriptional promoters by monitoring the synthesis of green fluorescent protein (GFP) both in vivo in E. coli and in vitro in a E. coli cell-free transcription and translation reaction.
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Living on the edge of chaos: minimally nonlinear models of genetic regulatory dynamics.
Hanel, Rudolf; Pöchacker, Manfred; Thurner, Stefan
2010-12-28
Linearized catalytic reaction equations (modelling, for example, the dynamics of genetic regulatory networks), under the constraint that expression levels, i.e. molecular concentrations of nucleic material, are positive, exhibit non-trivial dynamical properties, which depend on the average connectivity of the reaction network. In these systems, an inflation of the edge of chaos and multi-stability have been demonstrated to exist. The positivity constraint introduces a nonlinearity, which makes chaotic dynamics possible. Despite the simplicity of such minimally nonlinear systems, their basic properties allow us to understand the fundamental dynamical properties of complex biological reaction networks. We analyse the Lyapunov spectrum, determine the probability of finding stationary oscillating solutions, demonstrate the effect of the nonlinearity on the effective in- and out-degree of the active interaction network, and study how the frequency distributions of oscillatory modes of such a system depend on the average connectivity.
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Unlocking Potentials of Microwaves for Food Safety and Quality
Tang, Juming
2015-01-01
Microwave is an effective means to deliver energy to food through polymeric package materials, offering potential for developing short-time in-package sterilization and pasteurization processes. The complex physics related to microwave propagation and microwave heating require special attention to the design of process systems and development of thermal processes in compliance with regulatory requirements for food safety. This article describes the basic microwave properties relevant to heating uniformity and system design, and provides a historical overview on the development of microwave-assisted thermal sterilization (MATS) and pasteurization systems in research laboratories and used in food plants. It presents recent activities on the development of 915 MHz single-mode MATS technology, the procedures leading to regulatory acceptance, and sensory results of the processed products. The article discusses needs for further efforts to bridge remaining knowledge gaps and facilitate transfer of academic research to industrial implementation. PMID:26242920
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Unlocking Potentials of Microwaves for Food Safety and Quality.
Tang, Juming
2015-08-01
Microwave is an effective means to deliver energy to food through polymeric package materials, offering potential for developing short-time in-package sterilization and pasteurization processes. The complex physics related to microwave propagation and microwave heating require special attention to the design of process systems and development of thermal processes in compliance with regulatory requirements for food safety. This article describes the basic microwave properties relevant to heating uniformity and system design, and provides a historical overview on the development of microwave-assisted thermal sterilization (MATS) and pasteurization systems in research laboratories and used in food plants. It presents recent activities on the development of 915 MHz single-mode MATS technology, the procedures leading to regulatory acceptance, and sensory results of the processed products. The article discusses needs for further efforts to bridge remaining knowledge gaps and facilitate transfer of academic research to industrial implementation. © 2015 Institute of Food Technologists®
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NASA Astrophysics Data System (ADS)
Haghnevis, Moeed
The main objective of this research is to develop an integrated method to study emergent behavior and consequences of evolution and adaptation in engineered complex adaptive systems (ECASs). A multi-layer conceptual framework and modeling approach including behavioral and structural aspects is provided to describe the structure of a class of engineered complex systems and predict their future adaptive patterns. The approach allows the examination of complexity in the structure and the behavior of components as a result of their connections and in relation to their environment. This research describes and uses the major differences of natural complex adaptive systems (CASs) with artificial/engineered CASs to build a framework and platform for ECAS. While this framework focuses on the critical factors of an engineered system, it also enables one to synthetically employ engineering and mathematical models to analyze and measure complexity in such systems. In this way concepts of complex systems science are adapted to management science and system of systems engineering. In particular an integrated consumer-based optimization and agent-based modeling (ABM) platform is presented that enables managers to predict and partially control patterns of behaviors in ECASs. Demonstrated on the U.S. electricity markets, ABM is integrated with normative and subjective decision behavior recommended by the U.S. Department of Energy (DOE) and Federal Energy Regulatory Commission (FERC). The approach integrates social networks, social science, complexity theory, and diffusion theory. Furthermore, it has unique and significant contribution in exploring and representing concrete managerial insights for ECASs and offering new optimized actions and modeling paradigms in agent-based simulation.
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Enzyme-free nucleic acid dynamical systems.
Srinivas, Niranjan; Parkin, James; Seelig, Georg; Winfree, Erik; Soloveichik, David
2017-12-15
Chemistries exhibiting complex dynamics-from inorganic oscillators to gene regulatory networks-have been long known but either cannot be reprogrammed at will or rely on the sophisticated enzyme chemistry underlying the central dogma. Can simpler molecular mechanisms, designed from scratch, exhibit the same range of behaviors? Abstract chemical reaction networks have been proposed as a programming language for complex dynamics, along with their systematic implementation using short synthetic DNA molecules. We developed this technology for dynamical systems by identifying critical design principles and codifying them into a compiler automating the design process. Using this approach, we built an oscillator containing only DNA components, establishing that Watson-Crick base-pairing interactions alone suffice for complex chemical dynamics and that autonomous molecular systems can be designed via molecular programming languages. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Molecular farming on the rise--GMO regulators still walking a tightrope.
Spök, Armin
2007-02-01
Recent increases in EU commercial and academic activities in molecular farming, and the proximity to market-stage of the first plant-made pharmaceuticals, represent a call to action for EU regulators. Drawing on the North American debate on molecular farming, it will be argued that both the rationale and the risks of molecular farming will differ significantly from those of first generation GM crops. Based on these differences, the suitability of the existing regulatory frameworks, which were developed in response to the arrival of earlier products, is discussed, and specific options for adapting the already complex EU regulatory system to cater for molecular farming are examined.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-08-06
... rules. See id. A. SAL SAL is a feature within CBOE's Hybrid System designed to provide price improvement... before being booked in the electronic complex order book (``COB'') or on a PAR workstation.\\22\\ To the... rules of a national securities exchange be designed to prevent fraudulent and manipulative acts and...
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ERIC Educational Resources Information Center
Lintean, Mihai; Rus, Vasile; Azevedo, Roger
2012-01-01
This article describes the problem of detecting the student mental models, i.e. students' knowledge states, during the self-regulatory activity of prior knowledge activation in MetaTutor, an intelligent tutoring system that teaches students self-regulation skills while learning complex science topics. The article presents several approaches to…
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Since humans and wildlife are exposed to more than one chemical at a time, concern has arisen about the effects of complex mixtures on reproduction and development. To date, different regulatory groups have not yet developed consistent approaches to conducting assessments of the ...
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Measuring and Modeling the U.S. Regulatory Ecosystem
NASA Astrophysics Data System (ADS)
Bommarito, Michael J., II; Katz, Daniel Martin
2017-09-01
Over the last 23 years, the U.S. Securities and Exchange Commission has required over 34,000 companies to file over 165,000 annual reports. These reports, the so-called "Form 10-Ks," contain a characterization of a company's financial performance and its risks, including the regulatory environment in which a company operates. In this paper, we analyze over 4.5 million references to U.S. Federal Acts and Agencies contained within these reports to measure the regulatory ecosystem, in which companies are organisms inhabiting a regulatory environment. While individuals across the political, economic, and academic world frequently refer to trends in this regulatory ecosystem, far less attention has been paid to supporting such claims with large-scale, longitudinal data. In this paper, in addition to positing a model of regulatory ecosystems, we document an increase in the regulatory energy per filing, i.e., a warming "temperature." We also find that the diversity of the regulatory ecosystem has been increasing over the past two decades. These findings support the claim that regulatory activity and complexity are increasing, and this framework contributes an important step towards improving academic and policy discussions around legal complexity and regulation.
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Gene regulation of plasmid- and chromosome-determined inorganic ion transport in bacteria.
Silver, S; Walderhaug, M
1992-01-01
Regulation of chromosomally determined nutrient cation and anion uptake systems shows important similarities to regulation of plasmid-determined toxic ion resistance systems that mediate the outward transport of deleterious ions. Chromosomally determined transport systems result in accumulation of K+, Mg2+, Fe3+, Mn2+, PO4(3-), SO4(2-), and additional trace nutrients, while bacterial plasmids harbor highly specific resistance systems for AsO2-, AsO4(3-), CrO4(2-), Cd2+, Co2+, Cu2+, Hg2+, Ni2+, SbO2-, TeO3(2-), Zn2+, and other toxic ions. To study the regulation of these systems, we need to define both the trans-acting regulatory proteins and the cis-acting target operator DNA regions for the proteins. The regulation of gene expression for K+ and PO4(3-) transport systems involves two-component sensor-effector pairs of proteins. The first protein responds to an extracellular ionic (or related) signal and then transmits the signal to an intracellular DNA-binding protein. Regulation of Fe3+ transport utilizes the single iron-binding and DNA-binding protein Fur. The MerR regulatory protein for mercury resistance both represses and activates transcription. The ArsR regulatory protein functions as a repressor for the arsenic and antimony(III) efflux system. Although the predicted cadR regulatory gene has not been identified, cadmium, lead, bismuth, zinc, and cobalt induce this system in a carefully regulated manner from a single mRNA start site. The cadA Cd2+ resistance determinant encodes an E1(1)-1E2-class efflux ATPase (consisting of two polypeptides, rather than the one earlier identified). Cadmium resistance is also conferred by the czc system (which confers resistances to zinc and cobalt in Alcaligenes species) via a complex efflux pump consisting of four polypeptides. These two cadmium efflux systems are not otherwise related. For chromate resistance, reduced cellular accumulation is again the resistance mechanism, but the regulatory components are not identified. For other toxic heavy metals (with few exceptions), there exist specific plasmid resistances that remain relatively terra incognita for future exploration of bioinorganic molecular genetics and gene regulation. PMID:1579110
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-11-07
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-70797; File No. SR-BOX-2013-43] Self-Regulatory... Proposed Rule Change To Permit Complex Orders To Participate in Price Improvement Periods November 1, 2013... to permit Complex Orders to participate in Price Improvement Periods (the ``COPIP'') and to make...
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Newton, Laplace, and The Epistemology of Systems Biology
Bittner, Michael L.; Dougherty, Edward R.
2012-01-01
For science, theoretical or applied, to significantly advance, researchers must use the most appropriate mathematical methods. A century and a half elapsed between Newton’s development of the calculus and Laplace’s development of celestial mechanics. One cannot imagine the latter without the former. Today, more than three-quarters of a century has elapsed since the birth of stochastic systems theory. This article provides a perspective on the utilization of systems theory as the proper vehicle for the development of systems biology and its application to complex regulatory diseases such as cancer. PMID:23170064
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Epigenomics and the concept of degeneracy in biological systems
Mason, Paul H.; Barron, Andrew B.
2014-01-01
Researchers in the field of epigenomics are developing more nuanced understandings of biological complexity, and exploring the multiple pathways that lead to phenotypic expression. The concept of degeneracy—referring to the multiple pathways that a system recruits to achieve functional plasticity—is an important conceptual accompaniment to the growing body of knowledge in epigenomics. Distinct from degradation, redundancy and dilapidation; degeneracy refers to the plasticity of traits whose function overlaps in some environments, but diverges in others. While a redundant system is composed of repeated identical elements performing the same function, a degenerate system is composed of different elements performing similar or overlapping functions. Here, we describe the degenerate structure of gene regulatory systems from the basic genetic code to flexible epigenomic modifications, and discuss how these structural features have contributed to organism complexity, robustness, plasticity and evolvability. PMID:24335757
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Mitchison, A
1997-01-01
In considering genetic variation in eukaryotes, a fundamental distinction can be made between variation in regulatory (software) and coding (hardware) gene segments. For quantitative traits the bulk of variation, particularly that near the population mean, appears to reside in regulatory segments. The main exceptions to this rule concern proteins which handle extrinsic substances, here termed extrovert proteins. The immune system includes an unusually large proportion of this exceptional category, but even so its chief source of variation may well be polymorphism in regulatory gene segments. The main evidence for this view emerges from genome scanning for quantitative trait loci (QTL), which in the case of the immune system points to a major contribution of pro-inflammatory cytokine genes. Further support comes from sequencing of major histocompatibility complex (Mhc) class II promoters, where a high level of polymorphism has been detected. These Mhc promoters appear to act, in part at least, by gating the back-signal from T cells into antigen-presenting cells. Both these forms of polymorphism are likely to be sustained by the need for flexibility in the immune response. Future work on promoter polymorphism is likely to benefit from the input from genome informatics.
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Martínez, A; Buchan, A M; López, J; Sesma, P
2000-05-01
The colocalization of regulatory peptide immunoreactivities in endocrine cells of the chicken proventriculus at hatching has been investigated using the avidin-biotin technique in serial sections and double immunofluorescence in the same section for light microscopy, and double immunogold staining for electron microscopy. In addition to the eight immunoreactivities previously described in this organ, cells immunoreactive for peptide histidine isoleucine (PHI), peptide gene product 9.5 (PGP), and the amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM) were observed. All the cells immunoreactive to glucagon were also immunostained by the PHI antiserum. In addition, all the glucagon-like peptide 1, avian pancreatic polypeptide, and some of the neurotensin-like cells costored also glucagon- and PHI-immunoreactive substances. PGP- and PAM-immunoreactivities were also found in the glucagon-positive cells. A small proportion of the somatostatin-containing cells were positive for PHI but not for other regulatory peptides. These results could suggest either the existence of a very complex regulatory system or that the endocrine system of the newborn chickens is not yet fully developed.
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Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K
2016-01-01
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001 PMID:26880555
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Soundararajan, Rama; Ziera, Tim; Koo, Eric; Ling, Karen; Wang, Jian; Borden, Steffen A.; Pearce, David
2012-01-01
Hormone regulation of ion transport in the kidney tubules is essential for fluid and electrolyte homeostasis in vertebrates. A large body of evidence has suggested that transporters and channels exist in multiprotein regulatory complexes; however, relatively little is known about the composition of these complexes or their assembly. The epithelial sodium channel (ENaC) in particular is tightly regulated by the salt-regulatory hormone aldosterone, which acts at least in part by increasing expression of the serine-threonine kinase SGK1. Here we show that aldosterone induces the formation of a 1.0–1.2-MDa plasma membrane complex, which includes ENaC, SGK1, and the ENaC inhibitor Nedd4-2, a key target of SGK1. We further show that this complex contains the PDZ domain-containing protein connector enhancer of kinase suppressor of Ras isoform 3 (CNK3). CNK3 physically interacts with ENaC, Nedd4-2, and SGK1; enhances the interactions among them; and stimulates ENaC function in a PDZ domain-dependent, aldosterone-induced manner. These results strongly suggest that CNK3 is a molecular scaffold, which coordinates the assembly of a multiprotein ENaC-regulatory complex and hence plays a central role in Na+ homeostasis. PMID:22851176
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Clinical metabolomics paves the way towards future healthcare strategies
Collino, Sebastiano; Martin, François‐Pierre J.; Rezzi, Serge
2013-01-01
Metabolomics is recognized as a powerful top‐down system biological approach to understand genetic‐environment‐health paradigms paving new avenues to identify clinically relevant biomarkers. It is nowadays commonly used in clinical applications shedding new light on physiological regulatory processes of complex mammalian systems with regard to disease aetiology, diagnostic stratification and, potentially, mechanism of action of therapeutic solutions. A key feature of metabolomics lies in its ability to underpin the complex metabolic interactions of the host with its commensal microbial partners providing a new way to define individual and population phenotypes. This review aims at describing recent applications of metabolomics in clinical fields with insight into diseases, diagnostics/monitoring and improvement of homeostatic metabolic regulation. PMID:22348240
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ERIC Educational Resources Information Center
Muis, Krista R.; Psaradellis, Cynthia; Chevrier, Marianne; Di Leo, Ivana; Lajoie, Susanne P.
2016-01-01
We developed an intervention based on the learning by teaching paradigm to foster self-regulatory processes and better learning outcomes during complex mathematics problem solving in a technology-rich learning environment. Seventy-eight elementary students were randomly assigned to 1 of 2 conditions: learning by preparing to teach, or learning for…
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Chasman, Deborah; Walters, Kevin B.; Lopes, Tiago J. S.; Eisfeld, Amie J.; Kawaoka, Yoshihiro; Roy, Sushmita
2016-01-01
Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection. PMID:27403523
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Hamed, Mohamed; Spaniol, Christian; Nazarieh, Maryam; Helms, Volkhard
2015-07-01
TFmiR is a freely available web server for deep and integrative analysis of combinatorial regulatory interactions between transcription factors, microRNAs and target genes that are involved in disease pathogenesis. Since the inner workings of cells rely on the correct functioning of an enormously complex system of activating and repressing interactions that can be perturbed in many ways, TFmiR helps to better elucidate cellular mechanisms at the molecular level from a network perspective. The provided topological and functional analyses promote TFmiR as a reliable systems biology tool for researchers across the life science communities. TFmiR web server is accessible through the following URL: http://service.bioinformatik.uni-saarland.de/tfmir. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L.; Robertson, Julie M.; Harley, John B.; James, Judith A.; Guthridge, Joel M.
2013-01-01
Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients. PMID:23977035
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Mittra, James; Tait, Joyce; Wield, David
2011-03-01
The pharmaceutical and agro-biotechnology industries have been confronted by dwindling product pipelines and rapid developments in life sciences, thus demanding a strategic rethink of conventional research and development. Despite offering both industries a solution to the pipeline problem, the life sciences have also brought complex regulatory challenges for firms. In this paper, we comment on the response of these industries to the life science trajectory, in the context of maturing conventional small-molecule product pipelines and routes to market. The challenges of managing transition from maturity to new high-value-added innovation models are addressed. Furthermore, we argue that regulation plays a crucial role in shaping the innovation systems of both industries, and as such, we suggest potentially useful changes to the current regulatory system. Copyright © 2010 Elsevier Ltd. All rights reserved.
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SATRAT: Staphylococcus aureus transcript regulatory network analysis tool.
Gopal, Tamilselvi; Nagarajan, Vijayaraj; Elasri, Mohamed O
2015-01-01
Staphylococcus aureus is a commensal organism that primarily colonizes the nose of healthy individuals. S. aureus causes a spectrum of infections that range from skin and soft-tissue infections to fatal invasive diseases. S. aureus uses a large number of virulence factors that are regulated in a coordinated fashion. The complex regulatory mechanisms have been investigated in numerous high-throughput experiments. Access to this data is critical to studying this pathogen. Previously, we developed a compilation of microarray experimental data to enable researchers to search, browse, compare, and contrast transcript profiles. We have substantially updated this database and have built a novel exploratory tool-SATRAT-the S. aureus transcript regulatory network analysis tool, based on the updated database. This tool is capable of performing deep searches using a query and generating an interactive regulatory network based on associations among the regulators of any query gene. We believe this integrated regulatory network analysis tool would help researchers explore the missing links and identify novel pathways that regulate virulence in S. aureus. Also, the data model and the network generation code used to build this resource is open sourced, enabling researchers to build similar resources for other bacterial systems.
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Dual Nature of Translational Control by Regulatory BC RNAs ▿
Eom, Taesun; Berardi, Valerio; Zhong, Jun; Risuleo, Gianfranco; Tiedge, Henri
2011-01-01
In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3′ stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems. PMID:21930783
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Decoding the role of regulatory element polymorphisms in complex disease.
Vockley, Christopher M; Barrera, Alejandro; Reddy, Timothy E
2017-04-01
Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non-coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Ceccarelli, Michele; Cerulo, Luigi; Santone, Antonella
2014-10-01
Reverse engineering of gene regulatory relationships from genomics data is a crucial task to dissect the complex underlying regulatory mechanism occurring in a cell. From a computational point of view the reconstruction of gene regulatory networks is an undetermined problem as the large number of possible solutions is typically high in contrast to the number of available independent data points. Many possible solutions can fit the available data, explaining the data equally well, but only one of them can be the biologically true solution. Several strategies have been proposed in literature to reduce the search space and/or extend the amount of independent information. In this paper we propose a novel algorithm based on formal methods, mathematically rigorous techniques widely adopted in engineering to specify and verify complex software and hardware systems. Starting with a formal specification of gene regulatory hypotheses we are able to mathematically prove whether a time course experiment belongs or not to the formal specification, determining in fact whether a gene regulation exists or not. The method is able to detect both direction and sign (inhibition/activation) of regulations whereas most of literature methods are limited to undirected and/or unsigned relationships. We empirically evaluated the approach on experimental and synthetic datasets in terms of precision and recall. In most cases we observed high levels of accuracy outperforming the current state of art, despite the computational cost increases exponentially with the size of the network. We made available the tool implementing the algorithm at the following url: http://www.bioinformatics.unisannio.it. Copyright © 2014 Elsevier Inc. All rights reserved.
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Evolution of regulatory networks towards adaptability and stability in a changing environment
NASA Astrophysics Data System (ADS)
Lee, Deok-Sun
2014-11-01
Diverse biological networks exhibit universal features distinguished from those of random networks, calling much attention to their origins and implications. Here we propose a minimal evolution model of Boolean regulatory networks, which evolve by selectively rewiring links towards enhancing adaptability to a changing environment and stability against dynamical perturbations. We find that sparse and heterogeneous connectivity patterns emerge, which show qualitative agreement with real transcriptional regulatory networks and metabolic networks. The characteristic scaling behavior of stability reflects the balance between robustness and flexibility. The scaling of fluctuation in the perturbation spread shows a dynamic crossover, which is analyzed by investigating separately the stochasticity of internal dynamics and the network structure differences depending on the evolution pathways. Our study delineates how the ambivalent pressure of evolution shapes biological networks, which can be helpful for studying general complex systems interacting with environments.
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Zinc in Cellular Regulation: The Nature and Significance of "Zinc Signals".
Maret, Wolfgang
2017-10-31
In the last decade, we witnessed discoveries that established Zn 2+ as a second major signalling metal ion in the transmission of information within cells and in communication between cells. Together with Ca 2+ and Mg 2+ , Zn 2+ covers biological regulation with redox-inert metal ions over many orders of magnitude in concentrations. The regulatory functions of zinc ions, together with their functions as a cofactor in about three thousand zinc metalloproteins, impact virtually all aspects of cell biology. This article attempts to define the regulatory functions of zinc ions, and focuses on the nature of zinc signals and zinc signalling in pathways where zinc ions are either extracellular stimuli or intracellular messengers. These pathways interact with Ca 2+ , redox, and phosphorylation signalling. The regulatory functions of zinc require a complex system of precise homeostatic control for transients, subcellular distribution and traffic, organellar homeostasis, and vesicular storage and exocytosis of zinc ions.
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Transposable elements and G-quadruplexes.
Kejnovsky, Eduard; Tokan, Viktor; Lexa, Matej
2015-09-01
A significant part of eukaryotic genomes is formed by transposable elements (TEs) containing not only genes but also regulatory sequences. Some of the regulatory sequences located within TEs can form secondary structures like hairpins or three-stranded (triplex DNA) and four-stranded (quadruplex DNA) conformations. This review focuses on recent evidence showing that G-quadruplex-forming sequences in particular are often present in specific parts of TEs in plants and humans. We discuss the potential role of these structures in the TE life cycle as well as the impact of G-quadruplexes on replication, transcription, translation, chromatin status, and recombination. The aim of this review is to emphasize that TEs may serve as vehicles for the genomic spread of G-quadruplexes. These non-canonical DNA structures and their conformational switches may constitute another regulatory system that, together with small and long non-coding RNA molecules and proteins, contribute to the complex cellular network resulting in the large diversity of eukaryotes.
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Kitchen, James L.; Allaby, Robin G.
2013-01-01
Selection and adaptation of individuals to their underlying environments are highly dynamical processes, encompassing interactions between the individual and its seasonally changing environment, synergistic or antagonistic interactions between individuals and interactions amongst the regulatory genes within the individual. Plants are useful organisms to study within systems modeling because their sedentary nature simplifies interactions between individuals and the environment, and many important plant processes such as germination or flowering are dependent on annual cycles which can be disrupted by climate behavior. Sedentism makes plants relevant candidates for spatially explicit modeling that is tied in with dynamical environments. We propose that in order to fully understand the complexities behind plant adaptation, a system that couples aspects from systems biology with population and landscape genetics is required. A suitable system could be represented by spatially explicit individual-based models where the virtual individuals are located within time-variable heterogeneous environments and contain mutable regulatory gene networks. These networks could directly interact with the environment, and should provide a useful approach to studying plant adaptation. PMID:27137364
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-03-14
..., ``Certain Types of Orders Defined,'' Rule 6.53C, ``Complex Orders on the Hybrid System,'' Rule 8.7... trades in individual NMS Stocks from occurring outside of specified price bands, as defined in Section I(N) of the Plan. These requirements would be coupled with trading pauses, as defined in Section I(Y...
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Toll-like receptors and intestinal defence: molecular basis and therapeutic implications.
Cario, Elke
2003-07-07
Toll-like receptors (TLRs) play a principle role in distinct pathogen recognition and in the initiation of innate immune responses of the intestinal mucosa. Activated innate immunity interconnects downstream with adaptive immunity in complex feedback regulatory loops. Intestinal disease might result from inappropriate activation of the mucosal immune system driven by TLRs in response to normal luminal flora.
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Permanent Closure of MFC Biodiesel Underground Storage Tank 99ANL00013
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kerry L. Nisson
2012-10-01
This closure package documents the site assessment and permanent closure of the Materials and Fuels Complex biodiesel underground storage tank 99ANL00013 in accordance with the regulatory requirements established in 40 CFR 280.71, “Technical Standards and Corrective Action Requirements for Owners and Operators of Underground Storage Tanks: Out-of-Service UST Systems and Closure.”
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-11
... ratio at the conclusion of COA, the order, or any remaining balance, will route to the CBOE's Complex... basis, to route the remaining balance of the option leg(s) of such an order to CBOE's Hybrid System for... remaining balance of the stock leg of such an order to the CBOE Stock Exchange (``CBSX''), CBOE's stock...
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Ruby, P K; Pathak, Shriram M; Aggarwal, Deepika
2014-11-01
Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.
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A toolbox for discrete modelling of cell signalling dynamics.
Paterson, Yasmin Z; Shorthouse, David; Pleijzier, Markus W; Piterman, Nir; Bendtsen, Claus; Hall, Benjamin A; Fisher, Jasmin
2018-06-18
In an age where the volume of data regarding biological systems exceeds our ability to analyse it, many researchers are looking towards systems biology and computational modelling to help unravel the complexities of gene and protein regulatory networks. In particular, the use of discrete modelling allows generation of signalling networks in the absence of full quantitative descriptions of systems, which are necessary for ordinary differential equation (ODE) models. In order to make such techniques more accessible to mainstream researchers, tools such as the BioModelAnalyzer (BMA) have been developed to provide a user-friendly graphical interface for discrete modelling of biological systems. Here we use the BMA to build a library of discrete target functions of known canonical molecular interactions, translated from ordinary differential equations (ODEs). We then show that these BMA target functions can be used to reconstruct complex networks, which can correctly predict many known genetic perturbations. This new library supports the accessibility ethos behind the creation of BMA, providing a toolbox for the construction of complex cell signalling models without the need for extensive experience in computer programming or mathematical modelling, and allows for construction and simulation of complex biological systems with only small amounts of quantitative data.
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Lemmens, Karen; De Bie, Tijl; Dhollander, Thomas; De Keersmaecker, Sigrid C; Thijs, Inge M; Schoofs, Geert; De Weerdt, Ami; De Moor, Bart; Vanderleyden, Jos; Collado-Vides, Julio; Engelen, Kristof; Marchal, Kathleen
2009-01-01
We present DISTILLER, a data integration framework for the inference of transcriptional module networks. Experimental validation of predicted targets for the well-studied fumarate nitrate reductase regulator showed the effectiveness of our approach in Escherichia coli. In addition, the condition dependency and modularity of the inferred transcriptional network was studied. Surprisingly, the level of regulatory complexity seemed lower than that which would be expected from RegulonDB, indicating that complex regulatory programs tend to decrease the degree of modularity.
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Risk Management Technique for design and operation of facilities and equipment
NASA Technical Reports Server (NTRS)
Fedor, O. H.; Parsons, W. N.; Coutinho, J. De S.
1975-01-01
The Risk Management System collects information from engineering, operating, and management personnel to identify potentially hazardous conditions. This information is used in risk analysis, problem resolution, and contingency planning. The resulting hazard accountability system enables management to monitor all identified hazards. Data from this system are examined in project reviews so that management can decide to eliminate or accept these risks. This technique is particularly effective in improving the management of risks in large, complex, high-energy facilities. These improvements are needed for increased cooperation among industry, regulatory agencies, and the public.
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Regulation of host-pathogen interactions via the post-transcriptional Csr/Rsm system.
Kusmierek, Maria; Dersch, Petra
2018-02-01
A successful colonization of specific hosts requires a rapid and efficient adaptation of the virulence-relevant gene expression program by bacterial pathogens. An important element in this endeavor is the Csr/Rsm system. This multi-component, post-transcriptional control system forms a central hub within complex regulatory networks and coordinately adjusts virulence properties with metabolic and physiological attributes of the pathogen. A key function is elicited by the RNA-binding protein CsrA/RsmA. CsrA/RsmA interacts with numerous target mRNAs, many of which encode crucial virulence factors, and alters their translation, stability or elongation of transcription. Recent studies highlighted that important colonization factors, toxins, and bacterial secretion systems are under CsrA/RsmA control. CsrA/RsmA deficiency impairs host colonization and attenuates virulence, making this post-transcriptional regulator a suitable drug target. The CsrA/RsmA protein can be inactivated through sequestration by non-coding RNAs, or via binding to specific highly abundant mRNAs and interacting proteins. The wide range of interaction partners and RNA targets, as well as the overarching, interlinked genetic control circuits illustrate the complexity of this regulatory system in the different pathogens. Future work addressing spatio-temporal changes of Csr/Rsm-mediated control during the course of an infection will help us to understand how bacteria reprogram their expression profile to cope with continuous changes experienced in colonized niches. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Winickoff, David E; Mondou, Matthieu
2017-02-01
While there is ample scholarly work on regulatory science within the state, or single-sited global institutions, there is less on its operation within complex modes of global governance that are decentered, overlapping, multi-sectorial and multi-leveled. Using a co-productionist framework, this study identifies 'epistemic jurisdiction' - the power to produce or warrant technical knowledge for a given political community, topical arena or geographical territory - as a central problem for regulatory science in complex governance. We explore these dynamics in the arena of global sustainability standards for biofuels. We select three institutional fora as sites of inquiry: the European Union's Renewable Energy Directive, the Roundtable on Sustainable Biomaterials, and the International Organization for Standardization. These cases allow us to analyze how the co-production of sustainability science responds to problems of epistemic jurisdiction in the global regulatory order. First, different problems of epistemic jurisdiction beset different standard-setting bodies, and these problems shape both the content of regulatory science and the procedures designed to make it authoritative. Second, in order to produce global regulatory science, technical bodies must manage an array of conflicting imperatives - including scientific virtue, due process and the need to recruit adoptees to perpetuate the standard. At different levels of governance, standard drafters struggle to balance loyalties to country, to company or constituency and to the larger project of internationalization. Confronted with these sometimes conflicting pressures, actors across the standards system quite self-consciously maneuver to build or retain authority for their forum through a combination of scientific adjustment and political negotiation. Third, the evidentiary demands of regulatory science in global administrative spaces are deeply affected by 1) a market for standards, in which firms and states can choose the cheapest sustainability certification, and 2) the international trade regime, in which the long shadow of WTO law exerts a powerful disciplining function.
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Modeling stochastic noise in gene regulatory systems
Meister, Arwen; Du, Chao; Li, Ye Henry; Wong, Wing Hung
2014-01-01
The Master equation is considered the gold standard for modeling the stochastic mechanisms of gene regulation in molecular detail, but it is too complex to solve exactly in most cases, so approximation and simulation methods are essential. However, there is still a lack of consensus about the best way to carry these out. To help clarify the situation, we review Master equation models of gene regulation, theoretical approximations based on an expansion method due to N.G. van Kampen and R. Kubo, and simulation algorithms due to D.T. Gillespie and P. Langevin. Expansion of the Master equation shows that for systems with a single stable steady-state, the stochastic model reduces to a deterministic model in a first-order approximation. Additional theory, also due to van Kampen, describes the asymptotic behavior of multistable systems. To support and illustrate the theory and provide further insight into the complex behavior of multistable systems, we perform a detailed simulation study comparing the various approximation and simulation methods applied to synthetic gene regulatory systems with various qualitative characteristics. The simulation studies show that for large stochastic systems with a single steady-state, deterministic models are quite accurate, since the probability distribution of the solution has a single peak tracking the deterministic trajectory whose variance is inversely proportional to the system size. In multistable stochastic systems, large fluctuations can cause individual trajectories to escape from the domain of attraction of one steady-state and be attracted to another, so the system eventually reaches a multimodal probability distribution in which all stable steady-states are represented proportional to their relative stability. However, since the escape time scales exponentially with system size, this process can take a very long time in large systems. PMID:25632368
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NASA Astrophysics Data System (ADS)
Makowiec, Danuta; Graff, Beata; Struzik, Zbigniew R.
2017-02-01
Biological regulation is sufficiently complex to pose an enduring challenge for characterization of both its equilibrium and transient non-equilibrium dynamics. Two univariate but coupled observables, heart rate and systolic blood pressure, are commonly characterized in the benchmark example of the human cardiovascular regulatory system. Asymmetric distributions of accelerations and decelerations of heart rate, as well as rises and falls in systolic blood pressure, recorded in humans during a head-up tilt test provide insights into the dynamics of cardiovascular response to a rapid, controlled deregulation of the system's homeostasis. The baroreflex feedback loop is assumed to be the fundamental physiological mechanism for ensuring homeostatic blood supply to distant organs at rest and during orthostatic stress, captured in a classical beat-to-beat autoregressive model of baroreflex by de Boer et al. (1987). For model corroboration, a multistructure index statistic is proposed, seamlessly evaluating the size spectrum of magnitudes of neural reflexes such as baroreflex, responsible for maintaining the homeostatic dynamics. The multistructure index exposes a distinctly different dynamics of multiscale asymmetry between results obtained from real-life signals recorded from healthy subjects and those simulated using both the classical and perturbed versions of the model. Nonlinear effects observed suggest the pronounced presence of complex mechanisms resulting from baroreflex regulation when a human is at rest, which is aggravated in the system's response to orthostatic stress. Using our methodology of multistructure index, we therefore show a marked difference between model and real-life scenarios, which we attribute to multiscale asymmetry of non-linear origin in real-life signals, which we are not reproducible by the classical model.
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Nandi, Anjan K; Sumana, Annagiri; Bhattacharya, Kunal
2014-12-06
Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata-a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure-the 'feed-forward loop'-a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony. © 2014 The Author(s) Published by the Royal Society. All rights reserved.
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Faggioli, A; Capasso, L
2015-01-01
Indoor environment is one of major health determinants, and the regulations that set the sanitary requirements are of primary importance for the protection of public health. The authors analyse the critical aspects of the complex Italian regulatory system, starting from the EU regulations, through national and regional laws, and finally the municipal regulations. They underline the need for more uniformity and clarity in the determination of health standards, as well as for a simplification of the existing legislation. Moreover, they highlight the importance of controlling and monitoring indoor environment, currently almost completely absent in Italy due to the effects of the regulatory changes of the latest years.
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Engineering Synthetic Gene Circuits in Living Cells with CRISPR Technology.
Jusiak, Barbara; Cleto, Sara; Perez-Piñera, Pablo; Lu, Timothy K
2016-07-01
One of the goals of synthetic biology is to build regulatory circuits that control cell behavior, for both basic research purposes and biomedical applications. The ability to build transcriptional regulatory devices depends on the availability of programmable, sequence-specific, and effective synthetic transcription factors (TFs). The prokaryotic clustered regularly interspaced short palindromic repeat (CRISPR) system, recently harnessed for transcriptional regulation in various heterologous host cells, offers unprecedented ease in designing synthetic TFs. We review how CRISPR can be used to build synthetic gene circuits and discuss recent advances in CRISPR-mediated gene regulation that offer the potential to build increasingly complex, programmable, and efficient gene circuits in the future. Copyright © 2016. Published by Elsevier Ltd.
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Mechanism of phosphoryl transfer and protein-protein interaction in the PTS system-an NMR study
DOE Office of Scientific and Technical Information (OSTI.GOV)
Rajagopal, P.; Klevit, R.E.
1994-12-01
HPr and Enzyme IIA{sup Glc} are two of the components of the bacterial PTS (phosphoenolpyruvate: sugar phosphotranferase system) and are involved in the phosphorylation and concomitant translocation of sugars across the membrane. These PTS protein complexes also regulate sugar transport. HPr, phosphorylated at a histidine N1 site by Enzyme I and phosphoenol pyruvate, transfers the phosphoryl group to a histidine N3 position in Enzyme IIA{sup Glc}. HPrs from Gram-positive bacteria undergo regulatory phosphorylation at Ser{sup 46}, whereby phosphorylation of the histidine residue is inhibited. Conversely, histidine phosphorylation inhibits phosphorylation at Ser{sup 46}. HPrs from Gram-negative bacteria possess a serine residuemore » at position 46, but do not undergo regulatory phosphorylation. HPr forms an open-faced sandwich structure with a four-strand S-sheet and 2 to 3 helices lying on top of the sheet. The active-site histidine and Ser{sup 46} occur in conformationally flexible regions. P-His-HPr from the Gram-positive bacterium Bacillus subtilus has been investigated by both homonuclear and heteronuclear two-dimensional and three-dimensional NMR experiments using an in-situ enzymatic regeneration system to maintain a constant level of P-His-HPr. The results show that localized conformational changes occur in the vicinity of the active-site histidine and also near Ser{sup 46}. HPr-Enzyme IIA{sup Glc} complexes from both Bacillus subtilis and Gram-negative Escherichia coli were also studied by a variety of {sup 15}N-edited two-dimensional NMR experiments, which were performed on uniformly {sup 15}N-labeled HPr complexed to unlabeled Enzyme IIA{sup Glc}. The complex is in fast exchange with a molecular weight of about 27 kDa. The focus of our work is to assess the changes undergone by HPr (the smaller of the two components), and so all the experiments were performed with excess Enzyme IIA present in the system.« less
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A framework for modelling gene regulation which accommodates non-equilibrium mechanisms.
Ahsendorf, Tobias; Wong, Felix; Eils, Roland; Gunawardena, Jeremy
2014-12-05
Gene regulation has, for the most part, been quantitatively analysed by assuming that regulatory mechanisms operate at thermodynamic equilibrium. This formalism was originally developed to analyse the binding and unbinding of transcription factors from naked DNA in eubacteria. Although widely used, it has made it difficult to understand the role of energy-dissipating, epigenetic mechanisms, such as DNA methylation, nucleosome remodelling and post-translational modification of histones and co-regulators, which act together with transcription factors to regulate gene expression in eukaryotes. Here, we introduce a graph-based framework that can accommodate non-equilibrium mechanisms. A gene-regulatory system is described as a graph, which specifies the DNA microstates (vertices), the transitions between microstates (edges) and the transition rates (edge labels). The graph yields a stochastic master equation for how microstate probabilities change over time. We show that this framework has broad scope by providing new insights into three very different ad hoc models, of steroid-hormone responsive genes, of inherently bounded chromatin domains and of the yeast PHO5 gene. We find, moreover, surprising complexity in the regulation of PHO5, which has not yet been experimentally explored, and we show that this complexity is an inherent feature of being away from equilibrium. At equilibrium, microstate probabilities do not depend on how a microstate is reached but, away from equilibrium, each path to a microstate can contribute to its steady-state probability. Systems that are far from equilibrium thereby become dependent on history and the resulting complexity is a fundamental challenge. To begin addressing this, we introduce a graph-based concept of independence, which can be applied to sub-systems that are far from equilibrium, and prove that history-dependent complexity can be circumvented when sub-systems operate independently. As epigenomic data become increasingly available, we anticipate that gene function will come to be represented by graphs, as gene structure has been represented by sequences, and that the methods introduced here will provide a broader foundation for understanding how genes work.
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Computational Study of the Genomic and Epigenomic Phenomena
NASA Astrophysics Data System (ADS)
Yang, Wenjing
Biological systems are perhaps the ultimate complex systems, uniquely capable of processing and communicating information, reproducing in their lifetimes, and adapting in evolutionary time scales. My dissertation research focuses on using computational approaches to understand the biocomplexity manifested in the multitude of length scales and time scales. At the molecular and cellular level, central to the complex behavior of a biological system is the regulatory network. My research study focused on epigenetics, which is essential for multicellular organisms to establish cellular identity during development or in response to intracellular and environmental stimuli. My computational study of epigenomics is greatly facilitated by recent advances in high-throughput sequencing technology, which enables high-resolution snapshots of epigenomes and transcriptomes. Using human CD4+ T cell as a model system, the dynamical changes in epigenome and transcriptome pertinent to T cell activation were investigated at the genome scale. Going beyond traditional focus on transcriptional regulation, I provided evidences that post-transcriptional regulation may serve as a major component of the regulatory network. In addition, I explored alternative polyadenylation, another novel aspect of gene regulation, and how it cross-talks with the local chromatin structure. As the renowned theoretical biologist Theodosius Dobzhansky said eloquently, "Nothing in biology makes sense except in the light of evolution''. To better understand this ubiquitous driving force in the biological world, I went beyond molecular events in a single organism, and investigated the dynamical changes of population structure along the evolutionary time scale. To this end, we used HIV virus population dynamics in the host immune system as a model system. The evolution of HIV viral population plays a key role in AIDS immunopathogenesis with its exceptionally high mutation rate. However, the theoretical studies of the effect of recombination have been rather limited. Given the phylogenetic and experimental evidences for the high recombination rate and its important role in HIV evolution and epidemics, I established a mathematical model to study the effect of recombination, and explored the complex behavior of this dynamics system.
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Koski, Greg; Tobin, Mary F; Whalen, Matthew
2014-10-01
The pharmaceutical industry, once highly respected, productive, and profitable, is in the throes of major change driven by many forces, including economics, science, regulation, and ethics. A variety of initiatives and partnerships have been launched to improve efficiency and productivity but without significant effect because they have failed to consider the process as a system. Addressing the challenges facing this complex endeavor requires more than modifications of individual processes; it requires a fully integrated application of systems thinking and an understanding of the desired goals and complex interactions among essential components and stakeholders of the whole. A multistakeholder collaborative effort, led by the Alliance for Clinical Research Excellence and Safety (ACRES), a global nonprofit organization operating in the public interest, is now under way to build a shared global system for clinical research. Its systems approach focuses on the interconnection of stakeholders at critical points of interaction within 4 operational domains: site development and support, quality management, information technology, and safety. The ACRES initiatives, Site Accreditation and Standards, Product Safety Culture, Global Ethical Review and Regulatory Innovation, and Quality Assurance and Safety, focus on building and implementing systems solutions. Underpinning these initiatives is an open, shared, integrated technology (site and optics and quality informatics initiative). We describe the rationale, challenges, progress, and successes of this effort to date and lessons learned. The complexity and fragmentation of the intensely proprietary ecosystem of drug development, challenging regulatory climate, and magnitude of the endeavor itself pose significant challenges, but the economic, social, and scientific rewards will more than justify the effort. An effective alliance model requires a willingness of multiple stakeholders to work together to build a shared system within a noncompetitive space that will have major benefits for all, including better access to medicines, better health, and more productive lives. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.
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Dolatshahi, Sepideh; Fonseca, Luis L; Voit, Eberhard O
2016-01-01
This article and the companion paper use computational systems modeling to decipher the complex coordination of regulatory signals controlling the glycolytic pathway in the dairy bacterium Lactococcus lactis. In this first article, the development of a comprehensive kinetic dynamic model is described. The model is based on in vivo NMR data that consist of concentration trends in key glycolytic metabolites and cofactors. The model structure and parameter values are identified with a customized optimization strategy that uses as its core the method of dynamic flux estimation. For the first time, a dynamic model with a single parameter set fits all available glycolytic time course data under anaerobic operation. The model captures observations that had not been addressed so far and suggests the existence of regulatory effects that had been observed in other species, but not in L. lactis. The companion paper uses this model to analyze details of the dynamic control of glycolysis under aerobic and anaerobic conditions.
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Pathogenesis and pharmacologic treatment of obesity: the role of energy regulatory mechanism.
Manulu, Mangatas S M; Sutanegara, I N Dwi
2006-01-01
Obesity has become a worldwide public health problem affecting millions of people. This is a chronic, stigmatized, and costly disease, rarely curable and is increasing in prevalence to a point today where we define obesity as an epidemic disease that not only in developed but also on developing countries. The pathogenesis of obesity is largely unknown, especially about energy regulatory mechanism that involved wide area of neuroendocrinology that is very interesting but very complex and makes internists "refuse" to learn. Obesity occurs through a longstanding imbalance between energy intake and energy expenditure, influenced by a complex biologic system that regulates appetite and adiposity. Obesity influences the pathogenesis of hypertension, type 2 diabetes, dyslipidemia, kidney, heart, and cerebrovascular disease. It is very wise for every internist to learn the pathogenesis and treatment of this worldwide diseases. Until now, the available treatments, including drugs, are palliative and are effective only while the treatment is being actively used; and besides so many side effects reported.
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Biodiversity maintenance in food webs with regulatory environmental feedbacks.
Bagdassarian, Carey K; Dunham, Amy E; Brown, Christopher G; Rauscher, Daniel
2007-04-21
Although the food web is one of the most fundamental and oldest concepts in ecology, elucidating the strategies and structures by which natural communities of species persist remains a challenge to empirical and theoretical ecologists. We show that simple regulatory feedbacks between autotrophs and their environment when embedded within complex and realistic food-web models enhance biodiversity. The food webs are generated through the niche-model algorithm and coupled with predator-prey dynamics, with and without environmental feedbacks at the autotroph level. With high probability and especially at lower, more realistic connectance levels, regulatory environmental feedbacks result in fewer species extinctions, that is, in increased species persistence. These same feedback couplings, however, also sensitize food webs to environmental stresses leading to abrupt collapses in biodiversity with increased forcing. Feedback interactions between species and their material environments anchor food-web persistence, adding another dimension to biodiversity conservation. We suggest that the regulatory features of two natural systems, deep-sea tubeworms with their microbial consortia and a soil ecosystem manifesting adaptive homeostatic changes, can be embedded within niche-model food-web dynamics.
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Viruses Associated with Human Cancer
McLaughlin-Drubin, Margaret E.; Munger, Karl
2008-01-01
It is estimated that viral infections contribute to 15–20% of all human cancers. As obligatory intracellular parasites, viruses encode proteins that reprogram host cellular signaling pathways that control proliferation, differentiation, cell death, genomic integrity, and recognition by the immune system. These cellular processes are governed by complex and redundant regulatory networks and are surveyed by sentinel mechanisms that ensure that aberrant cells are removed from the proliferative pool. Given that the genome size of a virus is highly restricted to ensure packaging within an infectious structure, viruses must target cellular regulatory nodes with limited redundancy and need to inactivate surveillance mechanisms that would normally recognize and extinguish such abnormal cells. In many cases, key proteins in these same regulatory networks are subject to mutation in non-virally associated diseases and cancers. Oncogenic viruses have thus served as important experimental models to identify and molecularly investigate such cellular networks. These include the discovery of oncogenes and tumor suppressors, identification of regulatory networks that are critical for maintenance of genomic integrity, and processes that govern immune surveillance. PMID:18201576
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Peptides and the new endocrinology
NASA Astrophysics Data System (ADS)
Schwyzer, Robert
1982-01-01
The discovery of regulatory peptides common to the nervous and the endocrine systems (brain, gut, and skin) has brought about a revolution in our concepts of endocrinology and neurology. We are beginning to understand some of the complex interrelationships between soma and psyche that might, someday, be important for an integrated treatment of diseases. Examples of the actions of certain peptides in the periphery and in the central nervous system are given, and their biosynthesis and molecular anatomy as carriers for information are discussed.
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From CNS stem cells to neurons and glia: Sox for everyone.
Reiprich, Simone; Wegner, Michael
2015-01-01
Neuroepithelial precursor cells of the vertebrate central nervous system either self-renew or differentiate into neurons, oligodendrocytes or astrocytes under the influence of a gene regulatory network that consists in transcription factors, epigenetic modifiers and microRNAs. Sox transcription factors are central to this regulatory network, especially members of the SoxB, SoxC, SoxD, SoxE and SoxF groups. These Sox proteins are widely expressed in neuroepithelial precursor cells and in newly specified, differentiating and mature neurons, oligodendrocytes and astrocytes and influence their identity, survival and development. They exert their effect predominantly at the transcriptional level but also have substantial impact on expression at the epigenetic and posttranscriptional levels with some Sox proteins acting as pioneer factors, recruiting chromatin-modifying and -remodelling complexes or influencing microRNA expression. They interact with a large variety of other transcription factors and influence the expression of regulatory molecules and effector genes in a cell-type-specific and temporally controlled manner. As versatile regulators with context-dependent functions, they are not only indispensable for central nervous system development but might also be instrumental for the development of reprogramming and cell conversion strategies for replacement therapies and for assisted regeneration after injury or degeneration-induced cell loss in the central nervous system.
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Tuominen, H; Salminen, A; Oksanen, E; Jämsen, J; Heikkilä, O; Lehtiö, L; Magretova, N N; Goldman, A; Baykov, A A; Lahti, R
2010-05-07
Nucleotide-binding cystathionine beta-synthase (CBS) domains serve as regulatory units in numerous proteins distributed in all kingdoms of life. However, the underlying regulatory mechanisms remain to be established. Recently, we described a subfamily of CBS domain-containing pyrophosphatases (PPases) within family II PPases. Here, we express a novel CBS-PPase from Clostridium perfringens (CPE2055) and show that the enzyme is inhibited by AMP and activated by a novel effector, diadenosine 5',5-P1,P4-tetraphosphate (AP(4)A). The structures of the AMP and AP(4)A complexes of the regulatory region of C. perfringens PPase (cpCBS), comprising a pair of CBS domains interlinked by a DRTGG domain, were determined at 2.3 A resolution using X-ray crystallography. The structures obtained are the first structures of a DRTGG domain as part of a larger protein structure. The AMP complex contains two AMP molecules per cpCBS dimer, each bound to a single monomer, whereas in the activator-bound complex, one AP(4)A molecule bridges two monomers. In the nucleotide-bound structures, activator binding induces significant opening of the CBS domain interface, compared with the inhibitor complex. These results provide structural insight into the mechanism of CBS-PPase regulation by nucleotides. Copyright 2010 Elsevier Ltd. All rights reserved.
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Clinical profile of vigabatrin as monotherapy for treatment of infantile spasms
Lerner, Jason T; Salamon, Noriko; Sankar, Raman
2010-01-01
Vigabatrin, the first therapeutic agent to be approved by the Food and Drug Administration for the treatment of infantile spasms, as well as for adjunctive use in the treatment of refractory complex partial epilepsy, represents an important advance for patients with difficult-to-manage epilepsy. This review summarizes the complex history, chemistry, and pharmacology, as well as the clinical data leading to the approval of vigabatrin for infantile spasms in the US. The long path to its approval reflects the visual system and white matter toxicity concerns with this agent. This review provides a brief description of these concerns, and the regulatory safety monitoring and mitigation systems that have been put in place to enhance benefit over risk. PMID:21127692
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Li, X Y; Yang, G W; Zheng, D S; Guo, W S; Hung, W N N
2015-04-28
Genetic regulatory networks are the key to understanding biochemical systems. One condition of the genetic regulatory network under different living environments can be modeled as a synchronous Boolean network. The attractors of these Boolean networks will help biologists to identify determinant and stable factors. Existing methods identify attractors based on a random initial state or the entire state simultaneously. They cannot identify the fixed length attractors directly. The complexity of including time increases exponentially with respect to the attractor number and length of attractors. This study used the bounded model checking to quickly locate fixed length attractors. Based on the SAT solver, we propose a new algorithm for efficiently computing the fixed length attractors, which is more suitable for large Boolean networks and numerous attractors' networks. After comparison using the tool BooleNet, empirical experiments involving biochemical systems demonstrated the feasibility and efficiency of our approach.
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CLARA: an integrated clinical research administration system.
Bian, Jiang; Xie, Mengjun; Hogan, William; Hutchins, Laura; Topaloglu, Umit; Lane, Cheryl; Holland, Jennifer; Wells, Thomas
2014-10-01
Administration of human subject research is complex, involving not only the institutional review board but also many other regulatory and compliance entities within a research enterprise. Its efficiency has a direct and substantial impact on the conduct and management of clinical research. In this paper, we report on the Clinical Research Administration (CLARA) platform developed at the University of Arkansas for Medical Sciences. CLARA is a comprehensive web-based system that can streamline research administrative tasks such as submissions, reviews, and approval processes for both investigators and different review committees on a single integrated platform. CLARA not only helps investigators to meet regulatory requirements but also provides tools for managing other clinical research activities including budgeting, contracting, and participant schedule planning. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Self Organized Criticality as a new paradigm of sleep regulation
NASA Astrophysics Data System (ADS)
Ivanov, Plamen Ch.; Bartsch, Ronny P.
2012-02-01
Humans and animals often exhibit brief awakenings from sleep (arousals), which are traditionally viewed as random disruptions of sleep caused by external stimuli or pathologic perturbations. However, our recent findings show that arousals exhibit complex temporal organization and scale-invariant behavior, characterized by a power-law probability distribution for their durations, while sleep stage durations exhibit exponential behavior. The co-existence of both scale-invariant and exponential processes generated by a single regulatory mechanism has not been observed in physiological systems until now. Such co-existence resembles the dynamical features of non-equilibrium systems exhibiting self-organized criticality (SOC). Our empirical analysis and modeling approaches based on modern concepts from statistical physics indicate that arousals are an integral part of sleep regulation and may be necessary to maintain and regulate healthy sleep by releasing accumulated excitations in the regulatory neuronal networks, following a SOC-type temporal organization.
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The Roles and Regulation of Polycomb Complexes in Neural Development
Corley, Matthew; Kroll, Kristen L.
2014-01-01
In the developing mammalian nervous system, common progenitors integrate both cell extrinsic and intrinsic regulatory programs to produce distinct neuronal and glial cell types as development proceeds. This spatiotemporal restriction of neural progenitor differentiation is enforced, in part, by the dynamic reorganization of chromatin into repressive domains by Polycomb Repressive Complexes, effectively limiting the expression of fate-determining genes. Here, we review distinct roles that the Polycomb Repressive Complexes play during neurogenesis and gliogenesis, while also highlighting recent work describing the molecular mechanisms that govern their dynamic activity in neural development. Further investigation of how Polycomb complexes are regulated in neural development will enable more precise manipulation of neural progenitor differentiation, facilitating the efficient generation of specific neuronal and glial cell types for many biological applications. PMID:25367430
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NASA Astrophysics Data System (ADS)
Yadav, Basant; Ch, Sudheer; Mathur, Shashi; Adamowski, Jan
2016-12-01
In-situ bioremediation is the most common groundwater remediation procedure used for treating organically contaminated sites. A simulation-optimization approach, which incorporates a simulation model for groundwaterflow and transport processes within an optimization program, could help engineers in designing a remediation system that best satisfies management objectives as well as regulatory constraints. In-situ bioremediation is a highly complex, non-linear process and the modelling of such a complex system requires significant computational exertion. Soft computing techniques have a flexible mathematical structure which can generalize complex nonlinear processes. In in-situ bioremediation management, a physically-based model is used for the simulation and the simulated data is utilized by the optimization model to optimize the remediation cost. The recalling of simulator to satisfy the constraints is an extremely tedious and time consuming process and thus there is need for a simulator which can reduce the computational burden. This study presents a simulation-optimization approach to achieve an accurate and cost effective in-situ bioremediation system design for groundwater contaminated with BTEX (Benzene, Toluene, Ethylbenzene, and Xylenes) compounds. In this study, the Extreme Learning Machine (ELM) is used as a proxy simulator to replace BIOPLUME III for the simulation. The selection of ELM is done by a comparative analysis with Artificial Neural Network (ANN) and Support Vector Machine (SVM) as they were successfully used in previous studies of in-situ bioremediation system design. Further, a single-objective optimization problem is solved by a coupled Extreme Learning Machine (ELM)-Particle Swarm Optimization (PSO) technique to achieve the minimum cost for the in-situ bioremediation system design. The results indicate that ELM is a faster and more accurate proxy simulator than ANN and SVM. The total cost obtained by the ELM-PSO approach is held to a minimum while successfully satisfying all the regulatory constraints of the contaminated site.
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Lemmens, Karen; De Bie, Tijl; Dhollander, Thomas; De Keersmaecker, Sigrid C; Thijs, Inge M; Schoofs, Geert; De Weerdt, Ami; De Moor, Bart; Vanderleyden, Jos; Collado-Vides, Julio; Engelen, Kristof; Marchal, Kathleen
2009-01-01
We present DISTILLER, a data integration framework for the inference of transcriptional module networks. Experimental validation of predicted targets for the well-studied fumarate nitrate reductase regulator showed the effectiveness of our approach in Escherichia coli. In addition, the condition dependency and modularity of the inferred transcriptional network was studied. Surprisingly, the level of regulatory complexity seemed lower than that which would be expected from RegulonDB, indicating that complex regulatory programs tend to decrease the degree of modularity. PMID:19265557
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MicroRNA-mediated regulatory circuits: outlook and perspectives
NASA Astrophysics Data System (ADS)
Cora', Davide; Re, Angela; Caselle, Michele; Bussolino, Federico
2017-08-01
MicroRNAs have been found to be necessary for regulating genes implicated in almost all signaling pathways, and consequently their dysfunction influences many diseases, including cancer. Understanding of the complexity of the microRNA-mediated regulatory network has grown in terms of size, connectivity and dynamics with the development of computational and, more recently, experimental high-throughput approaches for microRNA target identification. Newly developed studies on recurrent microRNA-mediated circuits in regulatory networks, also known as network motifs, have substantially contributed to addressing this complexity, and therefore to helping understand the ways by which microRNAs achieve their regulatory role. This review provides a summarizing view of the state-of-the-art, and perspectives of research efforts on microRNA-mediated regulatory motifs. In this review, we discuss the topological properties characterizing different types of circuits, and the regulatory features theoretically enabled by such properties, with a special emphasis on examples of circuits typifying their biological significance in experimentally validated contexts. Finally, we will consider possible future developments, in particular regarding microRNA-mediated circuits involving long non-coding RNAs and epigenetic regulators.
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NASA Technical Reports Server (NTRS)
Simpson, M. L.; Sayler, G. S.; Fleming, J. T.; Applegate, B.
2001-01-01
The ability to manipulate systems on the molecular scale naturally leads to speculation about the rational design of molecular-scale machines. Cells might be the ultimate molecular-scale machines and our ability to engineer them is relatively advanced when compared with our ability to control the synthesis and direct the assembly of man-made materials. Indeed, engineered whole cells deployed in biosensors can be considered one of the practical successes of molecular-scale devices. However, these devices explore only a small portion of cellular functionality. Individual cells or self-organized groups of cells perform extremely complex functions that include sensing, communication, navigation, cooperation and even fabrication of synthetic nanoscopic materials. In natural systems, these capabilities are controlled by complex genetic regulatory circuits, which are only partially understood and not readily accessible for use in engineered systems. Here, we focus on efforts to mimic the functionality of man-made information-processing systems within whole cells.
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The Pseudomonas aeruginosa AlgZR two-component system coordinates multiple phenotypes
Okkotsu, Yuta; Little, Alexander S.; Schurr, Michael J.
2014-01-01
Pseudomonas aeruginosa is an opportunistic pathogen that causes a multitude of infections. These infections can occur at almost any site in the body and are usually associated with a breach of the innate immune system. One of the prominent sites where P. aeruginosa causes chronic infections is within the lungs of cystic fibrosis patients. P. aeruginosa uses two-component systems that sense environmental changes to differentially express virulence factors that cause both acute and chronic infections. The P. aeruginosa AlgZR two component system is one of its global regulatory systems that affects the organism's fitness in a broad manner. This two-component system is absolutely required for two P. aeruginosa phenotypes: twitching motility and alginate production, indicating its importance in both chronic and acute infections. Additionally, global transcriptome analyses indicate that it regulates the expression of many different genes, including those associated with quorum sensing, type IV pili, type III secretion system, anaerobic metabolism, cyanide and rhamnolipid production. This review examines the complex AlgZR regulatory network, what is known about the structure and function of each protein, and how it relates to the organism's ability to cause infections. PMID:24999454
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HPr antagonizes the anti-σ70 activity of Rsd in Escherichia coli.
Park, Young-Ha; Lee, Chang-Ro; Choe, Mangyu; Seok, Yeong-Jae
2013-12-24
The bacterial phosphoenolpyruvate:sugar phosphotransferase system (PTS) is a multicomponent system that participates in a variety of physiological processes in addition to the phosphorylation-coupled transport of numerous sugars. In Escherichia coli and other enteric bacteria, enzyme IIA(Glc) (EIIA(Glc)) is known as the central processing unit of carbon metabolism and plays multiple roles, including regulation of adenylyl cyclase, the fermentation/respiration switch protein FrsA, glycerol kinase, and several non-PTS transporters, whereas the only known regulatory role of the E. coli histidine-containing phosphocarrier protein HPr is in the activation of glycogen phosphorylase. Because HPr is known to be more abundant than EIIA(Glc) in enteric bacteria, we assumed that there might be more regulatory mechanisms connected with HPr. The ligand fishing experiment in this study identified Rsd, an anti-sigma factor known to complex with σ(70) in stationary-phase cells, as an HPr-binding protein in E. coli. Only the dephosphorylated form of HPr formed a tight complex with Rsd and thereby inhibited complex formation between Rsd and σ(70). Dephosphorylated HPr, but not phosphorylated HPr, antagonized the inhibitory effect of Rsd on σ(70)-dependent transcriptions both in vivo and in vitro, and also influenced the competition between σ(70) and σ(S) for core RNA polymerase in the presence of Rsd. Based on these data, we propose that the anti-σ(70) activity of Rsd is regulated by the phosphorylation state-dependent interaction of HPr with Rsd.
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HPr antagonizes the anti-σ70 activity of Rsd in Escherichia coli
Park, Young-Ha; Lee, Chang-Ro; Choe, Mangyu; Seok, Yeong-Jae
2013-01-01
The bacterial phosphoenolpyruvate:sugar phosphotransferase system (PTS) is a multicomponent system that participates in a variety of physiological processes in addition to the phosphorylation-coupled transport of numerous sugars. In Escherichia coli and other enteric bacteria, enzyme IIAGlc (EIIAGlc) is known as the central processing unit of carbon metabolism and plays multiple roles, including regulation of adenylyl cyclase, the fermentation/respiration switch protein FrsA, glycerol kinase, and several non-PTS transporters, whereas the only known regulatory role of the E. coli histidine-containing phosphocarrier protein HPr is in the activation of glycogen phosphorylase. Because HPr is known to be more abundant than EIIAGlc in enteric bacteria, we assumed that there might be more regulatory mechanisms connected with HPr. The ligand fishing experiment in this study identified Rsd, an anti-sigma factor known to complex with σ70 in stationary-phase cells, as an HPr-binding protein in E. coli. Only the dephosphorylated form of HPr formed a tight complex with Rsd and thereby inhibited complex formation between Rsd and σ70. Dephosphorylated HPr, but not phosphorylated HPr, antagonized the inhibitory effect of Rsd on σ70-dependent transcriptions both in vivo and in vitro, and also influenced the competition between σ70 and σS for core RNA polymerase in the presence of Rsd. Based on these data, we propose that the anti-σ70 activity of Rsd is regulated by the phosphorylation state-dependent interaction of HPr with Rsd. PMID:24324139
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Alignment and integration of complex networks by hypergraph-based spectral clustering
NASA Astrophysics Data System (ADS)
Michoel, Tom; Nachtergaele, Bruno
2012-11-01
Complex networks possess a rich, multiscale structure reflecting the dynamical and functional organization of the systems they model. Often there is a need to analyze multiple networks simultaneously, to model a system by more than one type of interaction, or to go beyond simple pairwise interactions, but currently there is a lack of theoretical and computational methods to address these problems. Here we introduce a framework for clustering and community detection in such systems using hypergraph representations. Our main result is a generalization of the Perron-Frobenius theorem from which we derive spectral clustering algorithms for directed and undirected hypergraphs. We illustrate our approach with applications for local and global alignment of protein-protein interaction networks between multiple species, for tripartite community detection in folksonomies, and for detecting clusters of overlapping regulatory pathways in directed networks.
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Alignment and integration of complex networks by hypergraph-based spectral clustering.
Michoel, Tom; Nachtergaele, Bruno
2012-11-01
Complex networks possess a rich, multiscale structure reflecting the dynamical and functional organization of the systems they model. Often there is a need to analyze multiple networks simultaneously, to model a system by more than one type of interaction, or to go beyond simple pairwise interactions, but currently there is a lack of theoretical and computational methods to address these problems. Here we introduce a framework for clustering and community detection in such systems using hypergraph representations. Our main result is a generalization of the Perron-Frobenius theorem from which we derive spectral clustering algorithms for directed and undirected hypergraphs. We illustrate our approach with applications for local and global alignment of protein-protein interaction networks between multiple species, for tripartite community detection in folksonomies, and for detecting clusters of overlapping regulatory pathways in directed networks.
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Gomelsky, Larissa; Moskvin, Oleg V; Stenzel, Rachel A; Jones, Denise F; Donohue, Timothy J; Gomelsky, Mark
2008-12-01
In the facultatively phototrophic proteobacterium Rhodobacter sphaeroides, formation of the photosynthetic apparatus is oxygen dependent. When oxygen tension decreases, the response regulator PrrA of the global two-component PrrBA system is believed to directly activate transcription of the puf, puh, and puc operons, encoding structural proteins of the photosynthetic complexes, and to indirectly upregulate the photopigment biosynthesis genes bch and crt. Decreased oxygen also results in inactivation of the photosynthesis-specific repressor PpsR, bringing about derepression of the puc, bch, and crt operons. We uncovered a hierarchical relationship between these two regulatory systems, earlier thought to function independently. We also more accurately assessed the spectrum of gene targets of the PrrBA system. First, expression of the appA gene, encoding the PpsR antirepressor, is PrrA dependent, which establishes one level of hierarchical dominance of the PrrBA system over AppA-PpsR. Second, restoration of the appA transcript to the wild-type level is insufficient for rescuing phototrophic growth impairment of the prrA mutant, whereas inactivation of ppsR is sufficient. This suggests that in addition to controlling appA transcription, PrrA affects the activity of the AppA-PpsR system via an as yet unidentified mechanism(s). Third, PrrA directly activates several bch and crt genes, traditionally considered to be the PpsR targets. Therefore, in R. sphaeroides, the global PrrBA system regulates photosynthesis gene expression (i) by rigorous control over the photosynthesis-specific AppA-PpsR regulatory system and (ii) by extensive direct transcription activation of genes encoding structural proteins of photosynthetic complexes as well as genes encoding photopigment biosynthesis enzymes.
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Clark, J A; Klincewicz, S L; Stang, P E
2001-01-01
AE signal detection and its techniques are part of the continuum of public health surveillance, borrowing from both its theory and application (171). Like public health surveillance networks, whose major goals are to identify early signs of new outbreaks, pinpoint new organisms, and monitor designated illnesses, AE signaling and surveillance systems attempt to provide early warnings of previously unsuspected product-AE pairs, hypothesize potential drug-event relations, identify populations "at risk," and facilitate case ascertainment and definition. In both examples, definitive research is often subsequently undertaken to quantify the strength of relations that may be proposed. As with any public health surveillance effort, AE surveillance provides an infrastructure for the ongoing collection of health data and its direct integration into the health regulatory policy (172), including its keystone role in risk assessment and management. However, unlike many surveillance systems, postmarketing AE systems collect case information that is often relatively incomplete and imperfect, estimate exposure based on surrogate values (e.g., sales data), and are used by both governmental and the private sector for preventive planning. These factors make AE signaling and surveillance more ambiguous, regulatory oriented, and complex than its disease counterparts (173). Despite such issues, AE signaling methods continue to evolve in extent, complexity, and acceptance (4, 131, 174). Undoubtedly, this is largely due to the widespread practical experience that has been gained with spontaneous reporting systems over the past 4 decades and the cumulative usefulness that has been demonstrated.
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Human Cardiovascular Responses to Passive Heat Stress
Crandall, Craig G.; Wilson, Thad E.
2016-01-01
Heat stress increases human morbidity and mortality compared to normothermic conditions. Many occupations, disease states, as well as stages of life are especially vulnerable to the stress imposed on the cardiovascular system during exposure to hot ambient conditions. This review focuses on the cardiovascular responses to heat stress that are necessary for heat dissipation. To accomplish this regulatory feat requires complex autonomic nervous system control of the heart and various vascular beds. For example, during heat stress cardiac output increases up to twofold, by increases in heart rate and an active maintenance of stroke volume via increases in inotropy in the presence of decreases in cardiac preload. Baroreflexes retain the ability to regulate blood pressure in many, but not all, heat stress conditions. Central hypovolemia is another cardiovascular challenge brought about by heat stress, which if added to a subsequent central volumetric stress, such as hemorrhage, can be problematic and potentially dangerous, as syncope and cardiovascular collapse may ensue. These combined stresses can compromise blood flow and oxygenation to important tissues such as the brain. It is notable that this compromised condition can occur at cardiac outputs that are adequate during normothermic conditions but are inadequate in heat because of the increased systemic vascular conductance associated with cutaneous vasodilation. Understanding the mechanisms within this complex regulatory system will allow for the development of treatment recommendations and countermeasures to reduce risks during the ever-increasing frequency of severe heat events that are predicted to occur. PMID:25589263
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Huang, Dandan; Yi, Xianfu; Zhang, Shijie; Zheng, Zhanye; Wang, Panwen; Xuan, Chenghao; Sham, Pak Chung; Wang, Junwen; Li, Mulin Jun
2018-05-16
Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.
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Wong, Keith S; Bhandari, Vaibhav; Janga, Sarath Chandra; Houry, Walid A
2017-01-20
Regulatory ATPase variant A (RavA) is a MoxR AAA+ protein that functions together with a partner protein that we termed VWA interacting with AAA+ ATPase (ViaA) containing a von Willebrand Factor A domain. However, the functional role of RavA-ViaA in the cell is not yet well established. Here, we show that RavA-ViaA are functionally associated with anaerobic respiration in Escherichia coli through interactions with the fumarate reductase (Frd) electron transport complex. Expression analysis of ravA and viaA genes showed that both proteins are co-expressed with multiple anaerobic respiratory genes, many of which are regulated by the anaerobic transcriptional regulator Fnr. Consistently, the expression of both ravA and viaA was found to be dependent on Fnr in cells grown under oxygen-limiting condition. ViaA was found to physically interact with FrdA, the flavin-containing subunit of the Frd complex. Both RavA and the Fe-S-containing subunit of the Frd complex, FrdB, regulate this interaction. Importantly, Frd activity was observed to increase in the absence of RavA and ViaA. This indicates that RavA and ViaA modulate the activity of the Frd complex, signifying a potential regulatory chaperone-like function for RavA-ViaA during bacterial anaerobic respiration with fumarate as the terminal electron acceptor. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Network dynamics and systems biology
NASA Astrophysics Data System (ADS)
Norrell, Johannes A.
The physics of complex systems has grown considerably as a field in recent decades, largely due to improved computational technology and increased availability of systems level data. One area in which physics is of growing relevance is molecular biology. A new field, systems biology, investigates features of biological systems as a whole, a strategy of particular importance for understanding emergent properties that result from a complex network of interactions. Due to the complicated nature of the systems under study, the physics of complex systems has a significant role to play in elucidating the collective behavior. In this dissertation, we explore three problems in the physics of complex systems, motivated in part by systems biology. The first of these concerns the applicability of Boolean models as an approximation of continuous systems. Studies of gene regulatory networks have employed both continuous and Boolean models to analyze the system dynamics, and the two have been found produce similar results in the cases analyzed. We ask whether or not Boolean models can generically reproduce the qualitative attractor dynamics of networks of continuously valued elements. Using a combination of analytical techniques and numerical simulations, we find that continuous networks exhibit two effects---an asymmetry between on and off states, and a decaying memory of events in each element's inputs---that are absent from synchronously updated Boolean models. We show that in simple loops these effects produce exactly the attractors that one would predict with an analysis of the stability of Boolean attractors, but in slightly more complicated topologies, they can destabilize solutions that are stable in the Boolean approximation, and can stabilize new attractors. Second, we investigate ensembles of large, random networks. Of particular interest is the transition between ordered and disordered dynamics, which is well characterized in Boolean systems. Networks at the transition point, called critical, exhibit many of the features of regulatory networks, and recent studies suggest that some specific regulatory networks are indeed near-critical. We ask whether certain statistical measures of the ensemble behavior of large continuous networks are reproduced by Boolean models. We find that, in spite of the lack of correspondence between attractors observed in smaller systems, the statistical characterization given by the continuous and Boolean models show close agreement, and the transition between order and disorder known in Boolean systems can occur in continuous systems as well. One effect that is not present in Boolean systems, the failure of information to propagate down chains of elements of arbitrary length, is present in a class of continuous networks. In these systems, a modified Boolean theory that takes into account the collective effect of propagation failure on chains throughout the network gives a good description of the observed behavior. We find that propagation failure pushes the system toward greater order, resulting in a partial or complete suppression of the disordered phase. Finally, we explore a dynamical process of direct biological relevance: asymmetric cell division in A. thaliana. The long term goal is to develop a model for the process that accurately accounts for both wild type and mutant behavior. To contribute to this endeavor, we use confocal microscopy to image roots in a SHORT-ROOT inducible mutant. We compute correlation functions between the locations of asymmetrically divided cells, and we construct stochastic models based on a few simple assumptions that accurately predict the non-zero correlations. Our result shows that intracellular processes alone cannot be responsible for the observed divisions, and that an intercell signaling mechanism could account for the measured correlations.
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Germline Stem Cells: Origin and Destiny
Lehmann, Ruth
2012-01-01
Germline stem cells are key to genome transmission to future generations. Over recent years, there have been numerous insights into the regulatory mechanisms that govern both germ cell specification and the maintenance of the germline in adults. Complex regulatory interactions with both the niche and the environment modulate germline stem cell function. This perspective highlights some examples of this regulation to illustrate the diversity and complexity of the mechanisms involved. PMID:22704513
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Characterization of new regulatory elements within the Drosophila bithorax complex.
Pérez-Lluch, Sílvia; Cuartero, Sergi; Azorín, Fernando; Espinàs, M Lluïsa
2008-12-01
The homeotic Abdominal-B (Abd-B) gene expression depends on a modular cis-regulatory region divided into discrete functional domains (iab) that control the expression of the gene in a particular segment of the fly. These domains contain regulatory elements implicated in both initiation and maintenance of homeotic gene expression and elements that separate the different domains. In this paper we have performed an extensive analysis of the iab-6 regulatory region, which regulates Abd-B expression at abdominal segment A6 (PS11), and we have characterized two new polycomb response elements (PREs) within this domain. We report that PREs at Abd-B cis-regulatory domains present a particular chromatin structure which is nuclease accessible all along Drosophila development and both in active and repressed states. We also show that one of these regions contains a dCTCF and CP190 dependent activity in transgenic enhancer-blocking assays, suggesting that it corresponds to the Fab-6 boundary element of the Drosophila bithorax complex.
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Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays.
Zacharewski, T
1998-01-01
It has been suggested that chemicals and complex mixtures capable of modulating the endocrine system may contribute to adverse health, reproduction, and developmental effects in humans and wildlife. These effects include increased incidence of hormone-dependent cancers, compromised reproductive fitness, and abnormal reproductive system development. In response to public concern, regulatory agencies in North America and Europe are formulating potential strategies to systematically test chemicals and complex mixtures for their endocrine-disrupting activities. Because of the complexity of the endocrine system and the number of potential endocrine disruptor targets, a tiered approach involving a complementary battery of short- and long-term in vivo and in vitro assays that assesses both receptor and nonreceptor-mediated mechanisms of action is being considered. However, the available established assays use a limited number of end points, and significant information gaps exist for other potential targets in the endocrine system. In addition to discussing the merits and limitations of the assays that may be adopted, this paper also highlights potential problems associated with the use of a tiered testing strategy. PMID:9599705
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Critical thinking as a self-regulatory process component in teaching and learning.
Phan, Huy P
2010-05-01
This article presents a theoretically grounded model of critical thinking and self-regulation in the context of teaching and learning. Critical thinking, deriving from an educational psychology perspective is a complex process of reflection that helps individuals become more analytical in their thinking and professional development. My conceptualisation in this discussion paper argues that both theoretical orientations (critical thinking and self-regulation) operate in a dynamic interactive system of teaching and learning. My argument, based on existing research evidence, suggests two important points: (i) critical thinking acts as another cognitive strategy of self-regulation that learners use in their learning, and (ii) critical thinking may be a product of various antecedents such as different self-regulatory strategies.
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Martinez-Sanchez, Mariana E; Hiriart, Marcia; Alvarez-Buylla, Elena R
2017-06-26
Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGFβ producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGFβ in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment. This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases.
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Mathematical modeling of physiological systems: an essential tool for discovery.
Glynn, Patric; Unudurthi, Sathya D; Hund, Thomas J
2014-08-28
Mathematical models are invaluable tools for understanding the relationships between components of a complex system. In the biological context, mathematical models help us understand the complex web of interrelations between various components (DNA, proteins, enzymes, signaling molecules etc.) in a biological system, gain better understanding of the system as a whole, and in turn predict its behavior in an altered state (e.g. disease). Mathematical modeling has enhanced our understanding of multiple complex biological processes like enzyme kinetics, metabolic networks, signal transduction pathways, gene regulatory networks, and electrophysiology. With recent advances in high throughput data generation methods, computational techniques and mathematical modeling have become even more central to the study of biological systems. In this review, we provide a brief history and highlight some of the important applications of modeling in biological systems with an emphasis on the study of excitable cells. We conclude with a discussion about opportunities and challenges for mathematical modeling going forward. In a larger sense, the review is designed to help answer a simple but important question that theoreticians frequently face from interested but skeptical colleagues on the experimental side: "What is the value of a model?" Copyright © 2014 Elsevier Inc. All rights reserved.
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Pharmacovigilance in Crisis: Drug Safety at a Crossroads.
Price, John
2018-05-01
Pharmacovigilance (PV) is under unprecedented stress from fundamental changes in a booming pharmaceutical industry, from the challenges of creating and maintaining an increasingly complex PV system in a globally diverse regulatory environment, and from unpredicted consequences of historical PV cost-reduction strategies. At the same time, talent availability lags demand, and many PV professionals may no longer be finding personal fulfillment in their careers. The situation creates risks for companies. Advantages and disadvantages of potential strategies to address this increasing problem at a corporate and industry level and in collaboration with regulatory agencies are discussed, as well as opportunities to adopt new technologies, including artificial intelligence and machine-learning to automate pharmacovigilance operations. These approaches would address burdensome and wasteful effort assuring regulatory compliance and free up resources to support the original mission of PV as an important public health activity and to reinvest in the development of new drugs. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.
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Guo, Xiaobo; Zhang, Ye; Hu, Wenhao; Tan, Haizhu; Wang, Xueqin
2014-01-01
Nonlinear dependence is general in regulation mechanism of gene regulatory networks (GRNs). It is vital to properly measure or test nonlinear dependence from real data for reconstructing GRNs and understanding the complex regulatory mechanisms within the cellular system. A recently developed measurement called the distance correlation (DC) has been shown powerful and computationally effective in nonlinear dependence for many situations. In this work, we incorporate the DC into inferring GRNs from the gene expression data without any underling distribution assumptions. We propose three DC-based GRNs inference algorithms: CLR-DC, MRNET-DC and REL-DC, and then compare them with the mutual information (MI)-based algorithms by analyzing two simulated data: benchmark GRNs from the DREAM challenge and GRNs generated by SynTReN network generator, and an experimentally determined SOS DNA repair network in Escherichia coli. According to both the receiver operator characteristic (ROC) curve and the precision-recall (PR) curve, our proposed algorithms significantly outperform the MI-based algorithms in GRNs inference.
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Inferring Nonlinear Gene Regulatory Networks from Gene Expression Data Based on Distance Correlation
Guo, Xiaobo; Zhang, Ye; Hu, Wenhao; Tan, Haizhu; Wang, Xueqin
2014-01-01
Nonlinear dependence is general in regulation mechanism of gene regulatory networks (GRNs). It is vital to properly measure or test nonlinear dependence from real data for reconstructing GRNs and understanding the complex regulatory mechanisms within the cellular system. A recently developed measurement called the distance correlation (DC) has been shown powerful and computationally effective in nonlinear dependence for many situations. In this work, we incorporate the DC into inferring GRNs from the gene expression data without any underling distribution assumptions. We propose three DC-based GRNs inference algorithms: CLR-DC, MRNET-DC and REL-DC, and then compare them with the mutual information (MI)-based algorithms by analyzing two simulated data: benchmark GRNs from the DREAM challenge and GRNs generated by SynTReN network generator, and an experimentally determined SOS DNA repair network in Escherichia coli. According to both the receiver operator characteristic (ROC) curve and the precision-recall (PR) curve, our proposed algorithms significantly outperform the MI-based algorithms in GRNs inference. PMID:24551058
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Forecasting PM10 in metropolitan areas: Efficacy of neural networks.
Fernando, H J S; Mammarella, M C; Grandoni, G; Fedele, P; Di Marco, R; Dimitrova, R; Hyde, P
2012-04-01
Deterministic photochemical air quality models are commonly used for regulatory management and planning of urban airsheds. These models are complex, computer intensive, and hence are prohibitively expensive for routine air quality predictions. Stochastic methods are becoming increasingly popular as an alternative, which relegate decision making to artificial intelligence based on Neural Networks that are made of artificial neurons or 'nodes' capable of 'learning through training' via historic data. A Neural Network was used to predict particulate matter concentration at a regulatory monitoring site in Phoenix, Arizona; its development, efficacy as a predictive tool and performance vis-à-vis a commonly used regulatory photochemical model are described in this paper. It is concluded that Neural Networks are much easier, quicker and economical to implement without compromising the accuracy of predictions. Neural Networks can be used to develop rapid air quality warning systems based on a network of automated monitoring stations. Copyright © 2011 Elsevier Ltd. All rights reserved.
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A Systems Biology Approach to Iron Metabolism
Chifman, J.; Laubenbacher, R.; Torti, S.V.
2015-01-01
Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes. PMID:25480643
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Towards systems metabolic engineering of microorganisms for amino acid production.
Park, Jin Hwan; Lee, Sang Yup
2008-10-01
Microorganisms capable of efficient production of amino acids have traditionally been developed by random mutation and selection method, which might cause unwanted physiological changes in cellular metabolism. Rational genome-wide metabolic engineering based on systems and synthetic biology tools, which is termed 'systems metabolic engineering', is rising as an alternative to overcome these problems. Recently, several amino acid producers have been successfully developed by systems metabolic engineering, where the metabolic engineering procedures were performed within a systems biology framework, and entire metabolic networks, including complex regulatory circuits, were engineered in an integrated manner. Here we review the current status of systems metabolic engineering successfully applied for developing amino acid producing strains and discuss future prospects.
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Stochastic simulation of multiscale complex systems with PISKaS: A rule-based approach.
Perez-Acle, Tomas; Fuenzalida, Ignacio; Martin, Alberto J M; Santibañez, Rodrigo; Avaria, Rodrigo; Bernardin, Alejandro; Bustos, Alvaro M; Garrido, Daniel; Dushoff, Jonathan; Liu, James H
2018-03-29
Computational simulation is a widely employed methodology to study the dynamic behavior of complex systems. Although common approaches are based either on ordinary differential equations or stochastic differential equations, these techniques make several assumptions which, when it comes to biological processes, could often lead to unrealistic models. Among others, model approaches based on differential equations entangle kinetics and causality, failing when complexity increases, separating knowledge from models, and assuming that the average behavior of the population encompasses any individual deviation. To overcome these limitations, simulations based on the Stochastic Simulation Algorithm (SSA) appear as a suitable approach to model complex biological systems. In this work, we review three different models executed in PISKaS: a rule-based framework to produce multiscale stochastic simulations of complex systems. These models span multiple time and spatial scales ranging from gene regulation up to Game Theory. In the first example, we describe a model of the core regulatory network of gene expression in Escherichia coli highlighting the continuous model improvement capacities of PISKaS. The second example describes a hypothetical outbreak of the Ebola virus occurring in a compartmentalized environment resembling cities and highways. Finally, in the last example, we illustrate a stochastic model for the prisoner's dilemma; a common approach from social sciences describing complex interactions involving trust within human populations. As whole, these models demonstrate the capabilities of PISKaS providing fertile scenarios where to explore the dynamics of complex systems. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Money, Tracy; Barrett, Jason; Dixon, Ray; Austin, Sara
2001-01-01
The enhancer binding protein NIFA and the sensor protein NIFL from Azotobacter vinelandii comprise an atypical two-component regulatory system in which signal transduction occurs via complex formation between the two proteins rather than by the phosphotransfer mechanism, which is characteristic of orthodox systems. The inhibitory activity of NIFL towards NIFA is stimulated by ADP binding to the C-terminal domain of NIFL, which bears significant homology to the histidine protein kinase transmitter domains. Adenosine nucleotides, particularly MgADP, also stimulate complex formation between NIFL and NIFA in vitro, allowing isolation of the complex by cochromatography. Using limited proteolysis of the purified proteins, we show here that changes in protease sensitivity of the Q linker regions of both NIFA and NIFL occurred when the complex was formed in the presence of MgADP. The N-terminal domain of NIFA adjacent to the Q linker was also protected by NIFL. Experiments with truncated versions of NIFA demonstrate that the central domain of NIFA is sufficient to cause protection of the Q linker of NIFL, although in this case, stable protein complexes are not detectable by cochromatography. PMID:11157949
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Jetha, Arif; Pransky, Glenn; Hettinger, Lawrence J
2016-01-01
Work disability (WD) is characterized by variable and occasionally undesirable outcomes. The underlying determinants of WD outcomes include patterns of dynamic relationships among health, personal, organizational and regulatory factors that have been challenging to characterize, and inadequately represented by contemporary WD models. System dynamics modeling (SDM) methodology applies a sociotechnical systems thinking lens to view WD systems as comprising a range of influential factors linked by feedback relationships. SDM can potentially overcome limitations in contemporary WD models by uncovering causal feedback relationships, and conceptualizing dynamic system behaviors. It employs a collaborative and stakeholder-based model building methodology to create a visual depiction of the system as a whole. SDM can also enable researchers to run dynamic simulations to provide evidence of anticipated or unanticipated outcomes that could result from policy and programmatic intervention. SDM may advance rehabilitation research by providing greater insights into the structure and dynamics of WD systems while helping to understand inherent complexity. Challenges related to data availability, determining validity, and the extensive time and technical skill requirements for model building may limit SDM's use in the field and should be considered. Contemporary work disability (WD) models provide limited insight into complexity associated with WD processes. System dynamics modeling (SDM) has the potential to capture complexity through a stakeholder-based approach that generates a simulation model consisting of multiple feedback loops. SDM may enable WD researchers and practitioners to understand the structure and behavior of the WD system as a whole, and inform development of improved strategies to manage straightforward and complex WD cases.
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Regulatory system reform of occupational health and safety in China.
Wu, Fenghong; Chi, Yan
2015-01-01
With the explosive economic growth and social development, China's regulatory system of occupational health and safety now faces more and more challenges. This article reviews the history of regulatory system of occupational health and safety in China, as well as the current reform of this regulatory system in the country. Comprehensive, a range of laws, regulations and standards that promulgated by Chinese government, duties and responsibilities of the regulatory departments are described. Problems of current regulatory system, the ongoing adjustments and changes for modifying and improving regulatory system are discussed. The aim of reform and the incentives to drive forward more health and safety conditions in workplaces are also outlined.
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Regulatory system reform of occupational health and safety in China
WU, Fenghong; CHI, Yan
2015-01-01
With the explosive economic growth and social development, China’s regulatory system of occupational health and safety now faces more and more challenges. This article reviews the history of regulatory system of occupational health and safety in China, as well as the current reform of this regulatory system in the country. Comprehensive, a range of laws, regulations and standards that promulgated by Chinese government, duties and responsibilities of the regulatory departments are described. Problems of current regulatory system, the ongoing adjustments and changes for modifying and improving regulatory system are discussed. The aim of reform and the incentives to drive forward more health and safety conditions in workplaces are also outlined. PMID:25843565
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Zoncu, Roberto; Perera, Rushika M; Sebastian, Rafael; Nakatsu, Fubito; Chen, Hong; Balla, Tamas; Ayala, Guillermo; Toomre, Derek; De Camilli, Pietro V
2007-03-06
Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], a phosphoinositide concentrated predominantly in the plasma membrane, binds endocytic clathrin adaptors, many of their accessory factors, and a variety of actin-regulatory proteins. Here we have used fluorescent fusion proteins and total internal reflection fluorescence microscopy to investigate the effect of acute PI(4,5)P(2) breakdown on the dynamics of endocytic clathrin-coated pit components and of the actin regulatory complex, Arp2/3. PI(4,5)P(2) breakdown was achieved by the inducible recruitment to the plasma membrane of an inositol 5-phosphatase module through the rapamycin/FRB/FKBP system or by treatment with ionomycin. PI(4,5)P(2) depletion resulted in a dramatic loss of clathrin puncta, which correlated with a massive dissociation of endocytic adaptors from the plasma membrane. Remaining clathrin spots at the cell surface had only weak fluorescence and were static over time. Dynamin and the p20 subunit of the Arp2/3 actin regulatory complex, which were concentrated at late-stage clathrin-coated pits and in lamellipodia, also dissociated from the plasma membrane, and these changes correlated with an arrest of motility at the cell edge. These findings demonstrate the critical importance of PI(4,5)P(2) in clathrin coat dynamics and Arp2/3-dependent actin regulation.
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Children, Families, and Disparities: Pediatric Provisions in the Affordable Care Act.
Grace, Aimee M; Horn, Ivor; Hall, Robert; Cheng, Tina L
2015-10-01
The Affordable Care Act has caused and continues to cause sweeping changes throughout the health system in the United States. Poorly explained, complex, controversial, confusing, and subject to continuous legal and regulatory definition, the law stands as a hallmark piece of legislation that will change the health sector in America forever. This article summarizes the Affordable Care Act with a focus on children, families, and disparities. Also provided is the context of the current system of health care coverage in the United States. Published by Elsevier Inc.
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Preventing type 2 diabetes: Changing the food industry
Popkin, Barry M.; Kenan, W. R.
2016-01-01
Improving our global diet by working with the food industry is a fairly complex task. Previously the global food manufacturing companies and governments were the major players. However, matters have shifted rapidly so that food retailers, food manufacturers, the restaurant–food service sector, and agribusinesses are now the major players. The current modern system of packaged processed food has now penetrated the globe—rich and poor, rural and urban are all in reach of this food system. Consequently, working with this complex sector when possible and an array of governmental regulatory large-scale options to improve our diet have increased in importance. Taxation of unhealthy foods and beverages, marketing controls, and front of the package labeling are the primary current options. Evaluations of the impacts of both public and industry initiatives are needed. PMID:27432072
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Tabita, F. Robert
2013-07-30
In this study, the Principal Investigator, F.R. Tabita has teamed up with J. C. Liao from UCLA. This project's main goal is to manipulate regulatory networks in phototrophic bacteria to affect and maximize the production of large amounts of hydrogen gas under conditions where wild-type organisms are constrained by inherent regulatory mechanisms from allowing this to occur. Unrestrained production of hydrogen has been achieved and this will allow for the potential utilization of waste materials as a feed stock to support hydrogen production. By further understanding the means by which regulatory networks interact, this study will seek to maximize themore » ability of currently available “unrestrained” organisms to produce hydrogen. The organisms to be utilized in this study, phototrophic microorganisms, in particular nonsulfur purple (NSP) bacteria, catalyze many significant processes including the assimilation of carbon dioxide into organic carbon, nitrogen fixation, sulfur oxidation, aromatic acid degradation, and hydrogen oxidation/evolution. Moreover, due to their great metabolic versatility, such organisms highly regulate these processes in the cell and since virtually all such capabilities are dispensable, excellent experimental systems to study aspects of molecular control and biochemistry/physiology are available.« less
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Molecular Regulation of Antibiotic Biosynthesis in Streptomyces
Liu, Gang; Chandra, Govind; Niu, Guoqing
2013-01-01
SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes. PMID:23471619
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Wilczynski, Bartek; Furlong, Eileen E M
2010-04-15
Development is regulated by dynamic patterns of gene expression, which are orchestrated through the action of complex gene regulatory networks (GRNs). Substantial progress has been made in modeling transcriptional regulation in recent years, including qualitative "coarse-grain" models operating at the gene level to very "fine-grain" quantitative models operating at the biophysical "transcription factor-DNA level". Recent advances in genome-wide studies have revealed an enormous increase in the size and complexity or GRNs. Even relatively simple developmental processes can involve hundreds of regulatory molecules, with extensive interconnectivity and cooperative regulation. This leads to an explosion in the number of regulatory functions, effectively impeding Boolean-based qualitative modeling approaches. At the same time, the lack of information on the biophysical properties for the majority of transcription factors within a global network restricts quantitative approaches. In this review, we explore the current challenges in moving from modeling medium scale well-characterized networks to more poorly characterized global networks. We suggest to integrate coarse- and find-grain approaches to model gene regulatory networks in cis. We focus on two very well-studied examples from Drosophila, which likely represent typical developmental regulatory modules across metazoans. Copyright (c) 2009 Elsevier Inc. All rights reserved.
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Enhancing the Relationship Between Regulators and Their Profession.
Austin, Zubin
2017-01-01
Regulators face unique pressures to balance competing priorities related to patient safety, public accountability, and practitioners' expectations. Historically, the collegial model of self-regulation has been used as a tool for risk management, to recognize the importance of profession- and context-specific judgment in complex, ambiguous clinical situations. Increasingly, as public accountability concerns have grown dominant within regulatory bodies, this collegial model has shifted toward a more antagonistic relationship between the regulators and the regulated. Wilkie and Tzountzouris (2017) highlight one profession's journey toward embedding professionalism within regulatory practices and policies through application of a right-touch regulatory philosophy. Given the complexity of regulatory work, this shift required significant strategic and deliberative thinking. The challenges of facilitating this sort of cultural shift in the role of a regulator are significant, but so too are the potential gains associated with a more engaged relationship between regulators and their practitioners.
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Book, Adam J; Gladman, Nicholas P; Lee, Sang-Sook; Scalf, Mark; Smith, Lloyd M; Vierstra, Richard D
2010-08-13
Selective proteolysis in plants is largely mediated by the ubiquitin (Ub)/proteasome system in which substrates, marked by the covalent attachment of Ub, are degraded by the 26 S proteasome. The 26 S proteasome is composed of two subparticles, the 20 S core protease (CP) that compartmentalizes the protease active sites and the 19 S regulatory particle that recognizes and translocates appropriate substrates into the CP lumen for breakdown. Here, we describe an affinity method to rapidly purify epitope-tagged 26 S proteasomes intact from Arabidopsis thaliana. In-depth mass spectrometric analyses of preparations generated from young seedlings confirmed that the 2.5-MDa CP-regulatory particle complex is actually a heterogeneous set of particles assembled with paralogous pairs for most subunits. A number of these subunits are modified post-translationally by proteolytic processing, acetylation, and/or ubiquitylation. Several proteasome-associated proteins were also identified that likely assist in complex assembly and regulation. In addition, we detected a particle consisting of the CP capped by the single subunit PA200 activator that may be involved in Ub-independent protein breakdown. Taken together, it appears that a diverse and highly dynamic population of proteasomes is assembled in plants, which may expand the target specificity and functions of intracellular proteolysis.
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Book, Adam J.; Gladman, Nicholas P.; Lee, Sang-Sook; Scalf, Mark; Smith, Lloyd M.; Vierstra, Richard D.
2010-01-01
Selective proteolysis in plants is largely mediated by the ubiquitin (Ub)/proteasome system in which substrates, marked by the covalent attachment of Ub, are degraded by the 26 S proteasome. The 26 S proteasome is composed of two subparticles, the 20 S core protease (CP) that compartmentalizes the protease active sites and the 19 S regulatory particle that recognizes and translocates appropriate substrates into the CP lumen for breakdown. Here, we describe an affinity method to rapidly purify epitope-tagged 26 S proteasomes intact from Arabidopsis thaliana. In-depth mass spectrometric analyses of preparations generated from young seedlings confirmed that the 2.5-MDa CP-regulatory particle complex is actually a heterogeneous set of particles assembled with paralogous pairs for most subunits. A number of these subunits are modified post-translationally by proteolytic processing, acetylation, and/or ubiquitylation. Several proteasome-associated proteins were also identified that likely assist in complex assembly and regulation. In addition, we detected a particle consisting of the CP capped by the single subunit PA200 activator that may be involved in Ub-independent protein breakdown. Taken together, it appears that a diverse and highly dynamic population of proteasomes is assembled in plants, which may expand the target specificity and functions of intracellular proteolysis. PMID:20516081
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Efficient Reverse-Engineering of a Developmental Gene Regulatory Network
Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes
2012-01-01
Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to discover whether there are rules or regularities governing development and evolution of complex multi-cellular organisms. PMID:22807664
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Principles and Benefits of Explicitly Designed Medical Device Safety Architecture.
Larson, Brian R; Jones, Paul; Zhang, Yi; Hatcliff, John
The complexity of medical devices and the processes by which they are developed pose considerable challenges to producing safe designs and regulatory submissions that are amenable to effective reviews. Designing an appropriate and clearly documented architecture can be an important step in addressing this complexity. Best practices in medical device design embrace the notion of a safety architecture organized around distinct operation and safety requirements. By explicitly separating many safety-related monitoring and mitigation functions from operational functionality, the aspects of a device most critical to safety can be localized into a smaller and simpler safety subsystem, thereby enabling easier verification and more effective reviews of claims that causes of hazardous situations are detected and handled properly. This article defines medical device safety architecture, describes its purpose and philosophy, and provides an example. Although many of the presented concepts may be familiar to those with experience in realization of safety-critical systems, this article aims to distill the essence of the approach and provide practical guidance that can potentially improve the quality of device designs and regulatory submissions.
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The expanding universe of noncoding RNAs.
Hannon, G J; Rivas, F V; Murchison, E P; Steitz, J A
2006-01-01
The 71st Cold Spring Harbor Symposium on Quantitative Biology celebrated the numerous and expanding roles of regulatory RNAs in systems ranging from bacteria to mammals. It was clearly evident that noncoding RNAs are undergoing a renaissance, with reports of their involvement in nearly every cellular process. Previously known classes of longer noncoding RNAs were shown to function by every possible means-acting catalytically, sensing physiological states through adoption of complex secondary and tertiary structures, or using their primary sequences for recognition of target sites. The many recently discovered classes of small noncoding RNAs, generally less than 35 nucleotides in length, most often exert their effects by guiding regulatory complexes to targets via base-pairing. With the ability to analyze the RNA products of the genome in ever greater depth, it has become clear that the universe of noncoding RNAs may extend far beyond the boundaries we had previously imagined. Thus, as much as the Symposium highlighted exciting progress in the field, it also revealed how much farther we must go to understand fully the biological impact of noncoding RNAs.
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Malleable machines in transcription regulation: the mediator complex.
Tóth-Petróczy, Agnes; Oldfield, Christopher J; Simon, István; Takagi, Yuichiro; Dunker, A Keith; Uversky, Vladimir N; Fuxreiter, Monika
2008-12-01
The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordered regions and their embedded interaction sites are quite similar in the two organisms. All of these data suggest an integral role for intrinsic disorder in Mediator's function.
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Directed Evolution as a Powerful Synthetic Biology Tool
Cobb, Ryan E.; Sun, Ning; Zhao, Huimin
2012-01-01
At the heart of synthetic biology lies the goal of rationally engineering a complete biological system to achieve a specific objective, such as bioremediation and synthesis of a valuable drug, chemical, or biofuel molecule. However, the inherent complexity of natural biological systems has heretofore precluded generalized application of this approach. Directed evolution, a process which mimics Darwinian selection on a laboratory scale, has allowed significant strides to be made in the field of synthetic biology by allowing rapid identification of desired properties from large libraries of variants. Improvement in biocatalyst activity and stability, engineering of biosynthetic pathways, tuning of functional regulatory systems and logic circuits, and development of desired complex phenotypes in industrial host organisms have all been achieved by way of directed evolution. Here, we review recent contributions of directed evolution to synthetic biology at the protein, pathway, network, and whole cell levels. PMID:22465795
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Integrating patient safety into the clinical microsystem
Mohr, J; Batalden, P; Barach, P
2004-01-01
Healthcare institutions continue to face challenges in providing safe patient care in increasingly complex organisational and regulatory environments while striving to maintain financial viability. The clinical microsystem provides a conceptual and practical framework for approaching organisational learning and delivery of care. Tensions exist between the conceptual theory and the daily practical applications of providing safe and effective care within healthcare systems. Healthcare organisations are often complex, disorganised, and opaque systems to their users and their patients. This disorganisation may lead to patient discomfort and harm as well as much waste. Healthcare organisations are in some sense conglomerates of smaller systems, not coherent monolithic organisations. The microsystem unit allows organisational leaders to embed quality and safety into a microsystem's developmental journey. Leaders can set the stage for making safety a priority for the organisation while allowing individual microsystems to create innovative strategies for improvement. PMID:15576690
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Vibrio Iron Transport: Evolutionary Adaptation to Life in Multiple Environments
Mey, Alexandra R.; Wyckoff, Elizabeth E.
2015-01-01
SUMMARY Iron is an essential element for Vibrio spp., but the acquisition of iron is complicated by its tendency to form insoluble ferric complexes in nature and its association with high-affinity iron-binding proteins in the host. Vibrios occupy a variety of different niches, and each of these niches presents particular challenges for acquiring sufficient iron. Vibrio species have evolved a wide array of iron transport systems that allow the bacteria to compete for this essential element in each of its habitats. These systems include the secretion and uptake of high-affinity iron-binding compounds (siderophores) as well as transport systems for iron bound to host complexes. Transporters for ferric and ferrous iron not complexed to siderophores are also common to Vibrio species. Some of the genes encoding these systems show evidence of horizontal transmission, and the ability to acquire and incorporate additional iron transport systems may have allowed Vibrio species to more rapidly adapt to new environmental niches. While too little iron prevents growth of the bacteria, too much can be lethal. The appropriate balance is maintained in vibrios through complex regulatory networks involving transcriptional repressors and activators and small RNAs (sRNAs) that act posttranscriptionally. Examination of the number and variety of iron transport systems found in Vibrio spp. offers insights into how this group of bacteria has adapted to such a wide range of habitats. PMID:26658001
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Anti-Sigma Factors in E. coli: Common Regulatory Mechanisms Controlling Sigma Factors Availability
Treviño-Quintanilla, Luis Gerardo; Freyre-González, Julio Augusto; Martínez-Flores, Irma
2013-01-01
In bacteria, transcriptional regulation is a key step in cellular gene expression. All bacteria contain a core RNA polymerase that is catalytically competent but requires an additional σ factor for specific promoter recognition and correct transcriptional initiation. The RNAP core is not able to selectively bind to a given σ factor. In contrast, different σ factors have different affinities for the RNAP core. As a consequence, the concentration of alternate σ factors requires strict regulation in order to properly control the delicate interplay among them, which favors the competence for the RNAP core. This control is archived by different σ/anti-σ controlling mechanisms that shape complex regulatory networks and cascades, and enable the response to sudden environmental cues, whose global understanding is a current challenge for systems biology. Although there have been a number of excellent studies on each of these σ/anti-σ post-transcriptional regulatory systems, no comprehensive comparison of these mechanisms in a single model organism has been conducted. Here, we survey all these systems in E. coli dissecting and analyzing their inner workings and highlightin their differences. Then, following an integral approach, we identify their commonalities and outline some of the principles exploited by the cell to effectively and globally reprogram the transcriptional machinery. These principles provide guidelines for developing biological synthetic circuits enabling an efficient and robust response to sudden stimuli. PMID:24396271
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-07-29
... on Proposed Rule Change Relating To Which Complex Orders Can Initiate a Complex Order Live Auction... Exchange to determine by order sender which complex orders can initiate a Complex Order Live Auction...
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Regulatory RNAs and the HptB/RetS signalling pathways fine-tune Pseudomonas aeruginosa pathogenesis
Bordi, Christophe; Lamy, Marie-Cécile; Ventre, Isabelle; Termine, Elise; Hachani, Abderrahman; Fillet, Sandy; Roche, Béatrice; Bleves, Sophie; Méjean, Vincent; Lazdunski, Andrée; Filloux, Alain
2010-01-01
Bacterial pathogenesis often depends on regulatory networks, two-component systems and small RNAs (sRNAs). In Pseudomonas aeruginosa, the RetS sensor pathway downregulates expression of two sRNAs, rsmY and rsmZ. Consequently, biofilm and the Type Six Secretion System (T6SS) are repressed, whereas the Type III Secretion System (T3SS) is activated. We show that the HptB signalling pathway controls biofilm and T3SS, and fine-tunes P. aeruginosa pathogenesis. We demonstrate that RetS and HptB intersect at the GacA response regulator, which directly controls sRNAs production. Importantly, RetS controls both sRNAs, whereas HptB exclusively regulates rsmY expression. We reveal that HptB signalling is a complex regulatory cascade. This cascade involves a response regulator, with an output domain belonging to the phosphatase 2C family, and likely an anti-anti-σ factor. This reveals that the initial input in the Gac system comes from several signalling pathways, and the final output is adjusted by a differential control on rsmY and rsmZ. This is exemplified by the RetS-dependent but HptB-independent control on T6SS. We also demonstrate a redundant action of the two sRNAs on T3SS gene expression, while the impact on pel gene expression is additive. These features underpin a novel mechanism in the fine-tuned regulation of gene expression. PMID:20398205
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Miot, Jacqui; Thiede, Michael
2017-01-01
Background: Pharmacoeconomics is receiving increasing attention globally as a set of tools ensuring efficient use of resources in health systems, albeit with different applications depending on the contextual, cultural and development stages of each country. The factors guiding design, implementation and optimisation of pharmacoeconomics as a steering tool under the universal health coverage paradigm are explored using case studies of Germany and South Africa. Findings: German social health insurance is subject to the efficiency precept. Pharmaco-regulatory tools reflect the respective framework conditions under which they developed at particular points in time. The institutionalization and integration of pharmacoeconomics into the remit of the Institute for Quality and Efficiency in Health Care occurred only rather recently. The road has not been smooth, requiring political discourse and complex processes of negotiation. Although enshrined in the National Drug Policy, South Africa has had a more fragmented approach to medicine selection and pricing with different policies in private and public sectors. The regulatory reform for use of pharmacoeconomic tools is ongoing and will be further shaped by the introduction of National Health Insurance. Conclusion: A clear vision or framework is essential as the regulatory introduction of pharmacoeconomics is not a single event but rather a growing momentum. The path will always be subject to influences of politics, economics and market forces beyond the healthcare system so delays and modifications to pharmacoeconomic tools are to be expected. Health systems are dynamic and pharmacoeconomic reforms need to be sufficiently flexible to evolve alongside.
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Function of fusion regulatory proteins (FRPs) in immune cells and virus-infected cells.
Tsurudome, M; Ito, Y
2000-01-01
Two molecules that regulate cell fusion have been identified and designated fusion regulatory protein-1 (FRP-1) and FRP-2. FRP-1 is a complex composed of a glycosylated heavy chain and a nonglycosylated light chain that are disulfide linked. FRP-1 heavy chain is identical to 4F2/CD98 heavy chain, whereas FRP-2 is identical to integrin alpha3 subunit. The FRP-1 heavy chain is a multifunctional molecule: that is, fusion regulator, amino acid transporter, integrin regulator, comitogenic factor, Na+-Ca2+ exchanger, oncogenic protein, and so on. Several aspects of the structure and function of the FRP-1 system are reviewed: fusion regulatory molecular mechanisms, cross-talk between the FRP-1 and integrin, the FRP-1 system as amino acid transporter, and FRP-1-mediated T-cell activation. The FRP-1 system is involved in virus-mediated cell fusion and multinucleated giant cell formation of blood monocytes. Monoclonal antibodies against human FRP-1 heavy chain induce polykaryocytes that have properties as osteoclasts. Multiple steps participate in molecular mechanisms regulating cell fusion. The FRP-1 heavy chain supports amino acid transport activity and the FRP-1 light chains have recently been cloned as amino acid transporters that require association with the heavy chain to exhibit their activity. Novel pathways for monocyte-dependent regulation of T-cell activation have recently been found that are mediated by the FRP-1 system. In conclusion, the FRP-1 molecules are essential factors for basic cellular functions.
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Albert, Nick W.; Davies, Kevin M.; Lewis, David H.; Zhang, Huaibi; Montefiori, Mirco; Brendolise, Cyril; Boase, Murray R.; Ngo, Hanh; Jameson, Paula E.; Schwinn, Kathy E.
2014-01-01
Plants require sophisticated regulatory mechanisms to ensure the degree of anthocyanin pigmentation is appropriate to myriad developmental and environmental signals. Central to this process are the activity of MYB-bHLH-WD repeat (MBW) complexes that regulate the transcription of anthocyanin genes. In this study, the gene regulatory network that regulates anthocyanin synthesis in petunia (Petunia hybrida) has been characterized. Genetic and molecular evidence show that the R2R3-MYB, MYB27, is an anthocyanin repressor that functions as part of the MBW complex and represses transcription through its C-terminal EAR motif. MYB27 targets both the anthocyanin pathway genes and basic-helix-loop-helix (bHLH) ANTHOCYANIN1 (AN1), itself an essential component of the MBW activation complex for pigmentation. Other features of the regulatory network identified include inhibition of AN1 activity by the competitive R3-MYB repressor MYBx and the activation of AN1, MYB27, and MYBx by the MBW activation complex, providing for both reinforcement and feedback regulation. We also demonstrate the intercellular movement of the WDR protein (AN11) and R3-repressor (MYBx), which may facilitate anthocyanin pigment pattern formation. The fundamental features of this regulatory network in the Asterid model of petunia are similar to those in the Rosid model of Arabidopsis thaliana and are thus likely to be widespread in the Eudicots. PMID:24642943
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Characterization of Mediator Complex and its Associated Proteins from Rice.
Samanta, Subhasis; Thakur, Jitendra Kumar
2017-01-01
The Mediator complex is a multi-protein complex that acts as a molecular bridge conveying transcriptional messages from the cis element-bound transcription factor to the RNA Polymerase II machinery. It is found in all eukaryotes including members of the plant kingdom. Increasing number of reports from plants regarding different Mediator subunits involved in a multitude of processes spanning from plant development to environmental interactions have firmly established it as a central hub of plant regulatory networks. Routine isolation of Mediator complex in a particular species is a necessity because of many reasons. First, composition of the Mediator complex varies from species to species. Second, the composition of the Mediator complex in a particular species is not static under all developmental and environmental conditions. Besides this, at times, Mediator complex is used in in vitro transcription systems. Rice, a staple food crop of the world, is used as a model monocot crop. Realizing the need of a reliable protocol for the isolation of Mediator complex from plants, we describe here the isolation of Mediator complex from rice.
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Brondz, B D; Kazansky, D B; Chernyshova, A D; Ivanov, V S
1995-01-01
Six individual peptides of the major histocompatibility complex (MHC) class I molecule H-2Kb were synthesized. Intravenous injection of peptide 6 into mice prolonged the survival of Kb (BL/6 or B10.MBR) skin grafts on allogeneic R101 and B10.AKM mice, respectively. This was specific, as control skin grafts from Kk (B10.BR) or Kd (DBA/2) donors, respectively, were rejected at the same time in both control and peptide-treated mice. The optimal doses for peptide 6, which is from the alpha 2 domain, were defined. The test system was the inhibition of proliferation in vitro of naive lymph node cells by syngeneic mitomycin c-treated spleen cells from R101 mice preimmunized with irradiated stimulator splenocytes of Kb (BL/6) origin. Down-regulation was specific, as proliferation in response to third-party allogeneic stimulator Kk (B10.BR) splenocytes was not inhibited. Of the six peptides of H-2Kb tested, potent down-regulatory cells were induced by peptides 2 (alpha 1 domain) and 5 and 6 (alpha 2 domain). The greatest down-regulatory activity was obtained by giving peptide 2 to mice that had already been immunized against H-2Kb by injecting EL4 cells. Under the same conditions, injecting peptide 2 did not induce any cytotoxic T cells. In contrast, specific cytotoxic lymphocytes (CTL) were induced when cells from primed mice were incubated for 4 days with heated stimulator cells from BL/6 mice. The data suggest that peptides from MHC class I molecules activate precursors of down-regulatory T cells, but not of CTL, and this may explain their ability to prolong skin allograft survival. PMID:7490121
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Alam, Md Ashiqul; Kamlangdee, Niyom; Kelly, Joan M
2017-08-01
Ubiquitination/deubiquitination pathways are now recognized as key components of gene regulatory mechanisms in eukaryotes. The major transcriptional repressor for carbon catabolite repression in Aspergillus nidulans is CreA, and mutational analysis led to the suggestion that a regulatory ubiquitination/deubiquitination pathway is involved. A key unanswered question is if and how this pathway, comprising CreB (deubiquitinating enzyme) and HulA (ubiquitin ligase) and other proteins, is involved in the regulatory mechanism. Previously, missense alleles of creA and creB were analysed for genetic interactions, and here we extended this to complete loss-of-function alleles of creA and creB, and compared morphological and biochemical phenotypes, which confirmed genetic interaction between the genes. We investigated whether CreA, or a protein in a complex with it, is a direct target of the CreB deubiquitination enzyme, using co-purifications of CreA and CreB, first using strains that overexpress the proteins and then using strains that express the proteins from their native promoters. The Phos-tag system was used to show that CreA is a phosphorylated protein, but no ubiquitination was detected using anti-ubiquitin antibodies and Western analysis. These findings were confirmed using mass spectrometry, which confirmed that CreA was differentially phosphorylated but not ubiquitinated. Thus, CreA is not a direct target of CreB, and nor are proteins that form part of a stable complex with CreA a target of CreB. These results open up new questions regarding the molecular mechanism of CreA repressing activity, and how the ubiquitination pathway involving CreB interacts with this regulatory network.
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Nikolić, Miloš; Papantonis, Argyris
2017-01-01
Abstract Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70–90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type-specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease-causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders. PMID:28007912
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Hasegawa, Takanori; Yamaguchi, Rui; Nagasaki, Masao; Miyano, Satoru; Imoto, Seiya
2014-01-01
Comprehensive understanding of gene regulatory networks (GRNs) is a major challenge in the field of systems biology. Currently, there are two main approaches in GRN analysis using time-course observation data, namely an ordinary differential equation (ODE)-based approach and a statistical model-based approach. The ODE-based approach can generate complex dynamics of GRNs according to biologically validated nonlinear models. However, it cannot be applied to ten or more genes to simultaneously estimate system dynamics and regulatory relationships due to the computational difficulties. The statistical model-based approach uses highly abstract models to simply describe biological systems and to infer relationships among several hundreds of genes from the data. However, the high abstraction generates false regulations that are not permitted biologically. Thus, when dealing with several tens of genes of which the relationships are partially known, a method that can infer regulatory relationships based on a model with low abstraction and that can emulate the dynamics of ODE-based models while incorporating prior knowledge is urgently required. To accomplish this, we propose a method for inference of GRNs using a state space representation of a vector auto-regressive (VAR) model with L1 regularization. This method can estimate the dynamic behavior of genes based on linear time-series modeling constructed from an ODE-based model and can infer the regulatory structure among several tens of genes maximizing prediction ability for the observational data. Furthermore, the method is capable of incorporating various types of existing biological knowledge, e.g., drug kinetics and literature-recorded pathways. The effectiveness of the proposed method is shown through a comparison of simulation studies with several previous methods. For an application example, we evaluated mRNA expression profiles over time upon corticosteroid stimulation in rats, thus incorporating corticosteroid kinetics/dynamics, literature-recorded pathways and transcription factor (TF) information. PMID:25162401
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Freyre-González, Julio A; Tauch, Andreas
2017-09-10
Corynebacterium glutamicum is a Gram-positive, anaerobic, rod-shaped soil bacterium able to grow on a diversity of carbon sources like sugars and organic acids. It is a biotechnological relevant organism because of its highly efficient ability to biosynthesize amino acids, such as l-glutamic acid and l-lysine. Here, we reconstructed the most complete C. glutamicum regulatory network to date and comprehensively analyzed its global organizational properties, systems-level features and functional architecture. Our analyses show the tremendous power of Abasy Atlas to study the functional organization of regulatory networks. We created two models of the C. glutamicum regulatory network: all-evidences (containing both weak and strong supported interactions, genomic coverage=73%) and strongly-supported (only accounting for strongly supported evidences, genomic coverage=71%). Using state-of-the-art methodologies, we prove that power-law behaviors truly govern the connectivity and clustering coefficient distributions. We found a non-previously reported circuit motif that we named complex feed-forward motif. We highlighted the importance of feedback loops for the functional architecture, beyond whether they are statistically over-represented or not in the network. We show that the previously reported top-down approach is inadequate to infer the hierarchy governing a regulatory network because feedback bridges different hierarchical layers, and the top-down approach disregards the presence of intermodular genes shaping the integration layer. Our findings all together further support a diamond-shaped, three-layered hierarchy exhibiting some feedback between processing and coordination layers, which is shaped by four classes of systems-level elements: global regulators, locally autonomous modules, basal machinery and intermodular genes. Copyright © 2016 Elsevier B.V. All rights reserved.
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REgulatory Management: Communication About Technology-Based Innovations Can Be Improved
2001-02-01
locations and was built to accommodate a variety of users’ computing environments. • FDA’s Center for Food Safety and Applied Nutrition’s Voluntary...transportation communities. Food Safety Initiative Ensuring the safety of the nation’s food supply is the responsibility of an interlocking monitoring system...that watches over food production and distribution at every level of government—local, state, and national. Given the complex set of food safety laws
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2009-12-01
a weapon in food and water. The case involved the radiological poisoning of former Russian spy Alexander Litvinenko with Polonium 210 . An article...SECURITY Gary Wayne Elliott Emergency Management Coordinator for Environmental Health and Division of Food Protection Supervisor, South Carolina...31 c. Bioterrorism, Biodefense, and Health Security .....................31 9. Other Barriers to Comprehensible Food Safety/Defense
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Wingender, Edgar
2008-07-01
Since its beginning as a data collection more than 20 years ago, the TRANSFAC project underwent an evolution to become the basis for a complex platform for the description and analysis of gene regulatory events and networks. In the following, I describe what the original concepts were, what their present status is and how they may be expected to contribute to future system biology approaches.
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Gene Regulatory Networks governing lung specification
Rankin, Scott A.; Zorn, Aaron M.
2014-01-01
The epithelial lining of the respiratory system originates from a small group of progenitor cells in the ventral foregut endoderm of the early embryo. Research in the last decade has revealed a number of paracrine signaling pathways that are critical for the development of these respiratory progenitors. In the post genomic era the challenge now is to figure out at the genome wide level how these different signaling pathways and their downstream transcription factors interact in a complex “gene regulatory network” (GRN) to orchestrate early lung development. In this prospective we review our growing understanding of the GRN governing lung specification. We discuss key gaps in our knowledge and describe emerging opportunities that will soon provide an unprecedented understanding of lung development and accelerate our ability to apply this knowledge to regenerative medicine. PMID:24644080
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Gallego-Paez, L M; Bordone, M C; Leote, A C; Saraiva-Agostinho, N; Ascensão-Ferreira, M; Barbosa-Morais, N L
2017-09-01
Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. In this review, we aim to bring the splicing machinery on stage and raise the curtain on its mechanisms and regulation throughout several systems and tissues of the human body, from neurodevelopment to the interactions with the human microbiome. We discuss, on one hand, the essential role of alternative splicing in assuring tissue function, diversity, and swiftness of response in these systems or tissues, and on the other hand, what goes wrong when its regulatory mechanisms fail. We also focus on the possibilities that splicing modulation therapies open for the future of personalized medicine, along with the leading techniques in this field. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.
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FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis
2012-01-01
Background FK506 (Tacrolimus) is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. Results Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type) and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR) does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. Conclusions Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We have shown that regulatory mechanisms can differ substantially from other, even apparently closely similar FK506-producing strains, reported in literature. Finally, we have demonstrated the potential of these genetically modified strains of S. tsukubaensis for improving the yield of fermentative processes for production of FK506. PMID:23083511
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McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; MacDonald, Kelli P. A.; Hill, Geoffrey R.; Luznik, Leo; Serody, Jonathan S.; Murphy, William J.; Maillard, Ivan; Munn, David H.; Turka, Laurence A.; Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome
2016-01-01
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. PMID:27385791
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Sullivan, R M
2004-06-01
The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.
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Advancing a Vision for Regulatory Science Training
Adamo, Joan E.; Wilhelm, Erin E.
2015-01-01
Abstract Regulatory science, a complex field which draws on science, law, and policy, is a growing discipline in medical‐related applications. Competencies help define both a discipline and the criteria to measure high‐quality learning experiences. This paper identifies competencies for regulatory science, how they were developed, and broader recommendations to enhance education and training in this burgeoning field, including a multifaceted training approach. PMID:26083660
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Cortese-Krott, Miriam M; Koning, Anne; Kuhnle, Gunter G C; Nagy, Peter; Bianco, Christopher L; Pasch, Andreas; Wink, David A; Fukuto, Jon M; Jackson, Alan A; van Goor, Harry; Olson, Kenneth R; Feelisch, Martin
2017-10-01
Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete. Recent Advances: Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept defined as the reactive species interactome (RSI). The RSI is a primeval multilevel redox regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stressors to enhance fitness and resilience at the local and whole-organism level. To better characterize the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems, and effects on cellular, organ, and whole-organism bioenergetics using system-level/network analyses. Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other forms of stress will provide new prevention/intervention opportunities for personalized medicine. Antioxid. Redox Signal. 00, 000-000.
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Transcriptional Regulatory Network Analysis of MYB Transcription Factor Family Genes in Rice.
Smita, Shuchi; Katiyar, Amit; Chinnusamy, Viswanathan; Pandey, Dev M; Bansal, Kailash C
2015-01-01
MYB transcription factor (TF) is one of the largest TF families and regulates defense responses to various stresses, hormone signaling as well as many metabolic and developmental processes in plants. Understanding these regulatory hierarchies of gene expression networks in response to developmental and environmental cues is a major challenge due to the complex interactions between the genetic elements. Correlation analyses are useful to unravel co-regulated gene pairs governing biological process as well as identification of new candidate hub genes in response to these complex processes. High throughput expression profiling data are highly useful for construction of co-expression networks. In the present study, we utilized transcriptome data for comprehensive regulatory network studies of MYB TFs by "top-down" and "guide-gene" approaches. More than 50% of OsMYBs were strongly correlated under 50 experimental conditions with 51 hub genes via "top-down" approach. Further, clusters were identified using Markov Clustering (MCL). To maximize the clustering performance, parameter evaluation of the MCL inflation score (I) was performed in terms of enriched GO categories by measuring F-score. Comparison of co-expressed cluster and clads analyzed from phylogenetic analysis signifies their evolutionarily conserved co-regulatory role. We utilized compendium of known interaction and biological role with Gene Ontology enrichment analysis to hypothesize function of coexpressed OsMYBs. In the other part, the transcriptional regulatory network analysis by "guide-gene" approach revealed 40 putative targets of 26 OsMYB TF hubs with high correlation value utilizing 815 microarray data. The putative targets with MYB-binding cis-elements enrichment in their promoter region, functional co-occurrence as well as nuclear localization supports our finding. Specially, enrichment of MYB binding regions involved in drought-inducibility implying their regulatory role in drought response in rice. Thus, the co-regulatory network analysis facilitated the identification of complex OsMYB regulatory networks, and candidate target regulon genes of selected guide MYB genes. The results contribute to the candidate gene screening, and experimentally testable hypotheses for potential regulatory MYB TFs, and their targets under stress conditions.
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Laarits, T; Bordalo, P; Lemos, B
2016-08-01
Regulatory networks play a central role in the modulation of gene expression, the control of cellular differentiation, and the emergence of complex phenotypes. Regulatory networks could constrain or facilitate evolutionary adaptation in gene expression levels. Here, we model the adaptation of regulatory networks and gene expression levels to a shift in the environment that alters the optimal expression level of a single gene. Our analyses show signatures of natural selection on regulatory networks that both constrain and facilitate rapid evolution of gene expression level towards new optima. The analyses are interpreted from the standpoint of neutral expectations and illustrate the challenge to making inferences about network adaptation. Furthermore, we examine the consequence of variable stabilizing selection across genes on the strength and direction of interactions in regulatory networks and in their subsequent adaptation. We observe that directional selection on a highly constrained gene previously under strong stabilizing selection was more efficient when the gene was embedded within a network of partners under relaxed stabilizing selection pressure. The observation leads to the expectation that evolutionarily resilient regulatory networks will contain optimal ratios of genes whose expression is under weak and strong stabilizing selection. Altogether, our results suggest that the variable strengths of stabilizing selection across genes within regulatory networks might itself contribute to the long-term adaptation of complex phenotypes. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.
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Pliotas, Christos; Grayer, Samuel C; Ekkerman, Silvia; Chan, Anthony K N; Healy, Jess; Marius, Phedra; Bartlett, Wendy; Khan, Amjad; Cortopassi, Wilian A; Chandler, Shane A; Rasmussen, Tim; Benesch, Justin L P; Paton, Robert S; Claridge, Timothy D W; Miller, Samantha; Booth, Ian R; Naismith, James H; Conway, Stuart J
2017-08-15
Ligand binding is one of the most fundamental properties of proteins. Ligand functions fall into three basic types: substrates, regulatory molecules, and cofactors essential to protein stability, reactivity, or enzyme-substrate complex formation. The regulation of potassium ion movement in bacteria is predominantly under the control of regulatory ligands that gate the relevant channels and transporters, which possess subunits or domains that contain Rossmann folds (RFs). Here we demonstrate that adenosine monophosphate (AMP) is bound to both RFs of the dimeric bacterial Kef potassium efflux system (Kef), where it plays a structural role. We conclude that AMP binds with high affinity, ensuring that the site is fully occupied at all times in the cell. Loss of the ability to bind AMP, we demonstrate, causes protein, and likely dimer, instability and consequent loss of function. Kef system function is regulated via the reversible binding of comparatively low-affinity glutathione-based ligands at the interface between the dimer subunits. We propose this interfacial binding site is itself stabilized, at least in part, by AMP binding.
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2017-01-01
Ligand binding is one of the most fundamental properties of proteins. Ligand functions fall into three basic types: substrates, regulatory molecules, and cofactors essential to protein stability, reactivity, or enzyme–substrate complex formation. The regulation of potassium ion movement in bacteria is predominantly under the control of regulatory ligands that gate the relevant channels and transporters, which possess subunits or domains that contain Rossmann folds (RFs). Here we demonstrate that adenosine monophosphate (AMP) is bound to both RFs of the dimeric bacterial Kef potassium efflux system (Kef), where it plays a structural role. We conclude that AMP binds with high affinity, ensuring that the site is fully occupied at all times in the cell. Loss of the ability to bind AMP, we demonstrate, causes protein, and likely dimer, instability and consequent loss of function. Kef system function is regulated via the reversible binding of comparatively low-affinity glutathione-based ligands at the interface between the dimer subunits. We propose this interfacial binding site is itself stabilized, at least in part, by AMP binding. PMID:28656748
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Voluntary coordination as a strategy of plan implementation for health systems agencies.
Berry, D E; Candia, G R
1979-10-01
Health planning agencies are faced with the difficult mission of guiding change within a large complex social system whose power is dispersed. Initial short- and long-range plans have been established as frameworks, and now the major focus is implementation. Regulation (non-voluntary coordination) and voluntary coordination are the major means of implementation. Voluntary coordination is a significant strategy for consideration by Health Systems Agencies (HSAs). It may interact with regulation as a competitor, substitute, or complement. Because of limited regulatory powers, HSAs are dependent upon voluntary coordination as a major means of influencing behavior. Conflict, a major feature of voluntary coordination, has the potential of being used as a constructive means for dialogue; negotiation and bargaining may become positive approaches to arriving at decisions. Legitimized community authority is the primary source of authority in a strategy dominated by voluntary coordination as contrasted to state or federal mandates in a regulatory strategy. Knowledge of the environment within which the HSA operates will assist HSA staff and board to arrive at rational and realistic decisions.
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Martini, Paolo; Sales, Gabriele; Calura, Enrica; Brugiolo, Mattia; Lanfranchi, Gerolamo; Romualdi, Chiara; Cagnin, Stefano
2013-01-01
Genome-wide experiments are routinely used to increase the understanding of the biological processes involved in the development and maintenance of a variety of pathologies. Although the technical feasibility of this type of experiment has improved in recent years, data analysis remains challenging. In this context, gene set analysis has emerged as a fundamental tool for the interpretation of the results. Here, we review strategies used in the gene set approach, and using datasets for the pig cardiocirculatory system as a case study, we demonstrate how the use of a combination of these strategies can enhance the interpretation of results. Gene set analyses are able to distinguish vessels from the heart and arteries from veins in a manner that is consistent with the different cellular composition of smooth muscle cells. By integrating microRNA elements in the regulatory circuits identified, we find that vessel specificity is maintained through specific miRNAs, such as miR-133a and miR-143, which show anti-correlated expression with their mRNA targets. PMID:24284405
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Martínez-Núñez, Mario Alberto; Poot-Hernandez, Augusto Cesar; Rodríguez-Vázquez, Katya; Perez-Rueda, Ernesto
2013-01-01
In this work, the content of enzymes and DNA-binding transcription factors (TFs) in 794 non-redundant prokaryotic genomes was evaluated. The identification of enzymes was based on annotations deposited in the KEGG database as well as in databases of functional domains (COG and PFAM) and structural domains (Superfamily). For identifications of the TFs, hidden Markov profiles were constructed based on well-known transcriptional regulatory families. From these analyses, we obtained diverse and interesting results, such as the negative rate of incremental changes in the number of detected enzymes with respect to the genome size. On the contrary, for TFs the rate incremented as the complexity of genome increased. This inverse related performance shapes the diversity of metabolic and regulatory networks and impacts the availability of enzymes and TFs. Furthermore, the intersection of the derivatives between enzymes and TFs was identified at 9,659 genes, after this point, the regulatory complexity grows faster than metabolic complexity. In addition, TFs have a low number of duplications, in contrast to the apparent high number of duplications associated with enzymes. Despite the greater number of duplicated enzymes versus TFs, the increment by which duplicates appear is higher in TFs. A lower proportion of enzymes among archaeal genomes (22%) than in the bacterial ones (27%) was also found. This low proportion might be compensated by the interconnection between the metabolic pathways in Archaea. A similar proportion was also found for the archaeal TFs, for which the formation of regulatory complexes has been proposed. Finally, an enrichment of multifunctional enzymes in Bacteria, as a mechanism of ecological adaptation, was detected.
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Martínez-Núñez, Mario Alberto; Poot-Hernandez, Augusto Cesar; Rodríguez-Vázquez, Katya; Perez-Rueda, Ernesto
2013-01-01
In this work, the content of enzymes and DNA-binding transcription factors (TFs) in 794 non-redundant prokaryotic genomes was evaluated. The identification of enzymes was based on annotations deposited in the KEGG database as well as in databases of functional domains (COG and PFAM) and structural domains (Superfamily). For identifications of the TFs, hidden Markov profiles were constructed based on well-known transcriptional regulatory families. From these analyses, we obtained diverse and interesting results, such as the negative rate of incremental changes in the number of detected enzymes with respect to the genome size. On the contrary, for TFs the rate incremented as the complexity of genome increased. This inverse related performance shapes the diversity of metabolic and regulatory networks and impacts the availability of enzymes and TFs. Furthermore, the intersection of the derivatives between enzymes and TFs was identified at 9,659 genes, after this point, the regulatory complexity grows faster than metabolic complexity. In addition, TFs have a low number of duplications, in contrast to the apparent high number of duplications associated with enzymes. Despite the greater number of duplicated enzymes versus TFs, the increment by which duplicates appear is higher in TFs. A lower proportion of enzymes among archaeal genomes (22%) than in the bacterial ones (27%) was also found. This low proportion might be compensated by the interconnection between the metabolic pathways in Archaea. A similar proportion was also found for the archaeal TFs, for which the formation of regulatory complexes has been proposed. Finally, an enrichment of multifunctional enzymes in Bacteria, as a mechanism of ecological adaptation, was detected. PMID:23922780
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Coates, Brad S; Sun, Weilin; Clark, John M; Pittendrigh, Barry R
2017-01-01
Abstract The adaptation of insect populations to insecticidal control is a continual threat to human health and sustainable agricultural practices, but many complex genomic mechanisms involved in this adaption remain poorly understood. This study applied a systems approach to investigate the interconnections between structural and functional variance in response to dichlorodiphenyltrichloroethane (DDT) within the Drosophila melanogaster strain 91-R. Directional selection in 6 selective sweeps coincided with constitutive gene expression differences in DDT resistant flies, including the most highly upregulated transcript, Unc-115 b, which plays a central role in axon guidance, and the most highly downregulated transcript, the angiopoietin-like CG31832, which is involved in directing vascular branching and dendrite outgrowth but likely may be under trans-regulatory control. Direct functions and protein–protein interactions mediated by differentially expressed transcripts control changes in cell migration, signal transduction, and gene regulatory cascades that impact the nervous system. Although changes to cellular stress response pathways involve 8 different cytochrome P450s, stress response, and apoptosis is controlled by a multifacetted regulatory mechanism. These data demonstrate that DDT selection in 91-R may have resulted in genome-wide adaptations that impacts genetic and signal transduction pathways that converge to modify stress response, cell survival, and neurological functions. This study implicates the involvement of a multigenic mechanism in the adaptation to a chemical insecticide, which impact interconnected regulatory cascades. We propose that DDT selection within 91-R might act systemically, wherein pathway interactions function to reinforce the epistatic effects of individual adaptive changes on an additive or nonadditive basis. PMID:29211847
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Blokhina, Olga; Fagerstedt, Kurt V
2010-04-01
Plant mitochondria differ from their mammalian counterparts in many respects, which are due to the unique and variable surroundings of plant mitochondria. In green leaves, plant mitochondria are surrounded by ample respiratory substrates and abundant molecular oxygen, both resulting from active photosynthesis, while in roots and bulky rhizomes and fruit carbohydrates may be plenty, whereas oxygen levels are falling. Several enzymatic complexes in mitochondrial electron transport chain (ETC) are capable of reactive oxygen species (ROS) formation under physiological and pathological conditions. Inherently connected parameters such as the redox state of electron carriers in the ETC, ATP synthase activity and inner mitochondrial membrane potential, when affected by external stimuli, can give rise to ROS formation via complexes I and III, and by reverse electron transport (RET) from complex II. Superoxide radicals produced are quickly scavenged by superoxide dismutase (MnSOD), and the resulting H(2)O(2) is detoxified by peroxiredoxin-thioredoxin system or by the enzymes of ascorbate-glutathione cycle, found in the mitochondrial matrix. Arginine-dependent nitric oxide (NO)-releasing activity of enzymatic origin has been detected in plant mitochondria. The molecular identity of the enzyme is not clear but the involvement of mitochondria-localized enzymes responsible for arginine catabolism, arginase and ornithine aminotransferase has been shown in the regulation of NO efflux. Besides direct control by antioxidants, mitochondrial ROS production is tightly controlled by multiple redundant systems affecting inner membrane potential: NAD(P)H-dependent dehydrogenases, alternative oxidase (AOX), uncoupling proteins, ATP-sensitive K(+) channel and a number of matrix and intermembrane enzymes capable of direct electron donation to ETC. NO removal, on the other hand, takes place either by reactions with molecular oxygen or superoxide resulting in peroxynitrite, nitrite or nitrate ions or through interaction with non-symbiotic hemoglobins or glutathione. Mitochondrial ROS and NO production is tightly controlled by multiple redundant systems providing the regulatory mechanism for redox homeostasis and specific ROS/NO signaling.
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Power distribution in complex environmental negotiations: Does balance matter?
Burkardt, N.; Lamb, B.L.; Taylor, J.G.
1997-01-01
We studied six interagency negotiations covering Federal Energy Regulatory Commission (FERC) hydroelectric power licenses. Negotiations occurred between state and federal resource agencies and developers over project operations and natural resource mitigation. We postulated that a balance of power among parties was necessary for successful negotiations. We found a complex relationship between balanced power and success and conclude that a balance of power was associated with success in these negotiations. Power played a dynamic role in the bargaining and illuminates important considerations for regulatory design.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-06-14
.../taker fees and rebates, which are designed to attract complex orders to the Exchange, and has a specific... per contract applicable to customers that transact in complex orders, i.e., customer complex orders that interact with complex orders residing on the complex order book thereby taking liquidity from the...
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Schuster, Christoph; Gaillochet, Christophe; Medzihradszky, Anna; Busch, Wolfgang; Daum, Gabor; Krebs, Melanie; Kehle, Andreas; Lohmann, Jan U
2014-02-24
Plants continuously maintain pluripotent stem cells embedded in specialized tissues called meristems, which drive long-term growth and organogenesis. Stem cell fate in the shoot apical meristem (SAM) is controlled by the homeodomain transcription factor WUSCHEL (WUS) expressed in the niche adjacent to the stem cells. Here, we demonstrate that the bHLH transcription factor HECATE1 (HEC1) is a target of WUS and that it contributes to SAM function by promoting stem cell proliferation, while antagonizing niche cell activity. HEC1 represses the stem cell regulators WUS and CLAVATA3 (CLV3) and, like WUS, controls genes with functions in metabolism and hormone signaling. Among the targets shared by HEC1 and WUS are phytohormone response regulators, which we show to act as mobile signals in a universal feedback system. Thus, our work sheds light on the mechanisms guiding meristem function and suggests that the underlying regulatory system is far more complex than previously anticipated. Copyright © 2014 Elsevier Inc. All rights reserved.
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Wiig, Siri; Tharaldsen, Jorunn Elise
2012-01-01
The role of trust has been argued to play an increasingly important role in modern, complex, and ambivalent risk societies. Trust within organizational research is anticipated to have a general strategic impact on aspects such as organizational performance, communication and knowledge exchange, and learning from accidents. Trust is also an important aspect related to regulation of risk. Diverse regulatory regimes, their contexts and risks influence regulators use of trust and distrust in regulatory practice. The aim of this paper is to discuss the relationship between risk regulation and trust across diverse risk regulation regimes. By drawing from studies of risk regulation, risk perception, and trust the purpose is to discuss how regulation and trust are linked and used in practice to control risk across system levels in socio-technical systems in high risk industries. This paper provides new knowledge on 1) how functional and dysfunctional trust and distrust are grounded in the empirical realities of high risk industries, 2) how different perspectives on trust and distrust act together and bring new knowledge on how society control risk.
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Johnson, Michael R.; Rossetti, Tiziana; Speed, Doug; Srivastava, Prashant K.; Chadeau-Hyam, Marc; Hajji, Nabil; Dabrowska, Aleksandra; Rotival, Maxime; Razzaghi, Banafsheh; Kovac, Stjepana; Wanisch, Klaus; Grillo, Federico W.; Slaviero, Anna; Langley, Sarah R.; Shkura, Kirill; Roncon, Paolo; De, Tisham; Mattheisen, Manuel; Niehusmann, Pitt; O’Brien, Terence J.; Petrovski, Slave; von Lehe, Marec; Hoffmann, Per; Eriksson, Johan; Coffey, Alison J.; Cichon, Sven; Walker, Matthew; Simonato, Michele; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Schoch, Susanne; De Paola, Vincenzo; Kaminski, Rafal M.; Cunliffe, Vincent T.; Becker, Albert J.; Petretto, Enrico
2015-01-01
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo. PMID:25615886
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Medicine shortages: a commentary on causes and mitigation strategies.
Iyengar, Swathi; Hedman, Lisa; Forte, Gilles; Hill, Suzanne
2016-09-29
Shortages of medicines and vaccines have been reported in countries of all income levels in recent years. Shortages can result from one or multiple causes, including shortages of raw materials, manufacturing capacity problems, industry consolidation, marketing practices, and procurement and supply chain management. Existing approaches to mitigate shortages include advance notice systems managed through medicine regulatory authorities, special programmes that track medicines, and interventions to improve efficiency of the medicine supply chain. Redistribution of supplies at the national level can mitigate some shortages in the short term. International redistribution and exceptional regulatory approvals may be used in limited circumstances, with the understanding that such approaches are complex and may introduce cost and quality risks. If it is necessary to prioritise patients to receive a medicine that is in shortage, evidence-based practice should be used to ensure optimal allocation. Important steps in reducing medicine shortages and their impact include identifying medicines that are most at risk, developing reporting systems to share information on current and emerging shortages, and improving data from medicine supply chains.
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Nuss, Aaron M; Schuster, Franziska; Kathrin Heroven, Ann; Heine, Wiebke; Pisano, Fabio; Dersch, Petra
2014-01-01
In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrC(IP32953), which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs.
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Behnam, Babak; Iuchi, Satoshi; Fujita, Miki; Fujita, Yasunari; Takasaki, Hironori; Osakabe, Yuriko; Yamaguchi-Shinozaki, Kazuko; Kobayashi, Masatomo; Shinozaki, Kazuo
2013-01-01
Plants respond to dehydration stress and tolerate water-deficit status through complex physiological and cellular processes. Many genes are induced by water deficit. Abscisic acid (ABA) plays important roles in tolerance to dehydration stress by inducing many stress genes. ABA is synthesized de novo in response to dehydration. Most of the genes involved in ABA biosynthesis have been identified, and they are expressed mainly in leaf vascular tissues. Of the products of such genes, 9-cis-epoxycarotenoid dioxygenase (NCED) is a key enzyme in ABA biosynthesis. One of the five NCED genes in Arabidopsis, AtNCED3, is significantly induced by dehydration. To understand the regulatory mechanism of the early stages of the dehydration stress response, it is important to analyse the transcriptional regulatory systems of AtNCED3. In the present study, we found that an overlapping G-box recognition sequence (5′-CACGTG-3′) at −2248 bp from the transcriptional start site of AtNCED3 is an important cis-acting element in the induction of the dehydration response. We discuss the possible transcriptional regulatory system of dehydration-responsive AtNCED3 expression, and how this may control the level of ABA under water-deficit conditions. PMID:23604098
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Kennaway, Richard; Coen, Enrico; Green, Amelia; Bangham, Andrew
2011-01-01
A major problem in biology is to understand how complex tissue shapes may arise through growth. In many cases this process involves preferential growth along particular orientations raising the question of how these orientations are specified. One view is that orientations are specified through stresses in the tissue (axiality-based system). Another possibility is that orientations can be specified independently of stresses through molecular signalling (polarity-based system). The axiality-based system has recently been explored through computational modelling. Here we develop and apply a polarity-based system which we call the Growing Polarised Tissue (GPT) framework. Tissue is treated as a continuous material within which regionally expressed factors under genetic control may interact and propagate. Polarity is established by signals that propagate through the tissue and is anchored in regions termed tissue polarity organisers that are also under genetic control. Rates of growth parallel or perpendicular to the local polarity may then be specified through a regulatory network. The resulting growth depends on how specified growth patterns interact within the constraints of mechanically connected tissue. This constraint leads to the emergence of features such as curvature that were not directly specified by the regulatory networks. Resultant growth feeds back to influence spatial arrangements and local orientations of tissue, allowing complex shapes to emerge from simple rules. Moreover, asymmetries may emerge through interactions between polarity fields. We illustrate the value of the GPT-framework for understanding morphogenesis by applying it to a growing Snapdragon flower and indicate how the underlying hypotheses may be tested by computational simulation. We propose that combinatorial intractions between orientations and rates of growth, which are a key feature of polarity-based systems, have been exploited during evolution to generate a range of observed biological shapes. PMID:21698124
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3D printed drug delivery and testing systems - a passing fad or the future?
Lim, Seng Han; Kathuria, Himanshu; Tan, Justin Jia Yao; Kang, Lifeng
2018-05-18
The US Food and Drug Administration approval of the first 3D printed tablet in 2015 has ignited growing interest in 3D printing, or additive manufacturing (AM), for drug delivery and testing systems. Beyond just a novel method for rapid prototyping, AM provides key advantages over traditional manufacturing of drug delivery and testing systems. These includes the ability to fabricate complex geometries to achieve variable drug release kinetics; ease of personalising pharmacotherapy for patient and lowering the cost for fabricating personalised dosages. Furthermore, AM allows fabrication of complex and micron-sized tissue scaffolds and models for drug testing systems that closely resemble in vivo conditions. However, there are several limitations such as regulatory concerns that may impede the progression to market. Here, we provide an overview of the advantages of AM drug delivery and testing, as compared to traditional manufacturing techniques. Also, we discuss the key challenges and future directions for AM enabled pharmaceutical applications. Copyright © 2018 Elsevier B.V. All rights reserved.
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Behavior systems and reinforcement: an integrative approach.
Timberlake, W
1993-01-01
Most traditional conceptions of reinforcement are based on a simple causal model in which responding is strengthened by the presentation of a reinforcer. I argue that reinforcement is better viewed as the outcome of constraint of a functioning causal system comprised of multiple interrelated causal sequences, complex linkages between causes and effects, and a set of initial conditions. Using a simplified system conception of the reinforcement situation, I review the similarities and drawbacks of traditional reinforcement models and analyze the recent contributions of cognitive, regulatory, and ecological approaches. Finally, I show how the concept of behavior systems can begin to incorporate both traditional and recent conceptions of reinforcement in an integrative approach. PMID:8354963
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Preventing type 2 diabetes: Changing the food industry.
Popkin, Barry M; Kenan, W R
2016-06-01
Improving our global diet by working with the food industry is a fairly complex task. Previously the global food manufacturing companies and governments were the major players. However, matters have shifted rapidly so that food retailers, food manufacturers, the restaurant-food service sector, and agribusinesses are now the major players. The current modern system of packaged processed food has now penetrated the globe-rich and poor, rural and urban are all in reach of this food system. Consequently, working with this complex sector when possible and an array of governmental regulatory large-scale options to improve our diet have increased in importance. Taxation of unhealthy foods and beverages, marketing controls, and front of the package labeling are the primary current options. Evaluations of the impacts of both public and industry initiatives are needed. Copyright © 2016 Elsevier Ltd. All rights reserved.
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2011-01-01
Background Inferring regulatory interactions between genes from transcriptomics time-resolved data, yielding reverse engineered gene regulatory networks, is of paramount importance to systems biology and bioinformatics studies. Accurate methods to address this problem can ultimately provide a deeper insight into the complexity, behavior, and functions of the underlying biological systems. However, the large number of interacting genes coupled with short and often noisy time-resolved read-outs of the system renders the reverse engineering a challenging task. Therefore, the development and assessment of methods which are computationally efficient, robust against noise, applicable to short time series data, and preferably capable of reconstructing the directionality of the regulatory interactions remains a pressing research problem with valuable applications. Results Here we perform the largest systematic analysis of a set of similarity measures and scoring schemes within the scope of the relevance network approach which are commonly used for gene regulatory network reconstruction from time series data. In addition, we define and analyze several novel measures and schemes which are particularly suitable for short transcriptomics time series. We also compare the considered 21 measures and 6 scoring schemes according to their ability to correctly reconstruct such networks from short time series data by calculating summary statistics based on the corresponding specificity and sensitivity. Our results demonstrate that rank and symbol based measures have the highest performance in inferring regulatory interactions. In addition, the proposed scoring scheme by asymmetric weighting has shown to be valuable in reducing the number of false positive interactions. On the other hand, Granger causality as well as information-theoretic measures, frequently used in inference of regulatory networks, show low performance on the short time series analyzed in this study. Conclusions Our study is intended to serve as a guide for choosing a particular combination of similarity measures and scoring schemes suitable for reconstruction of gene regulatory networks from short time series data. We show that further improvement of algorithms for reverse engineering can be obtained if one considers measures that are rooted in the study of symbolic dynamics or ranks, in contrast to the application of common similarity measures which do not consider the temporal character of the employed data. Moreover, we establish that the asymmetric weighting scoring scheme together with symbol based measures (for low noise level) and rank based measures (for high noise level) are the most suitable choices. PMID:21771321
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Molecular switch-like regulation in motor proteins.
Tafoya, Sara; Bustamante, Carlos
2018-06-19
Motor proteins are powered by nucleotide hydrolysis and exert mechanical work to carry out many fundamental biological tasks. To ensure their correct and efficient performance, the motors' activities are allosterically regulated by additional factors that enhance or suppress their NTPase activity. Here, we review two highly conserved mechanisms of ATP hydrolysis activation and repression operating in motor proteins-the glutamate switch and the arginine finger-and their associated regulatory factors. We examine the implications of these regulatory mechanisms in proteins that are formed by multiple ATPase subunits. We argue that the regulatory mechanisms employed by motor proteins display features similar to those described in small GTPases, which require external regulatory elements, such as dissociation inhibitors, exchange factors and activating proteins, to switch the protein's function 'on' and 'off'. Likewise, similar regulatory roles are taken on by the motor's substrate, additional binding factors, and even adjacent subunits in multimeric complexes. However, in motor proteins, more than one regulatory factor and the two mechanisms described here often underlie the machine's operation. Furthermore, ATPase regulation takes place throughout the motor's cycle, which enables a more complex function than the binary 'active' and 'inactive' states.This article is part of a discussion meeting issue 'Allostery and molecular machines'. © 2018 The Author(s).
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Abduallah, Yasser; Turki, Turki; Byron, Kevin; Du, Zongxuan; Cervantes-Cervantes, Miguel; Wang, Jason T L
2017-01-01
Gene regulation is a series of processes that control gene expression and its extent. The connections among genes and their regulatory molecules, usually transcription factors, and a descriptive model of such connections are known as gene regulatory networks (GRNs). Elucidating GRNs is crucial to understand the inner workings of the cell and the complexity of gene interactions. To date, numerous algorithms have been developed to infer gene regulatory networks. However, as the number of identified genes increases and the complexity of their interactions is uncovered, networks and their regulatory mechanisms become cumbersome to test. Furthermore, prodding through experimental results requires an enormous amount of computation, resulting in slow data processing. Therefore, new approaches are needed to expeditiously analyze copious amounts of experimental data resulting from cellular GRNs. To meet this need, cloud computing is promising as reported in the literature. Here, we propose new MapReduce algorithms for inferring gene regulatory networks on a Hadoop cluster in a cloud environment. These algorithms employ an information-theoretic approach to infer GRNs using time-series microarray data. Experimental results show that our MapReduce program is much faster than an existing tool while achieving slightly better prediction accuracy than the existing tool.
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McFarland, Michael J; Nelson, Tim M; Rasmussen, Steve L; Palmer, Glenn R; Olivas, Arthur C
2005-03-01
All U.S. Department of Defense (DoD) facilities are required under Executive Order (EO) 13148, "Greening the Government through Leadership in Environmental Management," to establish quality-based environmental management systems (EMSs) that support environmental decision-making and verification of continuous environmental improvement by December 31, 2005. Compliance with EO 13148 as well as other federal, state, and local environmental regulations places a significant information management burden on DoD facilities. Cost-effective management of environmental data compels DoD facilities to establish robust database systems that not only address the complex and multifaceted environmental monitoring, record-keeping, and reporting requirements demanded by these rules but enable environmental management decision-makers to gauge improvements in environmental performance. The Enterprise Environmental Safety and Occupational Health Management Information System (EESOH-MIS) is a new electronic database developed by the U.S. Air Force to manage both the data needs associated with regulatory compliance programs across its facilities as well as the non-regulatory environmental information that supports installation business practices. The U.S. Air Force, which has adopted the Plan-Do-Check-Act methodology as the EMS standard that it will employ to address EO 13148 requirements.
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Mapping regulatory models for medicinal cannabis: a matrix of options.
Belackova, Vendula; Shanahan, Marian; Ritter, Alison
2017-05-30
Objective The aim of the present study was to develop a framework for assessing regulatory options for medicinal cannabis in Australia. Methods International regulatory regimes for medicinal cannabis were reviewed with a qualitative policy analysis approach and key policy features were synthesised, leading to a conceptual framework that facilitates decision making across multiple dimensions. Results Two central organising dimensions of medicinal cannabis regulation were identified: cannabis supply and patient authorisation (including patient access). A number of the different supply options can be matched with a number of different patient authorisation options, leading to a matrix of possible regulatory regimes. Conclusions The regulatory options, as used internationally, involve different forms of cannabis (synthetic and plant-based pharmaceutical preparations or herbal cannabis) and the varying extent to which patient authorisation policies and procedures are stringently or more loosely defined. The optimal combination of supply and patient authorisation options in any jurisdiction that chooses to make medicinal cannabis accessible will depend on policy goals. What is known about the topic? Internationally, regulation of medicinal cannabis has developed idiosyncratically, depending on formulations that were made available and local context. There has been no attempt to date in the scientific literature to systematically document the variety of regulatory possibilities for medicinal cannabis. What does this paper add? This paper presents a new conceptual schema for considering options for the regulation of medicinal cannabis, across both supply and patient authorisation aspects. What are the implications for practitioners? The design of regulatory systems in Australia, whether for pharmaceutical or herbal products, is a vital issue for policy makers right now as federal and state and territory governments grapple with the complexities of medicinal cannabis regulation. The conceptual schema presented herein provides a tool for more systematic thinking about the options.
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Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C
2016-08-02
Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Weidmann, Chase A.; Qiu, Chen; Arvola, René M.
Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation byDrosophilaPumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that aremore » not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulatedin vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less
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Complex Behavior of Contaminant Flux and the Ecology of the Lower Mississippi River
NASA Astrophysics Data System (ADS)
Barton, C. C.; Manheim, F. T.; De Cola, L.; Bollinger, J. E.; Jenkins, J. A.
2001-12-01
This presentation is an overview of a collaborative NSF/USGS/Tulane funded multi-scale study of the Lower Mississippi River system. The study examines the system in three major dimensional realms: space, time, and complexity (systems and their hierarchies). Researchers at Tulane University and the U.S. Geological Survey have initiated a collaborative effort to undertake the study of interacting elements which directly or indirectly affect the water quality, ecology and physical condition of the Mississippi River. These researchers include experts in the fields of water quality chemistry, geochemistry, hydrologic modeling, bioengineering, biology, fish ecology, statistics, complexity analysis, epidemiology, and computer science. Underlying this research are large databases that permit quantitative analysis of the system over the past 40 years. Results to date show that the variation in discharge and the contaminant flux scale independently both exhibit fractal scaling, the signature geometry of nonlinear dynamical and complex systems. Public perception is that the Lower Mississippi River is a health hazard, but for the past decade, traditional water quality measurements show that contaminants are within current regulatory guidelines for human consumption. This difference between public perception and scientific reality represents a complex scientific and social issue. The connections and feedback within the ecological system and the Mississippi River are few because engineering structures isolate the lower Mississippi River from its surroundings. Investigation of the connections and feedback between human health and the ecological health of the River and the surrounding region as well as perceptions of these states of health - holds promise for explaining epidemiological patterns of human disease.
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77 FR 48177 - Fuel Oil Systems for Emergency Power Supplies
Federal Register 2010, 2011, 2012, 2013, 2014
2012-08-13
... NUCLEAR REGULATORY COMMISSION [NRC-2012-0159] Fuel Oil Systems for Emergency Power Supplies AGENCY: Nuclear Regulatory Commission. ACTION: Draft regulatory guide; extension of comment period. SUMMARY: On... Regulatory Guide, DG- 1282, ``Fuel Oil Systems for Emergency Power Supplies,'' in the Federal Register for a...
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NASA Astrophysics Data System (ADS)
Ravindran, Vandana; Sunitha, V.; Bagler, Ganesh
2017-05-01
Cancer is characterized by a complex web of regulatory mechanisms which makes it difficult to identify features that are central to its control. Molecular integrative models of cancer, generated with the help of data from experimental assays, facilitate use of control theory to probe for ways of controlling the state of such a complex dynamic network. We modeled the human cancer signaling network as a directed graph and analyzed it for its controllability, identification of driver nodes and their characterization. We identified the driver nodes using the maximum matching algorithm and classified them as backbone, peripheral and ordinary based on their role in regulatory interactions and control of the network. We found that the backbone driver nodes were key to driving the regulatory network into cancer phenotype (via mutations) as well as for steering into healthy phenotype (as drug targets). This implies that while backbone genes could lead to cancer by virtue of mutations, they are also therapeutic targets of cancer. Further, based on their impact on the size of the set of driver nodes, genes were characterized as indispensable, dispensable and neutral. Indispensable nodes within backbone of the network emerged as central to regulatory mechanisms of control of cancer. In addition to probing the cancer signaling network from the perspective of control, our findings suggest that indispensable backbone driver nodes could be potentially leveraged as therapeutic targets. This study also illustrates the application of structural controllability for studying the mechanisms underlying the regulation of complex diseases.
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Modularity and design principles in the sea urchin embryo gene regulatory network
Peter, Isabelle S.; Davidson, Eric H.
2010-01-01
The gene regulatory network (GRN) established experimentally for the pre-gastrular sea urchin embryo provides causal explanations of the biological functions required for spatial specification of embryonic regulatory states. Here we focus on the structure of the GRN which controls the progressive increase in complexity of territorial regulatory states during embryogenesis; and on the types of modular subcircuits of which the GRN is composed. Each of these subcircuit topologies executes a particular operation of spatial information processing. The GRN architecture reflects the particular mode of embryogenesis represented by sea urchin development. Network structure not only specifies the linkages constituting the genomic regulatory code for development, but also indicates the various regulatory requirements of regional developmental processes. PMID:19932099
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A solid-state control system for dynein-based ciliary/flagellar motility
2013-01-01
Ciliary and flagellar beating requires the coordinated action of multiple dyneins with different enzymatic and motor properties. In this issue, Yamamoto et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201211048) identify the MIA (modifier of inner arms) complex within the Chlamydomonas reinhardtii axoneme that physically links to a known regulatory structure and provides a signaling conduit from the radial spokes to an inner arm dynein essential for waveform determination. PMID:23569213
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Riedl, Verena; Agatz, Annika; Benstead, Rachel; Ashauer, Roman
2018-04-01
Chemical impacts on the environment are routinely assessed in single-species tests. They are employed to measure direct effects on nontarget organisms, but indirect effects on ecological interactions can only be detected in multispecies tests. Micro- and mesocosms are more complex and environmentally realistic, yet they are less frequently used for environmental risk assessment because resource demand is high, whereas repeatability and statistical power are often low. Test systems fulfilling regulatory needs (i.e., standardization, repeatability, and replication) and the assessment of impacts on species interactions and indirect effects are lacking. In the present study we describe the development of the TriCosm, a repeatable aquatic multispecies test with 3 trophic levels and increased statistical power. High repeatability of community dynamics of 3 interacting aquatic populations (algae, Ceriodaphnia, and Hydra) was found with an average coefficient of variation of 19.5% and the ability to determine small effect sizes. The TriCosm combines benefits of both single-species tests (fulfillment of regulatory requirements) and complex multispecies tests (ecological relevance) and can be used, for instance, at an intermediate tier in environmental risk assessment. Furthermore, comparatively quickly generated population and community toxicity data can be useful for the development and testing of mechanistic effect models. Environ Toxicol Chem 2018;37:1051-1060. © 2017 SETAC. © 2017 SETAC.
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Simple method for assembly of CRISPR synergistic activation mediator gRNA expression array.
Vad-Nielsen, Johan; Nielsen, Anders Lade; Luo, Yonglun
2018-05-20
When studying complex interconnected regulatory networks, effective methods for simultaneously manipulating multiple genes expression are paramount. Previously, we have developed a simple method for generation of an all-in-one CRISPR gRNA expression array. We here present a Golden Gate Assembly-based system of synergistic activation mediator (SAM) compatible CRISPR/dCas9 gRNA expression array for the simultaneous activation of multiple genes. Using this system, we demonstrated the simultaneous activation of the transcription factors, TWIST, SNAIL, SLUG, and ZEB1 a human breast cancer cell line. Copyright © 2018 Elsevier B.V. All rights reserved.
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Kyrchanova, Olga; Mogila, Vladic; Wolle, Daniel; Deshpande, Girish; Parshikov, Alexander; Cléard, Fabienne; Karch, Francois; Schedl, Paul; Georgiev, Pavel
2016-07-01
Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors.
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Wolle, Daniel; Deshpande, Girish; Parshikov, Alexander; Cléard, Fabienne; Karch, Francois; Schedl, Paul; Georgiev, Pavel
2016-01-01
Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors. PMID:27428541
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-17
... to market participants that add or remove liquidity in the complex order book (``maker/taker fees and... quotations for complex order strategies in the complex order book.\\8\\ Given this enhancement to the complex... Customer orders, the Exchange has adopted maker fees that apply to transactions in the complex order book...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-31
... order type, the legging order, is designed to increase the opportunities for a complex order resting on.... Description A complex order resting on ISE's complex order book may be executed either by: (i) Trading against an incoming complex order that is marketable against the resting complex order, or (ii) legging into...
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Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.; ...
2016-09-29
Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.
Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less
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NASA Astrophysics Data System (ADS)
Wilds, Roy; Kauffman, Stuart A.; Glass, Leon
2008-09-01
We study the evolution of complex dynamics in a model of a genetic regulatory network. The fitness is associated with the topological entropy in a class of piecewise linear equations, and the mutations are associated with changes in the logical structure of the network. We compare hill climbing evolution, in which only mutations that increase the fitness are allowed, with neutral evolution, in which mutations that leave the fitness unchanged are allowed. The simple structure of the fitness landscape enables us to estimate analytically the rates of hill climbing and neutral evolution. In this model, allowing neutral mutations accelerates the rate of evolutionary advancement for low mutation frequencies. These results are applicable to evolution in natural and technological systems.
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Delage, Elise; Cervantes, Diégo Cordero; Pénard, Esthel; Schmitt, Christine; Syan, Sylvie; Disanza, Andrea; Scita, Giorgio; Zurzolo, Chiara
2016-12-23
Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as "freeways" to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT-mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion.
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Fanconi Anemia Core Complex Gene Promoters Harbor Conserved Transcription Regulatory Elements
Meier, Daniel; Schindler, Detlev
2011-01-01
The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5′ region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3′ regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters. PMID:21826217
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Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.
Meier, Daniel; Schindler, Detlev
2011-01-01
The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.
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African wildlife conservation and the evolution of hunting institutions
NASA Astrophysics Data System (ADS)
't Sas-Rolfes, Michael
2017-11-01
Hunting regulation presents a significant challenge for contemporary global conservation governance. Motivated by various incentives, hunters may act legally or illegally, for or against the interests of conservation. Hunter incentives are shaped by the interactions between unevenly evolving formal and informal institutions, embedded in socio-ecological systems. To work effectively for conservation, regulatory interventions must take these evolving institutional interactions into account. Drawing on analytical tools from evolutionary institutional economics, this article examines the trajectory of African hunting regulation and its consequences. Concepts of institutional dynamics, fit, scale, and interplay are applied to case studies of rhinoceros and lion hunting to highlight issues of significance to conservation outcomes. These include important links between different forms of hunting and dynamic interplay with institutions of trade. The case studies reveal that inappropriate formal regulatory approaches may be undermined by adaptive informal market responses. Poorly regulated hunting may lead to calls for stricter regulations or bans, but such legal restrictions may in turn perversely lead to more intensified and organised illegal hunting activity, further undermining conservation objectives. I conclude by offering insights and recommendations to guide more effective future regulatory interventions and priorities for further research. Specifically, I advocate approaches that move beyond simplistic regulatory interventions toward more complex, but supportive, institutional arrangements that align formal and informal institutions through inclusive stakeholder engagement.
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Nadeau, Owen W.; Anderson, David W.; Yang, Qing; Artigues, Antonio; Paschall, Justin E.; Wyckoff, Gerald J.; McClintock, Jennifer L.; Carlson, Gerald M.
2007-01-01
Phosphorylase kinase (PhK), an (αβγδ)4 complex, regulates glycogenolysis. Its activity, catalyzed by the γ subunit, is tightly controlled by phosphorylation and activators acting through allosteric sites on its regulatory α, β and δ subunits. Activation of the catalytic γ subunit in the PhK complex by phosphorylation is known to be predominantly mediated by the regulatory β subunit, which undergoes a conformational change that is structurally linked with the γ subunit and that is characterized by the ability to form β-β dimers using a short chemical crosslinker. To determine potential regions of interaction of the β and γ subunits, we have used chemical crosslinking and 2-hybrid screening. The β and γ subunits were chemically crosslinked to each other in phosphorylated PhK, and crosslinked peptides were identified in digests of the kinase by Fourier transform mass spectrometry in combination with a search engine developed ‘in house’ that generates a hypothetical list of crosslinked peptides. Such a conjugate between β and γ was identified, verified by MS/MS and shown to correspond to crosslinking between K303 in the C-terminal regulatory domain of γ (γCRD) and R18 in the N-terminal regulatory region of β (β1-31), which contains the phosphorylatable serines 11 and 26. A synthetic peptide corresponding to residues 1-22 of β inhibited the crosslinking between β and γ in the complex, and was itself crosslinked to K303 of γ. Through the use of 2-hybrid screening, the β1-31 region was also shown to control β subunit self-interactions, which were favored by truncation of this region or by mutation of the phosphorylatable serines 11 and 26, thus providing structural evidence for a phosphorylation-dependent subunit communication network in the PhK complex involving at least these two regulatory regions of the β and γ subunits. The sum of our results considered together with previous findings implicates the γCRD as being an allosteric activation switch in PhK that interacts with all three of the enzyme’s regulatory subunits and is proximal to the active site cleft. PMID:17123541
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Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars
Berkowitz, Steven A.; Engen, John R.; Mazzeo, Jeffrey R.; Jones, Graham B.
2013-01-01
Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation. PMID:22743980
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Thakkar, Jay; Barry, Tony; Thiagalingam, Aravinda; Redfern, Julie; McEwan, Alistair L; Rodgers, Anthony
2016-01-01
Background Mobile health (mHealth) has huge potential to deliver preventative health services. However, there is paucity of literature on theoretical constructs, technical, practical, and regulatory considerations that enable delivery of such services. Objectives The objective of this study was to outline the key considerations in the development of a text message-based mHealth program; thus providing broad recommendations and guidance to future researchers designing similar programs. Methods We describe the key considerations in designing the intervention with respect to functionality, technical infrastructure, data management, software components, regulatory requirements, and operationalization. We also illustrate some of the potential issues and decision points utilizing our experience of developing text message (short message service, SMS) management systems to support 2 large randomized controlled trials: TEXT messages to improve MEDication adherence & Secondary prevention (TEXTMEDS) and Tobacco, EXercise and dieT MEssages (TEXT ME). Results The steps identified in the development process were: (1) background research and development of the text message bank based on scientific evidence and disease-specific guidelines, (2) pilot testing with target audience and incorporating feedback, (3) software-hardware customization to enable delivery of complex personalized programs using prespecified algorithms, and (4) legal and regulatory considerations. Additional considerations in developing text message management systems include: balancing the use of customized versus preexisting software systems, the level of automation versus need for human inputs, monitoring, ensuring data security, interface flexibility, and the ability for upscaling. Conclusions A merging of expertise in clinical and behavioral sciences, health and research data management systems, software engineering, and mobile phone regulatory requirements is essential to develop a platform to deliver and manage support programs to hundreds of participants simultaneously as in TEXT ME and TEXTMEDS trials. This research provides broad principles that may assist other researchers in developing mHealth programs. PMID:27847350
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Thakkar, Jay; Barry, Tony; Thiagalingam, Aravinda; Redfern, Julie; McEwan, Alistair L; Rodgers, Anthony; Chow, Clara K
2016-11-15
Mobile health (mHealth) has huge potential to deliver preventative health services. However, there is paucity of literature on theoretical constructs, technical, practical, and regulatory considerations that enable delivery of such services. The objective of this study was to outline the key considerations in the development of a text message-based mHealth program; thus providing broad recommendations and guidance to future researchers designing similar programs. We describe the key considerations in designing the intervention with respect to functionality, technical infrastructure, data management, software components, regulatory requirements, and operationalization. We also illustrate some of the potential issues and decision points utilizing our experience of developing text message (short message service, SMS) management systems to support 2 large randomized controlled trials: TEXT messages to improve MEDication adherence & Secondary prevention (TEXTMEDS) and Tobacco, EXercise and dieT MEssages (TEXT ME). The steps identified in the development process were: (1) background research and development of the text message bank based on scientific evidence and disease-specific guidelines, (2) pilot testing with target audience and incorporating feedback, (3) software-hardware customization to enable delivery of complex personalized programs using prespecified algorithms, and (4) legal and regulatory considerations. Additional considerations in developing text message management systems include: balancing the use of customized versus preexisting software systems, the level of automation versus need for human inputs, monitoring, ensuring data security, interface flexibility, and the ability for upscaling. A merging of expertise in clinical and behavioral sciences, health and research data management systems, software engineering, and mobile phone regulatory requirements is essential to develop a platform to deliver and manage support programs to hundreds of participants simultaneously as in TEXT ME and TEXTMEDS trials. This research provides broad principles that may assist other researchers in developing mHealth programs. ©Jay Thakkar, Tony Barry, Aravinda Thiagalingam, Julie Redfern, Alistair L McEwan, Anthony Rodgers, Clara K Chow. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 15.11.2016.
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Prevalence of transcription promoters within archaeal operons and coding sequences
Koide, Tie; Reiss, David J; Bare, J Christopher; Pang, Wyming Lee; Facciotti, Marc T; Schmid, Amy K; Pan, Min; Marzolf, Bruz; Van, Phu T; Lo, Fang-Yin; Pratap, Abhishek; Deutsch, Eric W; Peterson, Amelia; Martin, Dan; Baliga, Nitin S
2009-01-01
Despite the knowledge of complex prokaryotic-transcription mechanisms, generalized rules, such as the simplified organization of genes into operons with well-defined promoters and terminators, have had a significant role in systems analysis of regulatory logic in both bacteria and archaea. Here, we have investigated the prevalence of alternate regulatory mechanisms through genome-wide characterization of transcript structures of ∼64% of all genes, including putative non-coding RNAs in Halobacterium salinarum NRC-1. Our integrative analysis of transcriptome dynamics and protein–DNA interaction data sets showed widespread environment-dependent modulation of operon architectures, transcription initiation and termination inside coding sequences, and extensive overlap in 3′ ends of transcripts for many convergently transcribed genes. A significant fraction of these alternate transcriptional events correlate to binding locations of 11 transcription factors and regulators (TFs) inside operons and annotated genes—events usually considered spurious or non-functional. Using experimental validation, we illustrate the prevalence of overlapping genomic signals in archaeal transcription, casting doubt on the general perception of rigid boundaries between coding sequences and regulatory elements. PMID:19536208
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Prevalence of transcription promoters within archaeal operons and coding sequences.
Koide, Tie; Reiss, David J; Bare, J Christopher; Pang, Wyming Lee; Facciotti, Marc T; Schmid, Amy K; Pan, Min; Marzolf, Bruz; Van, Phu T; Lo, Fang-Yin; Pratap, Abhishek; Deutsch, Eric W; Peterson, Amelia; Martin, Dan; Baliga, Nitin S
2009-01-01
Despite the knowledge of complex prokaryotic-transcription mechanisms, generalized rules, such as the simplified organization of genes into operons with well-defined promoters and terminators, have had a significant role in systems analysis of regulatory logic in both bacteria and archaea. Here, we have investigated the prevalence of alternate regulatory mechanisms through genome-wide characterization of transcript structures of approximately 64% of all genes, including putative non-coding RNAs in Halobacterium salinarum NRC-1. Our integrative analysis of transcriptome dynamics and protein-DNA interaction data sets showed widespread environment-dependent modulation of operon architectures, transcription initiation and termination inside coding sequences, and extensive overlap in 3' ends of transcripts for many convergently transcribed genes. A significant fraction of these alternate transcriptional events correlate to binding locations of 11 transcription factors and regulators (TFs) inside operons and annotated genes-events usually considered spurious or non-functional. Using experimental validation, we illustrate the prevalence of overlapping genomic signals in archaeal transcription, casting doubt on the general perception of rigid boundaries between coding sequences and regulatory elements.
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DGCA: A comprehensive R package for Differential Gene Correlation Analysis.
McKenzie, Andrew T; Katsyv, Igor; Song, Won-Min; Wang, Minghui; Zhang, Bin
2016-11-15
Dissecting the regulatory relationships between genes is a critical step towards building accurate predictive models of biological systems. A powerful approach towards this end is to systematically study the differences in correlation between gene pairs in more than one distinct condition. In this study we develop an R package, DGCA (for Differential Gene Correlation Analysis), which offers a suite of tools for computing and analyzing differential correlations between gene pairs across multiple conditions. To minimize parametric assumptions, DGCA computes empirical p-values via permutation testing. To understand differential correlations at a systems level, DGCA performs higher-order analyses such as measuring the average difference in correlation and multiscale clustering analysis of differential correlation networks. Through a simulation study, we show that the straightforward z-score based method that DGCA employs significantly outperforms the existing alternative methods for calculating differential correlation. Application of DGCA to the TCGA RNA-seq data in breast cancer not only identifies key changes in the regulatory relationships between TP53 and PTEN and their target genes in the presence of inactivating mutations, but also reveals an immune-related differential correlation module that is specific to triple negative breast cancer (TNBC). DGCA is an R package for systematically assessing the difference in gene-gene regulatory relationships under different conditions. This user-friendly, effective, and comprehensive software tool will greatly facilitate the application of differential correlation analysis in many biological studies and thus will help identification of novel signaling pathways, biomarkers, and targets in complex biological systems and diseases.
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Al-Nedawi, Khalid; Mian, M Firoz; Hossain, Nazia; Karimi, Khalil; Mao, Yu-Kang; Forsythe, Paul; Min, Kevin K; Stanisz, Andrew M; Kunze, Wolfgang A; Bienenstock, John
2015-02-01
Ingestion of a commensal bacteria, Lactobacillus rhamnosus JB-1, has potent immunoregulatory effects, and changes nerve-dependent colon migrating motor complexes (MMCs), enteric nerve function, and behavior. How these alterations occur is unknown. JB-1 microvesicles (MVs) are enriched for heat shock protein components such as chaperonin 60 heat-shock protein isolated from Escherichia coli (GroEL) and reproduce regulatory and neuronal effects in vitro and in vivo. Ingested labeled MVs were detected in murine Peyer's patch (PP) dendritic cells (DCs) within 18 h. After 3 d, PP and mesenteric lymph node DCs assumed a regulatory phenotype and increased functional regulatory CD4(+)25(+)Foxp3+ T cells. JB-1, MVs, and GroEL similarly induced phenotypic change in cocultured DCs via multiple pathways including C-type lectin receptors specific intercellular adhesion molecule-3 grabbing non-integrin-related 1 and Dectin-1, as well as TLR-2 and -9. JB-1 and MVs also decreased the amplitude of neuronally dependent MMCs in an ex vivo model of peristalsis. Gut epithelial, but not direct neuronal application of, MVs, replicated functional effects of JB-1 on in situ patch-clamped enteric neurons. GroEL and anti-TLR-2 were without effect in this system, suggesting the importance of epithelium neuron signaling and discrimination between pathways for bacteria-neuron and -immune communication. Together these results offer a mechanistic explanation of how Gram-positive commensals and probiotics may influence the host's immune and nervous systems. © FASEB.
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General and craniofacial development are complex adaptive processes influenced by diversity.
Brook, A H; O'Donnell, M Brook; Hone, A; Hart, E; Hughes, T E; Smith, R N; Townsend, G C
2014-06-01
Complex systems are present in such diverse areas as social systems, economies, ecosystems and biology and, therefore, are highly relevant to dental research, education and practice. A Complex Adaptive System in biological development is a dynamic process in which, from interacting components at a lower level, higher level phenomena and structures emerge. Diversity makes substantial contributions to the performance of complex adaptive systems. It enhances the robustness of the process, allowing multiple responses to external stimuli as well as internal changes. From diversity comes variation in outcome and the possibility of major change; outliers in the distribution enhance the tipping points. The development of the dentition is a valuable, accessible model with extensive and reliable databases for investigating the role of complex adaptive systems in craniofacial and general development. The general characteristics of such systems are seen during tooth development: self-organization; bottom-up emergence; multitasking; self-adaptation; variation; tipping points; critical phases; and robustness. Dental findings are compatible with the Random Network Model, the Threshold Model and also with the Scale Free Network Model which has a Power Law distribution. In addition, dental development shows the characteristics of Modularity and Clustering to form Hierarchical Networks. The interactions between the genes (nodes) demonstrate Small World phenomena, Subgraph Motifs and Gene Regulatory Networks. Genetic mechanisms are involved in the creation and evolution of variation during development. The genetic factors interact with epigenetic and environmental factors at the molecular level and form complex networks within the cells. From these interactions emerge the higher level tissues, tooth germs and mineralized teeth. Approaching development in this way allows investigation of why there can be variations in phenotypes from identical genotypes; the phenotype is the outcome of perturbations in the cellular systems and networks, as well as of the genotype. Understanding and applying complexity theory will bring about substantial advances not only in dental research and education but also in the organization and delivery of oral health care. © 2014 Australian Dental Association.
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Garp as a therapeutic target for modulation of T regulatory cell function.
Shevach, Ethan M
2017-02-01
Foxp3 + T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-β. As Treg-derived TGF-β may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity. Areas covered: This article will focus on 1) the role of Treg-derived TGF-β in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-β/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-β/GARP complex. Expert opinion: Two approaches are outlined for targeting the L-TGF-β1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-β1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-β1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF-β by Tregs at sites of chronic inflammation.
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The shifting functional balance of patents and drug regulation.
Eisenberg, R S
2001-01-01
Patents are often portrayed as the necessary reward to compensate pharmaceutical firms for the huge costs and risks associated with Food and Drug Administration (FDA)-mandated clinical trials of new drugs. But the relationship between the patent system and other regulation of drugs is more complex than this simple formulation suggests. Drug regulation operates in tandem with patents to make proprietary products profitable, and patents themselves increasingly threaten to limit profitability by diverting profits elsewhere. At the same time, resistance to high drug prices is prompting new state and federal regulatory initiatives that threaten to reduce the value of drug patents. The distinctive intertwining of patents with other regulatory regimes and the shifting role of patents in the biopharmaceutical sector call into question how this singular success story for innovation policy will play out in the future.
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Mohamed Salleh, Faridah Hani; Arif, Shereena Mohd; Zainudin, Suhaila; Firdaus-Raih, Mohd
2015-12-01
A gene regulatory network (GRN) is a large and complex network consisting of interacting elements that, over time, affect each other's state. The dynamics of complex gene regulatory processes are difficult to understand using intuitive approaches alone. To overcome this problem, we propose an algorithm for inferring the regulatory interactions from knock-out data using a Gaussian model combines with Pearson Correlation Coefficient (PCC). There are several problems relating to GRN construction that have been outlined in this paper. We demonstrated the ability of our proposed method to (1) predict the presence of regulatory interactions between genes, (2) their directionality and (3) their states (activation or suppression). The algorithm was applied to network sizes of 10 and 50 genes from DREAM3 datasets and network sizes of 10 from DREAM4 datasets. The predicted networks were evaluated based on AUROC and AUPR. We discovered that high false positive values were generated by our GRN prediction methods because the indirect regulations have been wrongly predicted as true relationships. We achieved satisfactory results as the majority of sub-networks achieved AUROC values above 0.5. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Maternal Prenatal Stress and Infant Regulatory Capacity in Mexican Americans
Lin, Betty; Crnic, Keith A.; Luecken, Linda J.; Gonzales, Nancy A.
2014-01-01
The early postpartum period lays important groundwork for later self-regulation as infants' dispositional traits interact with caregivers' co-regulatory behaviors to produce the earliest forms of self-regulation. Although emerging literature suggests that fetal exposure to maternal stress may be integral in determining child self-regulatory capacity, the complex pathways that characterize these early developmental processes remain unclear. The current study considers these complex, transactional processes in a low income, Mexican American sample. Data were collected from 295 Mexican American infants and their mothers during prenatal, 6- and 12-week postpartum home interviews. Mother reports of stress were obtained prenatally, and mother reports of infant temperament were obtained at 6 weeks. Observer ratings of maternal sensitivity and infant regulatory behaviors were obtained at the 6- and 12-week time points. Study results indicate that prenatal stress predicts higher levels of infant negativity and surgency, both of which directly or interactively predict later engagement in regulatory behaviors. Unexpectedly, prenatal stress also predicted more engagement in orienting, but not self-comforting behaviors. Advancing understandings about the nature of these developmental pathways may have significant implications for targets of early intervention in this high risk population. PMID:25113917
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Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.
Craddock, Travis J A; Del Rosario, Ryan R; Rice, Mark; Zysman, Joel P; Fletcher, Mary Ann; Klimas, Nancy G; Broderick, Gordon
2015-01-01
Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body's principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-01-17
... Symbols, 2) increase the maker fee for complex orders that trade against Priority Customer complex orders... provides volume-based tiered rebates for Priority Customer complex orders in the Select Symbols (excluding... orders trade with non-Priority Customer orders in the complex order book. In the Select Symbols, the...
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Carden, Tony; Goode, Natassia; Read, Gemma J M; Salmon, Paul M
2017-03-15
Like most work systems, the domain of adventure activities has seen a series of serious incidents and subsequent calls to improve regulation. Safety regulation systems aim to promote safety and reduce accidents. However, there is scant evidence they have led to improved safety outcomes. In fact there is some evidence that the poor integration of regulatory system components has led to adverse safety outcomes in some contexts. Despite this, there is an absence of methods for evaluating regulatory and compliance systems. This article argues that sociotechnical systems theory and methods provide a suitable framework for evaluating regulatory systems. This is demonstrated through an analysis of a recently introduced set of adventure activity regulations. Work Domain Analysis (WDA) was used to describe the regulatory system in terms of its functional purposes, values and priority measures, purpose-related functions, object-related processes and cognitive objects. This allowed judgement to be made on the nature of the new regulatory system and on the constraints that may impact its efficacy following implementation. Importantly, the analysis suggests that the new system's functional purpose of ensuring safe activities is not fully supported in terms of the functions and objects available to fulfil them. Potential improvements to the design of the system are discussed along with the implications for regulatory system design and evaluation across the safety critical domains generally. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Setting monitoring objectives for landscape-size areas
Craig M. Olson; Dean Angelides
2000-01-01
The setting of objectives for monitoring schemes for landscape-size areas should be a complex task in today's regulatory and sociopolitical atmosphere. The technology available today, the regulatory environment, and the sociopolitical considerations require multiresource inventory and monitoring schemes, whether tile ownership is industrial or for preservation....
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The interaction between intellectual property and drug regulatory systems: global perspectives.
Madden, Edward A
2007-02-01
Regulatory compliance in the development, production and sale of new drugs accounts for the largest single expense in bringing a drug product to market. To justify developmental and regulatory compliance costs, drug innovators turn to the intellectual property (IP) system to provide a means for securing returns on investment. Because the drug regulatory system in most countries operates in isolation of the IP system, one of the greatest challenges facing the pharmaceutical industry is the extent to which IP rights can be managed against an independent drug regulatory system. Many regulatory bodies in developed countries have sought to ensure a compromise between the rights of generic companies and IP owners by including safeguards in the regulatory framework, such as patent linking and data protection; however, these efforts are yet to be applied in some of the biggest potential drug markets in emerging economies.
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Koning, Anne; Kuhnle, Gunter G.C.; Nagy, Peter; Bianco, Christopher L.; Pasch, Andreas; Wink, David A.; Fukuto, Jon M.; Jackson, Alan A.; van Goor, Harry; Olson, Kenneth R.
2017-01-01
Abstract Significance: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete. Recent Advances: Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept defined as the reactive species interactome (RSI). The RSI is a primeval multilevel redox regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stressors to enhance fitness and resilience at the local and whole-organism level. Critical Issues: To better characterize the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems, and effects on cellular, organ, and whole-organism bioenergetics using system-level/network analyses. Future Directions: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other forms of stress will provide new prevention/intervention opportunities for personalized medicine. Antioxid. Redox Signal. 27, 684–712. PMID:28398072
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Industrial Adoption of Model-Based Systems Engineering: Challenges and Strategies
NASA Astrophysics Data System (ADS)
Maheshwari, Apoorv
As design teams are becoming more globally integrated, one of the biggest challenges is to efficiently communicate across the team. The increasing complexity and multi-disciplinary nature of the products are also making it difficult to keep track of all the information generated during the design process by these global team members. System engineers have identified Model-based Systems Engineering (MBSE) as a possible solution where the emphasis is placed on the application of visual modeling methods and best practices to systems engineering (SE) activities right from the beginning of the conceptual design phases through to the end of the product lifecycle. Despite several advantages, there are multiple challenges restricting the adoption of MBSE by industry. We mainly consider the following two challenges: a) Industry perceives MBSE just as a diagramming tool and does not see too much value in MBSE; b) Industrial adopters are skeptical if the products developed using MBSE approach will be accepted by the regulatory bodies. To provide counter evidence to the former challenge, we developed a generic framework for translation from an MBSE tool (Systems Modeling Language, SysML) to an analysis tool (Agent-Based Modeling, ABM). The translation is demonstrated using a simplified air traffic management problem and provides an example of a potential quite significant value: the ability to use MBSE representations directly in an analysis setting. For the latter challenge, we are developing a reference model that uses SysML to represent a generic infusion pump and SE process for planning, developing, and obtaining regulatory approval of a medical device. This reference model demonstrates how regulatory requirements can be captured effectively through model-based representations. We will present another case study at the end where we will apply the knowledge gained from both case studies to a UAV design problem.
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Khan, Mateen A; Ma, Jia; Walden, William E; Merrick, William C; Theil, Elizabeth C; Goss, Dixie J
2014-06-01
Metal ion binding was previously shown to destabilize IRE-RNA/IRP1 equilibria and enhanced IRE-RNA/eIF4F equilibria. In order to understand the relative importance of kinetics and stability, we now report rapid rates of protein/RNA complex assembly and dissociation for two IRE-RNAs with IRP1, and quantitatively different metal ion response kinetics that coincide with the different iron responses in vivo. kon, for FRT IRE-RNA binding to IRP1 was eight times faster than ACO2 IRE-RNA. Mn(2+) decreased kon and increased koff for IRP1 binding to both FRT and ACO2 IRE-RNA, with a larger effect for FRT IRE-RNA. In order to further understand IRE-mRNA regulation in terms of kinetics and stability, eIF4F kinetics with FRT IRE-RNA were determined. kon for eIF4F binding to FRT IRE-RNA in the absence of metal ions was 5-times slower than the IRP1 binding to FRT IRE-RNA. Mn(2+) increased the association rate for eIF4F binding to FRT IRE-RNA, so that at 50 µM Mn(2+) eIF4F bound more than 3-times faster than IRP1. IRP1/IRE-RNA complex has a much shorter life-time than the eIF4F/IRE-RNA complex, which suggests that both rate of assembly and stability of the complexes are important, and that allows this regulatory system to respond rapidly to change in cellular iron. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Analysis of potential trade-offs in regulation of disinfection by-products
DOE Office of Scientific and Technical Information (OSTI.GOV)
Cromwell, J.E.; Zhang, X.; Regli, S.
1992-11-01
Executive Order 12291 requires the preparation of a Regulatory Impact Analysis (RIA) on all new major federal regulations. The goal of an RIA is to develop and organize information on benefits, costs, and economic impacts so as to clarify trade-offs among alternative regulatory options. This paper outlines explicit methodology for assessing the technical potential for risk-risk tradeoffs. The strategies used to cope with complexities and uncertainties in developing the Disinfection By-Products Regulatory Analysis Model are explained. Results are presented and discussed in light of uncertainties, and in light of the analytical requirements for regulatory impact analysis.
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Structural Basis of Rap Phosphatase Inhibition by Phr Peptides
Gallego del Sol, Francisca; Marina, Alberto
2013-01-01
Two-component systems, composed of a sensor histidine kinase and an effector response regulator (RR), are the main signal transduction devices in bacteria. In Bacillus, the Rap protein family modulates complex signaling processes mediated by two-component systems, such as competence, sporulation, or biofilm formation, by inhibiting the RR components involved in these pathways. Despite the high degree of sequence homology, Rap proteins exert their activity by two completely different mechanisms of action: inducing RR dephosphorylation or blocking RR binding to its target promoter. However the regulatory mechanism involving Rap proteins is even more complex since Rap activity is antagonized by specific signaling peptides (Phr) through a mechanism that remains unknown at the molecular level. Using X-ray analyses, we determined the structure of RapF, the anti-activator of competence RR ComA, alone and in complex with its regulatory peptide PhrF. The structural and functional data presented herein reveal that peptide PhrF blocks the RapF-ComA interaction through an allosteric mechanism. PhrF accommodates in the C-terminal tetratricopeptide repeat domain of RapF by inducing its constriction, a conformational change propagated by a pronounced rotation to the N-terminal ComA-binding domain. This movement partially disrupts the ComA binding site by triggering the ComA disassociation, whose interaction with RapF is also sterically impaired in the PhrF-induced conformation of RapF. Sequence analyses of the Rap proteins, guided by the RapF-PhrF structure, unveil the molecular basis of Phr recognition and discrimination, allowing us to relax the Phr specificity of RapF by a single residue change. PMID:23526880
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Varas, Macarena; Valdivieso, Camilo; Mauriaca, Cecilia; Ortíz-Severín, Javiera; Paradela, Alberto; Poblete-Castro, Ignacio; Cabrera, Ricardo; Chávez, Francisco P
2017-04-01
Polyphosphate (polyP) is a linear biopolymer found in all living cells. In bacteria, mutants lacking polyphosphate kinase 1 (PPK1), the enzyme responsible for synthesis of most polyP, have many structural and functional defects. However, little is known about the causes of these pleiotropic alterations. The link between ppk1 deletion and those numerous phenotypes observed can be the result of complex molecular interactions that can be elucidated via a systems biology approach. By integrating different omics levels (transcriptome, proteome and phenome), we described the functioning of various metabolic pathways among Escherichia coli polyphosphate mutant strains (Δppk1, Δppx, and ΔpolyP). Bioinformatic analyses reveal the complex metabolic and regulatory bases of the phenotypes unique to polyP mutants. Our results suggest that during polyP deficiency (Δppk1 mutant), metabolic pathways needed for energy supply are up-regulated, including fermentation, aerobic and anaerobic respiration. Transcriptomic and q-proteomic contrasting changes between Δppk1 and Δppx mutant strains were observed in those central metabolic pathways and confirmed by using Phenotypic microarrays. In addition, our results suggest a regulatory connection between polyP, second messenger metabolism, alternative Sigma/Anti-Sigma factors and type-II toxin-antitoxin (TA) systems. We suggest a broader role for polyP via regulation of ATP-dependent proteolysis of type II toxin-antitoxin system and alternative Sigma/Anti-Sigma factors, that could explain the multiple structural and functional deficiencies described due to alteration of polyP metabolism. Understanding the interplay of polyP in bacterial metabolism using a systems biology approach can help to improve design of novel antimicrobials toward pathogens. Copyright © 2017 Elsevier B.V. All rights reserved.
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Variable-free exploration of stochastic models: a gene regulatory network example.
Erban, Radek; Frewen, Thomas A; Wang, Xiao; Elston, Timothy C; Coifman, Ronald; Nadler, Boaz; Kevrekidis, Ioannis G
2007-04-21
Finding coarse-grained, low-dimensional descriptions is an important task in the analysis of complex, stochastic models of gene regulatory networks. This task involves (a) identifying observables that best describe the state of these complex systems and (b) characterizing the dynamics of the observables. In a previous paper [R. Erban et al., J. Chem. Phys. 124, 084106 (2006)] the authors assumed that good observables were known a priori, and presented an equation-free approach to approximate coarse-grained quantities (i.e., effective drift and diffusion coefficients) that characterize the long-time behavior of the observables. Here we use diffusion maps [R. Coifman et al., Proc. Natl. Acad. Sci. U.S.A. 102, 7426 (2005)] to extract appropriate observables ("reduction coordinates") in an automated fashion; these involve the leading eigenvectors of a weighted Laplacian on a graph constructed from network simulation data. We present lifting and restriction procedures for translating between physical variables and these data-based observables. These procedures allow us to perform equation-free, coarse-grained computations characterizing the long-term dynamics through the design and processing of short bursts of stochastic simulation initialized at appropriate values of the data-based observables.
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Regulating healthcare complaints: a literature review.
Beaupert, Fleur; Carney, Terry; Chiarella, Mary; Satchell, Claudette; Walton, Merrilyn; Bennett, Belinda; Kelly, Patrick
2014-01-01
The purpose of this paper is to explore approaches to the regulation of healthcare complaints and disciplinary processes. A literature review was conducted across Medline, Sociological Abstracts, Web of Science, Google Scholar and the health, law and social sciences collections of Informit, using terms tapping both the complaints process and regulation generally. A total of 118 papers dealing with regulation of health complaints or disciplinary proceedings were located. The review reveals a shift away from self-regulation towards greater external oversight, including innovative regulatory approaches including "networked governance and flexible or "responsive" regulation. It reports growing interest in adoption of strategic and responsive approaches to health complaints governance, by rejecting traditional legal forms in favor of more strategic and responsive forms, taking account of the complexity of adverse health events by tailoring responses to individual circumstances of complainants and their local environments. The challenge of how to collect and harness complaints data to improve the quality of healthcare at a systemic level warrants further research. Scope also exists for researching health complaints commissions and other "meta-regulatory" bodies to explore how to make these processes fairer and better able to meet the complex needs of complainants, health professionals, health services and society.
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Wise, Alexandria; Schatoff, Emma; Flores, Julian; Hua, Shao-Ying; Ueda, Atsushi; Wu, Chun-Fang; Venkatesh, Tadmiri
2013-11-01
The assembly of functional synapses requires the orchestration of the synthesis and degradation of a multitude of proteins. Protein degradation and modification by the conserved ubiquitination pathway has emerged as a key cellular regulatory mechanism during nervous system development and function (Kwabe and Brose, 2011). The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin ligase complex primarily characterized for its role in the regulation of mitosis (Peters, 2002). In recent years, a role for APC/C in nervous system development and function has been rapidly emerging (Stegmuller and Bonni, 2005; Li et al., 2008). In the mammalian central nervous system the activator subunit, APC/C-Cdh1, has been shown to be a regulator of axon growth and dendrite morphogenesis (Konishi et al., 2004). In the Drosophila peripheral nervous system (PNS), APC2, a ligase subunit of the APC/C complex has been shown to regulate synaptic bouton size and activity (van Roessel et al., 2004). To investigate the role of APC/C-Cdh1 at the synapse we examined loss-of-function mutants of Rap/Fzr (Retina aberrant in pattern/Fizzy related), a Drosophila homolog of the mammalian Cdh1 during the development of the larval neuromuscular junction in Drosophila. Our cell biological, ultrastructural, electrophysiological, and behavioral data showed that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function as well as locomotion defects. Data presented here show changes in size and morphology of synaptic boutons, and, muscle tissue organization. Electrophysiological experiments show that loss-of-function mutants exhibit increased frequency of spontaneous miniature synaptic potentials, indicating a higher rate of spontaneous synaptic vesicle fusion events. In addition, larval locomotion and peristaltic movement were also impaired. These findings suggest a role for Drosophila APC/C-Cdh1 mediated ubiquitination in regulating synaptic morphology, function and integrity of muscle structure in the peripheral nervous system. Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.
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Serotoninergic and Circadian Systems: Driving Mammary Gland Development and Function
Suárez-Trujillo, Aridany; Casey, Theresa M.
2016-01-01
Since lactation is one of the most metabolically demanding states in adult female mammals, beautifully complex regulatory mechanisms are in place to time lactation to begin after birth and cease when the neonate is weaned. Lactation is regulated by numerous different homeorhetic factors, all of them tightly coordinated with the demands of milk production. Emerging evidence support that among these factors are the serotonergic and circadian clock systems. Here we review the serotoninergic and circadian clock systems and their roles in the regulation of mammary gland development and lactation physiology. We conclude by presenting our hypothesis that these two systems interact to accommodate the metabolic demands of lactation and thus adaptive changes in these systems occur to maintain mammary and systemic homeostasis through the reproductive cycles of female mammals. PMID:27471474
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Deutscher, Josef; Francke, Christof; Postma, Pieter W.
2006-01-01
The phosphoenolpyruvate(PEP):carbohydrate phosphotransferase system (PTS) is found only in bacteria, where it catalyzes the transport and phosphorylation of numerous monosaccharides, disaccharides, amino sugars, polyols, and other sugar derivatives. To carry out its catalytic function in sugar transport and phosphorylation, the PTS uses PEP as an energy source and phosphoryl donor. The phosphoryl group of PEP is usually transferred via four distinct proteins (domains) to the transported sugar bound to the respective membrane component(s) (EIIC and EIID) of the PTS. The organization of the PTS as a four-step phosphoryl transfer system, in which all P derivatives exhibit similar energy (phosphorylation occurs at histidyl or cysteyl residues), is surprising, as a single protein (or domain) coupling energy transfer and sugar phosphorylation would be sufficient for PTS function. A possible explanation for the complexity of the PTS was provided by the discovery that the PTS also carries out numerous regulatory functions. Depending on their phosphorylation state, the four proteins (domains) forming the PTS phosphorylation cascade (EI, HPr, EIIA, and EIIB) can phosphorylate or interact with numerous non-PTS proteins and thereby regulate their activity. In addition, in certain bacteria, one of the PTS components (HPr) is phosphorylated by ATP at a seryl residue, which increases the complexity of PTS-mediated regulation. In this review, we try to summarize the known protein phosphorylation-related regulatory functions of the PTS. As we shall see, the PTS regulation network not only controls carbohydrate uptake and metabolism but also interferes with the utilization of nitrogen and phosphorus and the virulence of certain pathogens. PMID:17158705
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USDA-ARS?s Scientific Manuscript database
Puberty is a complex physiological event by which animals mature into an adult capable of sexual reproduction. In order to enhance our understanding of the genes and regulatory pathways and networks involved in puberty, we characterized the transcriptome of five reproductive tissues (i.e., hypothal...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-11
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-64805; File No. SR-ISE-2011-30] Self-Regulatory Organizations; International Securities Exchange, LLC; Order Approving a Proposed Rule Change Relating to Complex Orders July 5, 2011. I. Introduction On May 23, 2011, the International Securities Exchange, LLC...
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2011-10-19
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65548; File No. SR-ISE-2011-39] Self-Regulatory Organizations; International Securities Exchange, LLC; Order Approving a Proposed Rule Change Relating to Complex Orders October 13, 2011. I. Introduction On July 1, 2011, the International Securities Exchange...
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Biochemical Reconstitution of the WAVE Regulatory Complex
Chen, Baoyu; Padrick, Shae B.; Henry, Lisa; Rosen, Michael K.
2014-01-01
The WAVE regulatory complex (WRC) is a 400-KDa heteropentameric protein assembly that plays a central role in controlling actin cytoskeletal dynamics in many cellular processes. The WRC acts by integrating diverse cellular cues and stimulating the actin nucleating activity of the Arp2/3 complex at membranes. Biochemical and biophysical studies of the underlying mechanisms of these processes require large amounts of purified WRC. Recent success in recombinant expression, reconstitution, purification and crystallization of the WRC has greatly advanced our understanding of the inhibition, activation and membrane recruitment mechanisms of this complex. But many important questions remain to be answered. Here we summarize and update the methods developed in our laboratory, which allow reliable and flexible production of tens of milligrams of recombinant WRC of crystallographic quality, sufficient for many biochemical and structural studies. PMID:24630101
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The identification of cis-regulatory elements: A review from a machine learning perspective.
Li, Yifeng; Chen, Chih-Yu; Kaye, Alice M; Wasserman, Wyeth W
2015-12-01
The majority of the human genome consists of non-coding regions that have been called junk DNA. However, recent studies have unveiled that these regions contain cis-regulatory elements, such as promoters, enhancers, silencers, insulators, etc. These regulatory elements can play crucial roles in controlling gene expressions in specific cell types, conditions, and developmental stages. Disruption to these regions could contribute to phenotype changes. Precisely identifying regulatory elements is key to deciphering the mechanisms underlying transcriptional regulation. Cis-regulatory events are complex processes that involve chromatin accessibility, transcription factor binding, DNA methylation, histone modifications, and the interactions between them. The development of next-generation sequencing techniques has allowed us to capture these genomic features in depth. Applied analysis of genome sequences for clinical genetics has increased the urgency for detecting these regions. However, the complexity of cis-regulatory events and the deluge of sequencing data require accurate and efficient computational approaches, in particular, machine learning techniques. In this review, we describe machine learning approaches for predicting transcription factor binding sites, enhancers, and promoters, primarily driven by next-generation sequencing data. Data sources are provided in order to facilitate testing of novel methods. The purpose of this review is to attract computational experts and data scientists to advance this field. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.
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Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.
Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M
2013-05-10
A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.
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Systems Biology and Biomechanical Model of Heart Failure
Louridas, George E; Lourida, Katerina G
2012-01-01
Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. PMID:22935019
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Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer: A Systems Approach
Shahab, Shubin W.; Matyunina, Lilya V.; Mezencev, Roman; Walker, L. DeEtte; Bowen, Nathan J.; Benigno, Benedict B.; McDonald, John F.
2011-01-01
MicroRNAs (miRNAs) are short (∼22 nucleotides) regulatory RNAs that can modulate gene expression and are aberrantly expressed in many diseases including cancer. Previous studies have shown that miRNAs inhibit the translation and facilitate the degradation of their targeted messenger RNAs (mRNAs) making them attractive candidates for use in cancer therapy. However, the potential clinical utility of miRNAs in cancer therapy rests heavily upon our ability to understand and accurately predict the consequences of fluctuations in levels of miRNAs within the context of complex tumor cells. To evaluate the predictive power of current models, levels of miRNAs and their targeted mRNAs were measured in laser captured micro-dissected (LCM) ovarian cancer epithelial cells (CEPI) and compared with levels present in ovarian surface epithelial cells (OSE). We found that the predicted inverse correlation between changes in levels of miRNAs and levels of their mRNA targets held for only ∼11% of predicted target mRNAs. We demonstrate that this low inverse correlation between changes in levels of miRNAs and their target mRNAs in vivo is not merely an artifact of inaccurate miRNA target predictions but the likely consequence of indirect cellular processes that modulate the regulatory effects of miRNAs in vivo. Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basis of these complexities in cancer cells before the therapeutic potential of miRNAs can be fully realized. PMID:21811625
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-20
... Priority Customer complex orders that they send to the Exchange in these symbols. In the Select Symbols, the Exchange currently provides a base rebate of $0.34 per contract, per leg, for Priority Customer complex orders when these orders trade with non-Priority Customer complex orders in the complex order book...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-06-24
... Market Maker Risk Parameters and Complex Orders June 18, 2013. Pursuant to Section 19(b)(1) of the... makers to enter values in the Exchange-provided risk parameters and by limiting the types of complex... complex instruments on the complex order book. Market makers establish a time frame during which the...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-06-05
... Amending NYSE MKT Rule 980NY, To Remove Provisions Governing How the Complex Matching Engine Handles Electronic Complex Orders That Contain a Stock Leg May 30, 2013. Pursuant to Section 19(b)(1)\\1\\ of the... governing how the Complex Matching Engine (``CME'') handles Electronic Complex Orders that contain a stock...
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47 CFR 101.1309 - Regulatory status.
Code of Federal Regulations, 2010 CFR
2010-10-01
... party may challenge the regulatory status granted an MAS licensee. System License Requirements ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Regulatory status. 101.1309 Section 101.1309... SERVICES Multiple Address Systems General Provisions § 101.1309 Regulatory status. (a) The Commission will...
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A sigma factor toolbox for orthogonal gene expression in Escherichia coli
Van Brempt, Maarten; Van Nerom, Katleen; Van Hove, Bob; Maertens, Jo; De Mey, Marjan; Charlier, Daniel
2018-01-01
Abstract Synthetic genetic sensors and circuits enable programmable control over timing and conditions of gene expression and, as a result, are increasingly incorporated into the control of complex and multi-gene pathways. Size and complexity of genetic circuits are growing, but stay limited by a shortage of regulatory parts that can be used without interference. Therefore, orthogonal expression and regulation systems are needed to minimize undesired crosstalk and allow for dynamic control of separate modules. This work presents a set of orthogonal expression systems for use in Escherichia coli based on heterologous sigma factors from Bacillus subtilis that recognize specific promoter sequences. Up to four of the analyzed sigma factors can be combined to function orthogonally between each other and toward the host. Additionally, the toolbox is expanded by creating promoter libraries for three sigma factors without loss of their orthogonal nature. As this set covers a wide range of transcription initiation frequencies, it enables tuning of multiple outputs of the circuit in response to different sensory signals in an orthogonal manner. This sigma factor toolbox constitutes an interesting expansion of the synthetic biology toolbox and may contribute to the assembly of more complex synthetic genetic systems in the future. PMID:29361130
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Cestari, Igor; Kalidas, Savitha; Monnerat, Severine; Anupama, Atashi; Phillips, Margaret A.
2013-01-01
The genes for all cytoplasmic and potentially all mitochondrial aminoacyl-tRNA synthetases (aaRSs) were identified, and all those tested by RNA interference were found to be essential for the growth of Trypanosoma brucei. Some of these enzymes were localized to the cytoplasm or mitochondrion, but most were dually localized to both cellular compartments. Cytoplasmic T. brucei aaRSs were organized in a multiprotein complex in both bloodstream and procyclic forms. The multiple aminoacyl-tRNA synthetase (MARS) complex contained at least six aaRS enzymes and three additional non-aaRS proteins. Steady-state kinetic studies showed that association in the MARS complex enhances tRNA-aminoacylation efficiency, which is in part dependent on a MARS complex-associated protein (MCP), named MCP2, that binds tRNAs and increases their aminoacylation by the complex. Conditional repression of MCP2 in T. brucei bloodstream forms resulted in reduced parasite growth and infectivity in mice. Thus, association in a MARS complex enhances tRNA-aminoacylation and contributes to parasite fitness. The MARS complex may be part of a cellular regulatory system and a target for drug development. PMID:24126051
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Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction
Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T.; Dufour, Eric
2012-01-01
Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an “emergency shutdown” system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. PMID:23007390
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Gene network analysis: from heart development to cardiac therapy.
Ferrazzi, Fulvia; Bellazzi, Riccardo; Engel, Felix B
2015-03-01
Networks offer a flexible framework to represent and analyse the complex interactions between components of cellular systems. In particular gene networks inferred from expression data can support the identification of novel hypotheses on regulatory processes. In this review we focus on the use of gene network analysis in the study of heart development. Understanding heart development will promote the elucidation of the aetiology of congenital heart disease and thus possibly improve diagnostics. Moreover, it will help to establish cardiac therapies. For example, understanding cardiac differentiation during development will help to guide stem cell differentiation required for cardiac tissue engineering or to enhance endogenous repair mechanisms. We introduce different methodological frameworks to infer networks from expression data such as Boolean and Bayesian networks. Then we present currently available temporal expression data in heart development and discuss the use of network-based approaches in published studies. Collectively, our literature-based analysis indicates that gene network analysis constitutes a promising opportunity to infer therapy-relevant regulatory processes in heart development. However, the use of network-based approaches has so far been limited by the small amount of samples in available datasets. Thus, we propose to acquire high-resolution temporal expression data to improve the mathematical descriptions of regulatory processes obtained with gene network inference methodologies. Especially probabilistic methods that accommodate the intrinsic variability of biological systems have the potential to contribute to a deeper understanding of heart development.
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Biological Signal Processing with a Genetic Toggle Switch
Hillenbrand, Patrick; Fritz, Georg; Gerland, Ulrich
2013-01-01
Complex gene regulation requires responses that depend not only on the current levels of input signals but also on signals received in the past. In digital electronics, logic circuits with this property are referred to as sequential logic, in contrast to the simpler combinatorial logic without such internal memory. In molecular biology, memory is implemented in various forms such as biochemical modification of proteins or multistable gene circuits, but the design of the regulatory interface, which processes the input signals and the memory content, is often not well understood. Here, we explore design constraints for such regulatory interfaces using coarse-grained nonlinear models and stochastic simulations of detailed biochemical reaction networks. We test different designs for biological analogs of the most versatile memory element in digital electronics, the JK-latch. Our analysis shows that simple protein-protein interactions and protein-DNA binding are sufficient, in principle, to implement genetic circuits with the capabilities of a JK-latch. However, it also exposes fundamental limitations to its reliability, due to the fact that biological signal processing is asynchronous, in contrast to most digital electronics systems that feature a central clock to orchestrate the timing of all operations. We describe a seemingly natural way to improve the reliability by invoking the master-slave concept from digital electronics design. This concept could be useful to interpret the design of natural regulatory circuits, and for the design of synthetic biological systems. PMID:23874595
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Goldie, Belinda J; Barnett, Michelle M; Cairns, Murray J
2014-01-01
The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human/primate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al. (2000) using integrative whole-genome gene and microRNA (miRNA) expression analysis. We report that ATRA-BDNF induced significant increases in expression of key synaptic genes, brain-specific miRNA and miRNA biogenesis machinery, and in AChE activity, compared with ATRA alone. Functional annotation clustering associated BDNF more significantly with neuronal terms, and with synaptic terms not found in ATRA-only clusters. While our results support use of SH-SY5Y as a neuronal model, we advocate considered selection of the differentiation agent/s relative to the system being modeled.
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Modeling static and dynamic human cardiovascular responses to exercise.
Stremel, R W; Bernauer, E M; Harter, L W; Schultz, R A; Walters, R F
1975-08-01
A human performance model has been developed and described [9] which portrays the human circulatory, thermo regulatory and energy-exchange systems as an intercoupled set. In this model, steady state or static relationships are used to describe oxygen consumption and blood flow. For example, heart rate (HTRT) is calculated as a function of the oxygen and the thermo-regulatory requirements of each body compartment, using the steady state work values of cardiac output (CO, sum of all compartment blood flows) and stroke volume (SV, assumed maximal after 40% maximal oxygen consumption): HTRT=CO/SV. The steady state model has proven to be an acceptable first approximation, but the inclusion of transient characteristics are essential in describing the overall systems' adjustment to exercise stress. In the present study, the dynamic transient characteristics of heart rate, stroke volume and cardiac output were obtained from experiments utilizing step and sinusoidal forcing of work. The gain and phase relationships reveal a probable first order system with a six minute time constant, and are utilized to model the transient characteristics of these parameters. This approach leads to a more complex model but a more accurate representation of the physiology involved. The instrumentation and programming essential to these experiments are described.
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Quality of clinical trials: A moving target
Bhatt, Arun
2011-01-01
Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials. PMID:22145122
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Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C
2016-01-01
Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics. DOI: http://dx.doi.org/10.7554/eLife.17096.001 PMID:27482653
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Weidmann, Chase A.; Qiu, Chen; Arvola, René M.; ...
2016-08-02
Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Weidmann, Chase A.; Qiu, Chen; Arvola, René M.
Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less
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National Strategy for Modernizing the Regulatory System for Biotechnology Products
This National Strategy for Modernizing the Regulatory System for Biotechnology Products sets forth a vision for ensuring that the federal regulatory system is prepared to efficiently assess the risks, if any, of the future products of biotechnology.
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NASA Astrophysics Data System (ADS)
Doursat, René
Exploding growth growth in computational systems forces us to gradually replace rigid design and control with decentralization and autonomy. Information technologies will progress, instead, by"meta-designing" mechanisms of system self-assembly, self-regulation and evolution. Nature offers a great variety of efficient complex systems, in which numerous small elements form large-scale, adaptive patterns. The new engineering challenge is to recreate this self-organization and let it freely generate innovative designs under guidance. This article presents an original model of artificial system growth inspired by embryogenesis. A virtual organism is a lattice of cells that proliferate, migrate and self-pattern into differentiated domains. Each cell's fate is controlled by an internal gene regulatory network network. Embryomorphic engineering emphasizes hyperdistributed architectures, and their development as a prerequisite of evolutionary design.
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Grassi, Angela; Di Camillo, Barbara; Ciccarese, Francesco; Agnusdei, Valentina; Zanovello, Paola; Amadori, Alberto; Finesso, Lorenzo; Indraccolo, Stefano; Toffolo, Gianna Maria
2016-03-12
Inference of gene regulation from expression data may help to unravel regulatory mechanisms involved in complex diseases or in the action of specific drugs. A challenging task for many researchers working in the field of systems biology is to build up an experiment with a limited budget and produce a dataset suitable to reconstruct putative regulatory modules worth of biological validation. Here, we focus on small-scale gene expression screens and we introduce a novel experimental set-up and a customized method of analysis to make inference on regulatory modules starting from genetic perturbation data, e.g. knockdown and overexpression data. To illustrate the utility of our strategy, it was applied to produce and analyze a dataset of quantitative real-time RT-PCR data, in which interferon-α (IFN-α) transcriptional response in endothelial cells is investigated by RNA silencing of two candidate IFN-α modulators, STAT1 and IFIH1. A putative regulatory module was reconstructed by our method, revealing an intriguing feed-forward loop, in which STAT1 regulates IFIH1 and they both negatively regulate IFNAR1. STAT1 regulation on IFNAR1 was object of experimental validation at the protein level. Detailed description of the experimental set-up and of the analysis procedure is reported, with the intent to be of inspiration for other scientists who want to realize similar experiments to reconstruct gene regulatory modules starting from perturbations of possible regulators. Application of our approach to the study of IFN-α transcriptional response modulators in endothelial cells has led to many interesting novel findings and new biological hypotheses worth of validation.
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77 FR 55877 - Initial Test Program of Condensate and Feedwater Systems for Light-Water Reactors
Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-11
...-492- 3668; email: [email protected] . NRC's Agencywide Documents Access and Management System... Systems for Light-Water Reactors AGENCY: Nuclear Regulatory Commission. ACTION: Regulatory guide; issuance... Systems for Boiling Water Reactor Power Plants.'' This regulatory guide is being revised to: (1) Expand...
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Global Gene Expression Profiles Identify Metastasis Regulatory Networks | Center for Cancer Research
Metastasis is a systemic disease in which cancer cells break away from a tumor and migrate to other parts of the body, usually via the blood or lymphatic systems, to form new tumors. Metastatic tumors are difficult to treat and account for the majority of cancer-related deaths. Susceptibility to metastasis is known to have a genetic component, with some individuals more predisposed than others. However, because of the complex interchange between random genomic and epigenetic events that contribute to the disease, characterization of individual genes or small numbers of genes is not sufficient to understand the processes leading up to metastasis.
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3D structure of eukaryotic flagella/cilia by cryo-electron tomography.
Ishikawa, Takashi
2013-01-01
Flagella/cilia are motile organelles with more than 400 proteins. To understand the mechanism of such complex systems, we need methods to describe molecular arrange-ments and conformations three-dimensionally in vivo. Cryo-electron tomography enabled us such a 3D structural analysis. Our group has been working on 3D structure of flagella/cilia using this method and revealed highly ordered and beautifully organized molecular arrangement. 3D structure gave us insights into the mechanism to gener-ate bending motion with well defined waveforms. In this review, I summarize our recent structural studies on fla-gella/cilia by cryo-electron tomography, mainly focusing on dynein microtubule-based ATPase motor proteins and the radial spoke, a regulatory protein complex.
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Phospholipase C-β in immune cells.
Kawakami, Toshiaki; Xiao, Wenbin
2013-09-01
Great progress has recently been made in structural and functional research of phospholipase C (PLC)-β. We now understand how PLC-β isoforms (β1-β4) are activated by GTP-bound Gαq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-βs participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-β3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-β3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Phospholipase C-β in Immune Cells
Kawakami, Toshiaki; Xiao, Wenbin
2013-01-01
Great progress has recently been made in structural and functional research of phospholipase C (PLC)-β. We now understand how PLC-β isoforms (β1-β4) are activated by GTP-bound Gαq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-βs participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-β3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-β3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. PMID:23981313
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3D structure of eukaryotic flagella/cilia by cryo-electron tomography
Ishikawa, Takashi
2013-01-01
Flagella/cilia are motile organelles with more than 400 proteins. To understand the mechanism of such complex systems, we need methods to describe molecular arrange-ments and conformations three-dimensionally in vivo. Cryo-electron tomography enabled us such a 3D structural analysis. Our group has been working on 3D structure of flagella/cilia using this method and revealed highly ordered and beautifully organized molecular arrangement. 3D structure gave us insights into the mechanism to gener-ate bending motion with well defined waveforms. In this review, I summarize our recent structural studies on fla-gella/cilia by cryo-electron tomography, mainly focusing on dynein microtubule-based ATPase motor proteins and the radial spoke, a regulatory protein complex. PMID:27493552
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-03-19
...-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Notice of Filing and Immediate Effectiveness of a Proposed Rule Change Relating to Complex Orders and Mini-Options March 13, 2013. Pursuant to...\\ notice is hereby given that on March 7, 2013, Chicago Board Options Exchange, Incorporated (the...
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In the Eyes of Others: Monitoring for Relational Value Cues
ERIC Educational Resources Information Center
Tyler, James M.
2008-01-01
It was hypothesized that monitoring the social environment for relational value (RV) cues both consumes and depletes self-regulatory resources. Consistent with predictions, the results suggest that regulatory resources are depleted when people monitor for relational cues (Experiments 1 and 2), that the capacity to monitor for complex (vs. simple)…
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USDA-ARS?s Scientific Manuscript database
Forty crossbred beef steers were used to determine the effects metabolizable energy (ME) intake and of site and complexity of carbohydrate (CHO) infusion on expression of genes encoding lipogenic enzymes and regulatory proteins in subcutaneous (SC), mesenteric (MES) and omental (OM) adipose. Treatm...
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Challenges in Developing Competency-based Training Curriculum for Food Safety Regulators in India.
Thippaiah, Anitha; Allagh, Komal Preet; Murthy, G V
2014-07-01
The Food Safety and Standards Act have redefined the roles and responsibilities of food regulatory workforce and calls for highly skilled human resources as it involves complex management procedures. 1) Identify the competencies needed among the food regulatory workforce in India. 2) Develop a competency-based training curriculum for food safety regulators in the country. 3) Develop training materials for use to train the food regulatory workforce. The Indian Institute of Public Health, Hyderabad, led the development of training curriculum on food safety with technical assistance from the Royal Society for Public Health, UK and the National Institute of Nutrition, India. The exercise was to facilitate the implementation of new Act by undertaking capacity building through a comprehensive training program. A competency-based training needs assessment was conducted before undertaking the development of the training materials. THE TRAINING PROGRAM FOR FOOD SAFETY OFFICERS WAS DESIGNED TO COMPRISE OF FIVE MODULES TO INCLUDE: Food science and technology, Food safety management systems, Food safety legislation, Enforcement of food safety regulations, and Administrative functions. Each module has a facilitator guide for the tutor and a handbook for the participant. Essentials of Food Hygiene-I (Basic level), II and III (Retail/ Catering/ Manufacturing) were primarily designed for training of food handlers and are part of essential reading for food safety regulators. The Food Safety and Standards Act calls for highly skilled human resources as it involves complex management procedures. Despite having developed a comprehensive competency-based training curriculum by joint efforts by the local, national, and international agencies, implementation remains a challenge in resource-limited setting.
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Gazi, Anastasia D; Charova, Spyridoula; Aivaliotis, Michalis; Panopoulos, Nicholas J; Kokkinidis, Michael
2015-01-01
Bacterial type III secretion systems (T3SSs) are specialized multicomponent nanomachines that mediate the transport of proteins either to extracellular locations or directly into eukaryotic host cell cytoplasm. Erwinia amylovora, the main agent of rosaceous plants fireblight disease, employs an Hrp/Hrc1 T3SS to accomplish its pathogenesis. The regulatory network that controls the activation of this T3SS is largely unknown in E. amylovora. However, in Pseudomonas syringae pathovars, the HrpG/HrpV complex has been shown to directly regulate the activity of transcription factor HrpS and consequently the upregulation of the Hrp/Hrc1 T3SS related genes. In this work, we report the successful recombinant production and purification of a stable E. amylovora HrpG/HrpV complex, using pPROpET, a bicistronic expression vector. Furthermore, we present the first solution structure of this complex based on small-angle X-ray scattering data. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Monti, Maria C; Hernández-Arriaga, Ana M; Kamphuis, Monique B; López-Villarejo, Juan; Heck, Albert J R; Boelens, Rolf; Díaz-Orejas, Ramón; van den Heuvel, Robert H H
2007-01-01
The parD operon of Escherichia coli plasmid R1 encodes a toxin-antitoxin system, which is involved in plasmid stabilization. The toxin Kid inhibits cell growth by RNA degradation and its action is neutralized by the formation of a tight complex with the antitoxin Kis. A fascinating but poorly understood aspect of the kid-kis system is its autoregulation at the transcriptional level. Using macromolecular (tandem) mass spectrometry and DNA binding assays, we here demonstrate that Kis pilots the interaction of the Kid-Kis complex in the parD regulatory region and that two discrete Kis-binding regions are present on parD. The data clearly show that only when the Kis concentration equals or exceeds the Kid concentration a strong cooperative effect exists between strong DNA binding and Kid2-Kis2-Kid2-Kis2 complex formation. We propose a model in which transcriptional repression of the parD operon is tuned by the relative molar ratio of the antitoxin and toxin proteins in solution. When the concentration of the toxin exceeds that of the antitoxin tight Kid2-Kis2-Kid2 complexes are formed, which only neutralize the lethal activity of Kid. Upon increasing the Kis concentration, (Kid2-Kis2)n complexes repress the kid-kis operon.
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Cross-β Polymerization of Low Complexity Sequence Domains.
Kato, Masato; McKnight, Steven L
2017-03-01
Most transcription factors and RNA regulatory proteins encoded by eukaryotic genomes ranging from yeast to humans contain polypeptide domains variously described as intrinsically disordered, prion-like, or of low complexity (LC). These LC domains exist in an unfolded state when DNA and RNA regulatory proteins are studied in biochemical isolation from cells. Upon incubation in the purified state, many of these LC domains polymerize into homogeneous, labile amyloid-like fibers. Here, we consider several lines of evidence that may favor biologic utility for LC domain polymers. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.
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Control of seed dormancy and germination by DOG1-AHG1 PP2C phosphatase complex via binding to heme.
Nishimura, Noriyuki; Tsuchiya, Wataru; Moresco, James J; Hayashi, Yuki; Satoh, Kouji; Kaiwa, Nahomi; Irisa, Tomoko; Kinoshita, Toshinori; Schroeder, Julian I; Yates, John R; Hirayama, Takashi; Yamazaki, Toshimasa
2018-06-06
Abscisic acid (ABA) regulates abiotic stress and developmental responses including regulation of seed dormancy to prevent seeds from germinating under unfavorable environmental conditions. ABA HYPERSENSITIVE GERMINATION1 (AHG1) encoding a type 2C protein phosphatase (PP2C) is a central negative regulator of ABA response in germination; however, the molecular function and regulation of AHG1 remain elusive. Here we report that AHG1 interacts with DELAY OF GERMINATION1 (DOG1), which is a pivotal positive regulator in seed dormancy. DOG1 acts upstream of AHG1 and impairs the PP2C activity of AHG1 in vitro. Furthermore, DOG1 has the ability to bind heme. Binding of DOG1 to AHG1 and heme are independent processes, but both are essential for DOG1 function in vivo. Our study demonstrates that AHG1 and DOG1 constitute an important regulatory system for seed dormancy and germination by integrating multiple environmental signals, in parallel with the PYL/RCAR ABA receptor-mediated regulatory system.
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Dong, Yi-Hu; Zhang, Xi-Fen; Zhang, Lian-Hui
2013-01-01
The opportunistic pathogen Pseudomonas aeruginosa utilizes type III secretion system (T3SS) to translocate effector proteins into eukaryotic host cells that subvert normal host cell functions to the benefit of the pathogen, and results in serious infections. T3SS in P. aeruginosa is controlled by a complex system of regulatory mechanisms and signaling pathways. In this study, we described that Crc, an RNA-binding protein, exerts a positive impact on T3SS in P. aeruginosa, as evidenced by promoter activity assays of several key T3SS genes, transcriptomics, RT-PCR, and immunoblotting in crc mutant. We further demonstrated that the regulatory function of Crc on the T3SS was mediated through the T3SS master regulator ExsA and linked to the Cbr/Crc signaling system. Expression profiling of the crc mutant revealed a downregulation of flagship T3SS genes as well as 16 other genes known to regulate T3SS gene expression in P. aeruginosa. On the basis of these data, we proposed that Crc may exert multifaceted control on the T3SS through various pathways, which may serve to fine-tune this virulence mechanism in response to environmental changes and nutrient sources. PMID:23292701
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In Vitro Exposure Systems and Dosimetry Assessment Tools ...
In 2009, the passing of The Family Smoking Prevention and Tobacco Control Act facilitated the establishment of the FDA Center for Tobacco Products (CTP) and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed “modified risk”. On 4-6 April 2016, the Institute for In Vitro Sciences, Inc. (IIVS) convened a workshop conference titled “In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products” to bring together stakeholders representing regulatory agencies, academia, and industry to address the research priorities articulated by the FDA CTP. Specific topics were covered to assess the status of current in vitro smoke and aerosol/vapor exposure systems, as well as the various approaches and challenges to quantifying the complex exposures, in in vitro pulmonary models developed for evaluating adverse pulmonary events resulting from tobacco product exposures. The four core topics covered were, 1) Tobacco Smoke And E-Cigarette Aerosols, 2) Air-Liquid Interface-In Vitro Exposure Systems, 3) Dosimetry Approaches For Particles And Vapors; In Vitro Dosimetry Determinations and 4) Exposure Microenvironment/Physiology Of Cells. The two and a half day workshop included presentations from 20 expert speakers, poster sessions, networking discussions, and breakout sessions which identified key findings and provided recommendations to advance these technologies. Here, we will re
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Central- and autonomic nervous system coupling in schizophrenia
Schulz, Steffen; Bolz, Mathias; Bär, Karl-Jürgen
2016-01-01
The autonomic nervous system (ANS) dysfunction has been well described in schizophrenia (SZ), a severe mental disorder. Nevertheless, the coupling between the ANS and central brain activity has been not addressed until now in SZ. The interactions between the central nervous system (CNS) and ANS need to be considered as a feedback–feed-forward system that supports flexible and adaptive responses to specific demands. For the first time, to the best of our knowledge, this study investigates central–autonomic couplings (CAC) studying heart rate, blood pressure and electroencephalogram in paranoid schizophrenic patients, comparing them with age–gender-matched healthy subjects (CO). The emphasis is to determine how these couplings are composed by the different regulatory aspects of the CNS–ANS. We found that CAC were bidirectional, and that the causal influence of central activity towards systolic blood pressure was more strongly pronounced than such causal influence towards heart rate in paranoid schizophrenic patients when compared with CO. In paranoid schizophrenic patients, the central activity was a much stronger variable, being more random and having fewer rhythmic oscillatory components. This study provides a more in-depth understanding of the interplay of neuronal and autonomic regulatory processes in SZ and most likely greater insights into the complex relationship between psychotic stages and autonomic activity. PMID:27044986
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Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges.
Jossen, Valentin; van den Bos, Christian; Eibl, Regine; Eibl, Dieter
2018-05-01
Human mesenchymal stem cell (hMSC)-based therapies are of increasing interest in the field of regenerative medicine. As economic considerations have shown, allogeneic therapy seems to be the most cost-effective method. Standardized procedures based on instrumented single-use bioreactors have been shown to provide billion of cells with consistent product quality and to be superior to traditional expansions in planar cultivation systems. Furthermore, under consideration of the complex nature and requirements of allogeneic hMSC-therapeutics, a new equipment for downstream processing (DSP) was successfully evaluated. This mini-review summarizes both the current state of the hMSC production process and the challenges which have to be taken into account when efficiently producing hMSCs for the clinical scale. Special emphasis is placed on the upstream processing (USP) and DSP operations which cover expansion, harvesting, detachment, separation, washing and concentration steps, and the regulatory demands.
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NASA Astrophysics Data System (ADS)
Banerjee, Ipsita
2009-03-01
Knowledge of pathways governing cellular differentiation to specific phenotype will enable generation of desired cell fates by careful alteration of the governing network by adequate manipulation of the cellular environment. With this aim, we have developed a novel method to reconstruct the underlying regulatory architecture of a differentiating cell population from discrete temporal gene expression data. We utilize an inherent feature of biological networks, that of sparsity, in formulating the network reconstruction problem as a bi-level mixed-integer programming problem. The formulation optimizes the network topology at the upper level and the network connectivity strength at the lower level. The method is first validated by in-silico data, before applying it to the complex system of embryonic stem (ES) cell differentiation. This formulation enables efficient identification of the underlying network topology which could accurately predict steps necessary for directing differentiation to subsequent stages. Concurrent experimental verification demonstrated excellent agreement with model prediction.
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Brook, Robert D; Franklin, Barry; Cascio, Wayne; Hong, Yuling; Howard, George; Lipsett, Michael; Luepker, Russell; Mittleman, Murray; Samet, Jonathan; Smith, Sidney C; Tager, Ira
2004-06-01
Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.
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Placenta immune infiltrates and perinatal outcomes.
Ozen, Maide; Novak, Christopher; Burd, Irina
2018-05-01
Pregnancy is a state of immunotolerance and loss of this immunotolerance may lead to fetal rejection, pregnancy complications, and neonatal complications. Immunobiology of pregnancy is complex and involves unique immune cell populations specific to pregnancy, changes in mucosal immune cells and peripheral immune system, and reciprocal adaptations between the mother and the fetus. The mechanisms required for sustaining a healthy feto-placental barrier and a healthy pregnancy such as activation of regulatory immune responses with a predominance of regulatory T cells lead to immune evasion and propagation of cancer. It is intriguing to note that the immune pathways which are effective in limiting or eliminating cancer form the very basis for loss of feto-maternal tolerance. In this article, we aim to compare and contrast immunobiology of healthy and pathological pregnancies mirroring with cancer immunobiology with a focus on immune checkpoint receptors. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Innate Immune Regulations and Liver Ischemia Reperfusion Injury
Lu, Ling; Zhou, Haoming; Ni, Ming; Wang, Xuehao; Busuttil, Ronald; Kupiec-Weglinski, Jerzy; Zhai, Yuan
2016-01-01
Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory, but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver IRI involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver IRI in patients. PMID:27861288
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Worms and the Treatment of Inflammatory Bowel Disease: Are Molecules the Answer?
Ruyssers, Nathalie E.; De Winter, Benedicte Y.; De Man, Joris G.; Loukas, Alex; Herman, Arnold G.; Pelckmans, Paul A.; Moreels, Tom G.
2008-01-01
The lack of exposure to helminth infections, as a result of improved living standards and medical conditions, may have contributed to the increased incidence of IBD in the developed world. Epidemiological, experimental, and clinical data sustain the idea that helminths could provide protection against IBD. Studies investigating the underlying mechanisms by which helminths might induce such protection have revealed the importance of regulatory pathways, for example, regulatory T-cells. Further investigation on how helminths influence both innate and adaptive immune reactions will shed more light on the complex pathways used by helminths to regulate the hosts immune system. Although therapy with living helminths appears to be effective in several immunological diseases, the disadvantages of a treatment based on living parasites are explicit. Therefore, the identification and characterization of helminth-derived immunomodulatory molecules that contribute to the protective effect could lead to new therapeutic approaches in IBD and other immune diseases. PMID:18509490
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The rise of biosimilars: How they got here and where they are going.
Patel, Dhiren; Gillis, Colin; Naggar, Joseph; Mistry, Amee; Mantzoros, Christos S
2017-10-01
Biosimilars have become a subject of great interest in the past few years. The European Union and the United States are seeing an increasing number of biosimilar applications and approvals. The development of a biosimilar is significantly more complex and costly than a small molecule generic product. In the European Union, there has been a wider use of these medications compared to the United States. More biosimilars are gaining approval in the United States, and these products will likely alter the healthcare system in highly impactful ways. Understanding the regulatory process, the risks, and benefits will enable clinicians to be prepared and maximize the utility of these medications when they enter the market. This article introduces the concept of a biosimilar, discusses the regulatory process in the United States, and reviews the risks and benefits of these products. Copyright © 2017 Elsevier Inc. All rights reserved.
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Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites.
Chen, Baoyu; Chou, Hui-Ting; Brautigam, Chad A; Xing, Wenmin; Yang, Sheng; Henry, Lisa; Doolittle, Lynda K; Walz, Thomas; Rosen, Michael K
2017-09-26
The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly.
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Regulation of microtubule nucleation mediated by γ-tubulin complexes.
Sulimenko, Vadym; Hájková, Zuzana; Klebanovych, Anastasiya; Dráber, Pavel
2017-05-01
The microtubule cytoskeleton is critically important for spatio-temporal organization of eukaryotic cells. The nucleation of new microtubules is typically restricted to microtubule organizing centers (MTOCs) and requires γ-tubulin that assembles into multisubunit complexes of various sizes. γ-Tubulin ring complexes (TuRCs) are efficient microtubule nucleators and are associated with large number of targeting, activating and modulating proteins. γ-Tubulin-dependent nucleation of microtubules occurs both from canonical MTOCs, such as spindle pole bodies and centrosomes, and additional sites such as Golgi apparatus, nuclear envelope, plasma membrane-associated sites, chromatin and surface of pre-existing microtubules. Despite many advances in structure of γ-tubulin complexes and characterization of γTuRC interacting factors, regulatory mechanisms of microtubule nucleation are not fully understood. Here, we review recent work on the factors and regulatory mechanisms that are involved in centrosomal and non-centrosomal microtubule nucleation.
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Evaluation of genetic and metabolic role of SKIP11 in Arabidopsis thaliana
NASA Astrophysics Data System (ADS)
Hassan, Muhammad Naeem ul; Ismail, Ismanizan
2015-09-01
Most of the regulatory proteins are degraded by 26S proteasome complex, only when they are tagged by Ubiquitin. A complex of four proteins, SKP1-Cullin-Ring box-F box (SCF) catalyses the final step to link the Ubiquitin tag with the target proteins. SCF complex interacts with the target proteins through F-box proteins, which confer the overall substrate specificity to the complex. F-box proteins, one of the largest family of proteins in plants have an N-terminal F-box domain and variable C-terminal domains, like leucine-rich repeat, WD-40 repeat and the kelch-repeat domains. In this study, we analysed the role of SKIP11, a kelch containing F-box protein (KFB) from Arabidopsis thaliana, by using reverse genetics strategy. The results show that SKIP11 is involved in the down-regulation of oxylipin pathway, possibly through the degradation of enzymes or/ and the regulatory factors of the pathway.
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Analysis of C. elegans VIG-1 expression.
Shin, Kyoung-Hwa; Choi, Boram; Park, Yang-Seo; Cho, Nam Jeong
2008-12-31
Double-stranded RNA (dsRNA) induces gene silencing in a sequence-specific manner by a process known as RNA interference (RNAi). The RNA-induced silencing complex (RISC) is a multi-subunit ribonucleoprotein complex that plays a key role in RNAi. VIG (Vasa intronic gene) has been identified as a component of Drosophila RISC; however, the role VIG plays in regulating RNAi is poorly understood. Here, we examined the spatial and temporal expression patterns of VIG-1, the C. elegans ortholog of Drosophila VIG, using a vig-1::gfp fusion construct. This construct contains the 908-bp region immediately upstream of vig-1 gene translation initiation site. Analysis by confocal microscopy demonstrated GFP-VIG-1 expression in a number of tissues including the pharynx, body wall muscle, hypodermis, intestine, reproductive system, and nervous system at the larval and adult stages. Furthermore, western blot analysis showed that VIG-1 is present in each developmental stage examined. To investigate regulatory sequences for vig-1 gene expression, we generated constructs containing deletions in the upstream region. It was determined that the GFP expression pattern of a deletion construct (delta-908 to -597) was generally similar to that of the non-deletion construct. In contrast, removal of a larger segment (delta-908 to -191) resulted in the loss of GFP expression in most cell types. Collectively, these results indicate that the 406-bp upstream region (-596 to -191) contains essential regulatory sequences required for VIG-1 expression.
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Network representations of immune system complexity
Subramanian, Naeha; Torabi-Parizi, Parizad; Gottschalk, Rachel A.; Germain, Ronald N.; Dutta, Bhaskar
2015-01-01
The mammalian immune system is a dynamic multi-scale system composed of a hierarchically organized set of molecular, cellular and organismal networks that act in concert to promote effective host defense. These networks range from those involving gene regulatory and protein-protein interactions underlying intracellular signaling pathways and single cell responses to increasingly complex networks of in vivo cellular interaction, positioning and migration that determine the overall immune response of an organism. Immunity is thus not the product of simple signaling events but rather non-linear behaviors arising from dynamic, feedback-regulated interactions among many components. One of the major goals of systems immunology is to quantitatively measure these complex multi-scale spatial and temporal interactions, permitting development of computational models that can be used to predict responses to perturbation. Recent technological advances permit collection of comprehensive datasets at multiple molecular and cellular levels while advances in network biology support representation of the relationships of components at each level as physical or functional interaction networks. The latter facilitate effective visualization of patterns and recognition of emergent properties arising from the many interactions of genes, molecules, and cells of the immune system. We illustrate the power of integrating ‘omics’ and network modeling approaches for unbiased reconstruction of signaling and transcriptional networks with a focus on applications involving the innate immune system. We further discuss future possibilities for reconstruction of increasingly complex cellular and organism-level networks and development of sophisticated computational tools for prediction of emergent immune behavior arising from the concerted action of these networks. PMID:25625853
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-22
... participants that add or remove liquidity in the Complex Order Book (``maker/taker fees'') in symbols that are... liquidity on the Complex Order Book and $0.30 per contract ($0.32 per contract in the Select Symbols) for taking liquidity from the Complex Order Book. ISE market makers who take liquidity from the Complex Order...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-12
... Change Related to the Opening of the Complex Order Book February 6, 2013. Pursuant to Section 19(b)(1) of... complex orders are currently processed through the Exchange's complex order book (``COB'') when the COB... individual orders and quotes in the electronic book or other complex orders in the COB, execute or cancel if...
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Murteira, Susana; Millier, Aurélie; Ghezaiel, Zied; Lamure, Michel
2014-01-01
Background Repurposing has become a mainstream strategy in drug development, but it faces multiple challenges, amongst them the increasing and ever changing regulatory framework. This is the second study of a series of three-part publication project with the ultimate goal of understanding the market access rationale and conditions attributed to drug repurposing in the United States and in Europe. The aim of the current study to evaluate the regulatory path associated with each type of repurposing strategy according to the previously proposed nomenclature in the first article of this series. Methods From the cases identified, a selection process retrieved a total of 141 case studies in all countries, harmonized for data availability and common approval in the United States and in Europe. Regulatory information for each original and repurposed drug product was extracted, and several related regulatory attributes were also extracted such as, designation change and filing before or after patent expiry, among others. Descriptive analyses were conducted to determine trends and to investigate potential associations between the different regulatory paths and attributes of interest, for reformulation and repositioning cases separately. Results Within the studied European countries, most of the applications for reformulated products were filed through national applications. In contrast, for repositioned products, the centralized procedure was the most frequent regulatory pathway. Most of the repurposing cases were approved before patent expiry, and those cases have followed more complex regulatory pathways in the United States and in Europe. For new molecular entities filed in the United States, a similar number of cases were developed by serendipity and by a hypothesis-driven approach. However, for the new indication's regulatory pathway in the United States, most of the cases were developed through a hypothesis-driven approach. Conclusion The regulations in the United States and in Europe for drug repositionings and reformulations allowed confirming that repositioning strategies were usually filed under a more complex regulatory process than reformulations. Also, it seems that parameters such as patent expiry and type of repositioning approach or reformulation affect the regulatory pathways chosen for each case. PMID:27226839
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Cai, Yu-Dong; Chou, Kuo-Chen
2011-01-01
Given a regulatory pathway system consisting of a set of proteins, can we predict which pathway class it belongs to? Such a problem is closely related to the biological function of the pathway in cells and hence is quite fundamental and essential in systems biology and proteomics. This is also an extremely difficult and challenging problem due to its complexity. To address this problem, a novel approach was developed that can be used to predict query pathways among the following six functional categories: (i) “Metabolism”, (ii) “Genetic Information Processing”, (iii) “Environmental Information Processing”, (iv) “Cellular Processes”, (v) “Organismal Systems”, and (vi) “Human Diseases”. The prediction method was established trough the following procedures: (i) according to the general form of pseudo amino acid composition (PseAAC), each of the pathways concerned is formulated as a 5570-D (dimensional) vector; (ii) each of components in the 5570-D vector was derived by a series of feature extractions from the pathway system according to its graphic property, biochemical and physicochemical property, as well as functional property; (iii) the minimum redundancy maximum relevance (mRMR) method was adopted to operate the prediction. A cross-validation by the jackknife test on a benchmark dataset consisting of 146 regulatory pathways indicated that an overall success rate of 78.8% was achieved by our method in identifying query pathways among the above six classes, indicating the outcome is quite promising and encouraging. To the best of our knowledge, the current study represents the first effort in attempting to identity the type of a pathway system or its biological function. It is anticipated that our report may stimulate a series of follow-up investigations in this new and challenging area. PMID:21980418
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An electronic regulatory document management system for a clinical trial network.
Zhao, Wenle; Durkalski, Valerie; Pauls, Keith; Dillon, Catherine; Kim, Jaemyung; Kolk, Deneil; Silbergleit, Robert; Stevenson, Valerie; Palesch, Yuko
2010-01-01
A computerized regulatory document management system has been developed as a module in a comprehensive Clinical Trial Management System (CTMS) designed for an NIH-funded clinical trial network in order to more efficiently manage and track regulatory compliance. Within the network, several institutions and investigators are involved in multiple trials, and each trial has regulatory document requirements. Some of these documents are trial specific while others apply across multiple trials. The latter causes a possible redundancy in document collection and management. To address these and other related challenges, a central regulatory document management system was designed. This manuscript shares the design of the system as well as examples of it use in current studies. Copyright (c) 2009 Elsevier Inc. All rights reserved.
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E3Net: a system for exploring E3-mediated regulatory networks of cellular functions.
Han, Youngwoong; Lee, Hodong; Park, Jong C; Yi, Gwan-Su
2012-04-01
Ubiquitin-protein ligase (E3) is a key enzyme targeting specific substrates in diverse cellular processes for ubiquitination and degradation. The existing findings of substrate specificity of E3 are, however, scattered over a number of resources, making it difficult to study them together with an integrative view. Here we present E3Net, a web-based system that provides a comprehensive collection of available E3-substrate specificities and a systematic framework for the analysis of E3-mediated regulatory networks of diverse cellular functions. Currently, E3Net contains 2201 E3s and 4896 substrates in 427 organisms and 1671 E3-substrate specific relations between 493 E3s and 1277 substrates in 42 organisms, extracted mainly from MEDLINE abstracts and UniProt comments with an automatic text mining method and additional manual inspection and partly from high throughput experiment data and public ubiquitination databases. The significant functions and pathways of the extracted E3-specific substrate groups were identified from a functional enrichment analysis with 12 functional category resources for molecular functions, protein families, protein complexes, pathways, cellular processes, cellular localization, and diseases. E3Net includes interactive analysis and navigation tools that make it possible to build an integrative view of E3-substrate networks and their correlated functions with graphical illustrations and summarized descriptions. As a result, E3Net provides a comprehensive resource of E3s, substrates, and their functional implications summarized from the regulatory network structures of E3-specific substrate groups and their correlated functions. This resource will facilitate further in-depth investigation of ubiquitination-dependent regulatory mechanisms. E3Net is freely available online at http://pnet.kaist.ac.kr/e3net.
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Abh and AbrB Control of Bacillus subtilis Antimicrobial Gene Expression▿
Strauch, Mark A.; Bobay, Benjamin G.; Cavanagh, John; Yao, Fude; Wilson, Angelo; Le Breton, Yoann
2007-01-01
The Bacillus subtilis abh gene encodes a protein whose N-terminal domain has 74% identity to the DNA-binding domain of the global regulatory protein AbrB. Strains with a mutation in abh showed alterations in the production of antimicrobial compounds directed against some other Bacillus species and gram-positive microbes. Relative to its wild-type parental strain, the abh mutant was found deficient, enhanced, or unaffected for the production of antimicrobial activity. Using lacZ fusions, we examined the effects of abh upon the expression of 10 promoters known to be regulated by AbrB, including five that transcribe well-characterized antimicrobial functions (SdpC, SkfA, TasA, sublancin, and subtilosin). For an otherwise wild-type background, the results show that Abh plays a negative regulatory role in the expression of four of the promoters, a positive role for the expression of three, and no apparent regulatory role in the expression of the other three promoters. Binding of AbrB and Abh to the promoter regions was examined using DNase I footprinting, and the results revealed significant differences. The transcription of abh is not autoregulated, but it is subject to a degree of AbrB-afforded negative regulation. The results indicate that Abh is part of the complex interconnected regulatory system that controls gene expression during the transition from active growth to stationary phase. PMID:17720793
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A regulatory network to segregate the identity of neuronal subtypes.
Lee, Seunghee; Lee, Bora; Joshi, Kaumudi; Pfaff, Samuel L; Lee, Jae W; Lee, Soo-Kyung
2008-06-01
Spinal motor neurons (MNs) and V2 interneurons (V2-INs) are specified by two related LIM-complexes, MN-hexamer and V2-tetramer, respectively. Here we show how multiple parallel and complementary feedback loops are integrated to assign these two cell fates accurately. While MN-hexamer response elements (REs) are specific to MN-hexamer, V2-tetramer-REs can bind both LIM-complexes. In embryonic MNs, however, two factors cooperatively suppress the aberrant activation of V2-tetramer-REs. First, LMO4 blocks V2-tetramer assembly. Second, MN-hexamer induces a repressor, Hb9, which binds V2-tetramer-REs and suppresses their activation. V2-INs use a similar approach; V2-tetramer induces a repressor, Chx10, which binds MN-hexamer-REs and blocks their activation. Thus, our study uncovers a regulatory network to segregate related cell fates, which involves reciprocal feedforward gene regulatory loops.
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Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression
Verd, Berta; Crombach, Anton
2017-01-01
Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development. PMID:28158178
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Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression.
Verd, Berta; Crombach, Anton; Jaeger, Johannes
2017-02-01
Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development.
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Gutiérrez, Jayson
2009-01-01
The way in which the information contained in genotypes is translated into complex phenotypic traits (i.e. embryonic expression patterns) depends on its decoding by a multilayered hierarchy of biomolecular systems (regulatory networks). Each layer of this hierarchy displays its own regulatory schemes (i.e. operational rules such as +/− feedback) and associated control parameters, resulting in characteristic variational constraints. This process can be conceptualized as a mapping issue, and in the context of highly-dimensional genotype-phenotype mappings (GPMs) epistatic events have been shown to be ubiquitous, manifested in non-linear correspondences between changes in the genotype and their phenotypic effects. In this study I concentrate on epistatic phenomena pervading levels of biological organization above the genetic material, more specifically the realm of molecular networks. At this level, systems approaches to studying GPMs are specially suitable to shed light on the mechanistic basis of epistatic phenomena. To this aim, I constructed and analyzed ensembles of highly-modular (fully interconnected) networks with distinctive topologies, each displaying dynamic behaviors that were categorized as either arbitrary or functional according to early patterning processes in the Drosophila embryo. Spatio-temporal expression trajectories in virtual syncytial embryos were simulated via reaction-diffusion models. My in silico mutational experiments show that: 1) the average fitness decay tendency to successively accumulated mutations in ensembles of functional networks indicates the prevalence of positive epistasis, whereas in ensembles of arbitrary networks negative epistasis is the dominant tendency; and 2) the evaluation of epistatic coefficients of diverse interaction orders indicates that, both positive and negative epistasis are more prevalent in functional networks than in arbitrary ones. Overall, I conclude that the phenotypic and fitness effects of multiple perturbations are strongly conditioned by both the regulatory architecture (i.e. pattern of coupled feedback structures) and the dynamic nature of the spatio-temporal expression trajectories displayed by the simulated networks. PMID:19738908
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USDA-ARS?s Scientific Manuscript database
During development, trithorax group (trxG) chromatin remodeling complexes counteract repression by Polycomb group (PcG) complexes to sustain active expression of key regulatory genes. Although PcG complexes are well characterized in plants, little is known about trxG activities. Here we demonstrate ...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-10-22
... Change Adding a New Rule To Adopt Price Protection Filters for Electronic Complex Orders October 11, 2013... a new rule to adopt price protection filters for Electronic Complex Orders. The text of the proposed... Commentary .04 [sic] governing price protections filters applicable to electronically entered Complex Orders...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-10-22
... Adding a New Rule To Adopt Price Protection Filters for Electronic Complex Orders October 11, 2013... to adopt price protection filters for Electronic Complex Orders. The text of the proposed rule change... Commentary .05 governing price protections filters applicable to electronically entered Complex Orders.\\4\\ \\4...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-12-17
... for Electronic Complex Order executions, and (vii) include days when the Exchange closes early in the... combined thresholds in contracts from Customer posted orders in Penny Pilot issues and Electronic Complex Orders.\\5\\ The Exchange proposes not to count Electronic Complex Orders toward the Customer monthly...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-17
... Change Relating to Complex Order Auctions September 11, 2012. Pursuant to Section 19(b)(1) of the... of the Proposed Rule Change The Exchange proposed to amend its Rules regarding complex order auctions... Exchange may activate the electronic complex order request for responses (``RFR'') auction (``COA''), which...
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Brinkmann, Christian; Przyklenk, Axel; Metten, Alexander; Schiffer, Thorsten; Bloch, Wilhelm; Brixius, Klara; Gehlert, Sebastian
2017-11-01
Mitophagy is a form of autophagy for the elimination of mitochondria. Mitochondrial content and function are reduced in the skeletal muscle of patients with type 2 diabetes mellitus (T2DM). Physical training has been shown to restore mitochondrial capacity in T2DM patients, but the role of mitophagy has not been examined in this context. This study analyzes the impact of a 3-month endurance training on important skeletal muscle mitophagy regulatory proteins and oxidative phosphorylation (OXPHOS) complexes in T2DM patients. Muscle biopsies were obtained from eight overweight/obese T2DM men (61±10 years) at T1 (6 weeks pre-training), T2 (1 week pre-training), and T3 (3 to 4 days post-training). Protein contents were determined by Western blotting. The training increased mitochondrial complex II significantly (T2-T3: +29%, p = 0.037). The protein contents of mitophagy regulatory proteins (phosphorylated form of forkhead box O3A (pFOXO3A), mitochondrial E3 ubiquitin protein ligase-1 (MUL1), Bcl-2/adenovirus E1B 19-kD interacting protein-3 (BNIP3), microtubule-associated protein 1 light chain-3B (the ratio LC3B-II/LC3B-I was determined)) did not differ significantly between T1, T2, and T3. The results imply that training-induced changes in OXPHOS subunits (significant increase in complex II) are not accompanied by changes in mitophagy regulatory proteins in T2DM men. Future studies should elucidate whether acute exercise might affect mitophagic processes in T2DM patients (and whether a transient regulation of mitophagy regulatory proteins is evident) to fully clarify the role of physical activity and mitophagy for mitochondrial health in this particular patient group.
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Jiang, Yunquan; Hossain, Ashfaque; Winkler, Maria Teresa; Holt, Todd; Doster, Alan; Jones, Clinton
1998-01-01
Despite productive viral gene expression in the peripheral nervous system during acute infection, the bovine herpesvirus 1 (BHV-1) infection cycle is blocked in sensory ganglionic neurons and consequently latency is established. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA. LR gene products inhibit S-phase entry, and binding of the LR protein (LRP) to cyclin A was hypothesized to block cell cycle progression. This study demonstrates LRP is a nuclear protein which is expressed in neurons of latently infected cattle. Affinity chromatography indicated that LRP interacts with cyclin-dependent kinase 2 (cdk2)-cyclin complexes or cdc2-cyclin complexes in transfected human cells or infected bovine cells. After partial purification using three different columns (DEAE-Sepharose, Econo S, and heparin-agarose), LRP was primarily associated with cdk2-cyclin E complexes, an enzyme which is necessary for G1-to-S-phase cell cycle progression. During acute infection of trigeminal ganglia or following dexamethasone-induced reactivation, BHV-1 induces expression of cyclin A in neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807–3814, 1996). Expression of S-phase regulatory proteins (cyclin A, for example) leads to neuronal apoptosis. Consequently, we hypothesize that interactions between LRP and cell cycle regulatory proteins promote survival of postmitotic neurons during acute infection and/or reactivation. PMID:9733854
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Jiang, Y; Hossain, A; Winkler, M T; Holt, T; Doster, A; Jones, C
1998-10-01
Despite productive viral gene expression in the peripheral nervous system during acute infection, the bovine herpesvirus 1 (BHV-1) infection cycle is blocked in sensory ganglionic neurons and consequently latency is established. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA. LR gene products inhibit S-phase entry, and binding of the LR protein (LRP) to cyclin A was hypothesized to block cell cycle progression. This study demonstrates LRP is a nuclear protein which is expressed in neurons of latently infected cattle. Affinity chromatography indicated that LRP interacts with cyclin-dependent kinase 2 (cdk2)-cyclin complexes or cdc2-cyclin complexes in transfected human cells or infected bovine cells. After partial purification using three different columns (DEAE-Sepharose, Econo S, and heparin-agarose), LRP was primarily associated with cdk2-cyclin E complexes, an enzyme which is necessary for G1-to-S-phase cell cycle progression. During acute infection of trigeminal ganglia or following dexamethasone-induced reactivation, BHV-1 induces expression of cyclin A in neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807-3814, 1996). Expression of S-phase regulatory proteins (cyclin A, for example) leads to neuronal apoptosis. Consequently, we hypothesize that interactions between LRP and cell cycle regulatory proteins promote survival of postmitotic neurons during acute infection and/or reactivation.
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Yu, Bin; Xu, Jia-Meng; Li, Shan; Chen, Cheng; Chen, Rui-Xin; Wang, Lei; Zhang, Yan; Wang, Ming-Hui
2017-01-01
Gene regulatory networks (GRNs) research reveals complex life phenomena from the perspective of gene interaction, which is an important research field in systems biology. Traditional Bayesian networks have a high computational complexity, and the network structure scoring model has a single feature. Information-based approaches cannot identify the direction of regulation. In order to make up for the shortcomings of the above methods, this paper presents a novel hybrid learning method (DBNCS) based on dynamic Bayesian network (DBN) to construct the multiple time-delayed GRNs for the first time, combining the comprehensive score (CS) with the DBN model. DBNCS algorithm first uses CMI2NI (conditional mutual inclusive information-based network inference) algorithm for network structure profiles learning, namely the construction of search space. Then the redundant regulations are removed by using the recursive optimization algorithm (RO), thereby reduce the false positive rate. Secondly, the network structure profiles are decomposed into a set of cliques without loss, which can significantly reduce the computational complexity. Finally, DBN model is used to identify the direction of gene regulation within the cliques and search for the optimal network structure. The performance of DBNCS algorithm is evaluated by the benchmark GRN datasets from DREAM challenge as well as the SOS DNA repair network in Escherichia coli, and compared with other state-of-the-art methods. The experimental results show the rationality of the algorithm design and the outstanding performance of the GRNs. PMID:29113310
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Yu, Bin; Xu, Jia-Meng; Li, Shan; Chen, Cheng; Chen, Rui-Xin; Wang, Lei; Zhang, Yan; Wang, Ming-Hui
2017-10-06
Gene regulatory networks (GRNs) research reveals complex life phenomena from the perspective of gene interaction, which is an important research field in systems biology. Traditional Bayesian networks have a high computational complexity, and the network structure scoring model has a single feature. Information-based approaches cannot identify the direction of regulation. In order to make up for the shortcomings of the above methods, this paper presents a novel hybrid learning method (DBNCS) based on dynamic Bayesian network (DBN) to construct the multiple time-delayed GRNs for the first time, combining the comprehensive score (CS) with the DBN model. DBNCS algorithm first uses CMI2NI (conditional mutual inclusive information-based network inference) algorithm for network structure profiles learning, namely the construction of search space. Then the redundant regulations are removed by using the recursive optimization algorithm (RO), thereby reduce the false positive rate. Secondly, the network structure profiles are decomposed into a set of cliques without loss, which can significantly reduce the computational complexity. Finally, DBN model is used to identify the direction of gene regulation within the cliques and search for the optimal network structure. The performance of DBNCS algorithm is evaluated by the benchmark GRN datasets from DREAM challenge as well as the SOS DNA repair network in Escherichia coli , and compared with other state-of-the-art methods. The experimental results show the rationality of the algorithm design and the outstanding performance of the GRNs.
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A Method for Visualization of Incoming Adenovirus Chromatin Complexes in Fixed and Living Cells
Komatsu, Tetsuro; Dacheux, Denis; Kreppel, Florian; Nagata, Kyosuke; Wodrich, Harald
2015-01-01
Inside the adenovirus virion, the genome forms a chromatin-like structure with viral basic core proteins. Core protein VII is the major DNA binding protein and was shown to remain associated with viral genomes upon virus entry even after nuclear delivery. It has been suggested that protein VII plays a regulatory role in viral gene expression and is a functional component of viral chromatin complexes in host cells. As such, protein VII could be used as a maker to track adenoviral chromatin complexes in vivo. In this study, we characterize a new monoclonal antibody against protein VII that stains incoming viral chromatin complexes following nuclear import. Furthermore, we describe the development of a novel imaging system that uses Template Activating Factor-I (TAF-I/SET), a cellular chromatin protein tightly bound to protein VII upon infection. This setup allows us not only to rapidly visualize protein VII foci in fixed cells but also to monitor their movement in living cells. These powerful tools can provide novel insights into the spatio-temporal regulation of incoming adenoviral chromatin complexes. PMID:26332038
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How Soluble GARP Enhances TGFβ Activation.
Fridrich, Sven; Hahn, Susanne A; Linzmaier, Marion; Felten, Matthias; Zwarg, Jenny; Lennerz, Volker; Tuettenberg, Andrea; Stöcker, Walter
2016-01-01
GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFβ (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity. This confirms a fundamental role of GARP in the basic function of regulatory T cells. Prerequisites postulated for physiological GARP function include membrane anchorage of GARP, disulfide bridges between the propeptide of TGFβ and GARP and connection of this propeptide to αvβ6 or αvβ8 integrins of target cells during mechanical TGFβ release. Other studies indicate the existence of soluble GARP complexes and a functionality of soluble GARP alone. In order to clarify the underlying molecular mechanism, we expressed and purified recombinant TGFβ and a soluble variant of GARP. Surprisingly, soluble GARP and TGFβ formed stable non-covalent complexes in addition to disulfide-coupled complexes, depending on the redox conditions of the microenvironment. We also show that soluble GARP alone and the two variants of complexes mediate different levels of TGFβ activity. TGFβ activation is enhanced by the non-covalent GARP-TGFβ complex already at low (nanomolar) concentrations, at which GARP alone does not show any effect. This supports the idea of soluble GARP acting as immune modulator in vivo.
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Genome-wide inference of regulatory networks in Streptomyces coelicolor.
Castro-Melchor, Marlene; Charaniya, Salim; Karypis, George; Takano, Eriko; Hu, Wei-Shou
2010-10-18
The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements. Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification.
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Lung evolution as a cipher for physiology
Torday, J. S.; Rehan, V. K.
2009-01-01
In the postgenomic era, we need an algorithm to readily translate genes into physiologic principles. The failure to advance biomedicine is due to the false hope raised in the wake of the Human Genome Project (HGP) by the promise of systems biology as a ready means of reconstructing physiology from genes. like the atom in physics, the cell, not the gene, is the smallest completely functional unit of biology. Trying to reassemble gene regulatory networks without accounting for this fundamental feature of evolution will result in a genomic atlas, but not an algorithm for functional genomics. For example, the evolution of the lung can be “deconvoluted” by applying cell-cell communication mechanisms to all aspects of lung biology development, homeostasis, and regeneration/repair. Gene regulatory networks common to these processes predict ontogeny, phylogeny, and the disease-related consequences of failed signaling. This algorithm elucidates characteristics of vertebrate physiology as a cascade of emergent and contingent cellular adaptational responses. By reducing complex physiological traits to gene regulatory networks and arranging them hierarchically in a self-organizing map, like the periodic table of elements in physics, the first principles of physiology will emerge. PMID:19366785
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Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling
Lebensohn, Andres M; Dubey, Ramin; Neitzel, Leif R; Tacchelly-Benites, Ofelia; Yang, Eungi; Marceau, Caleb D; Davis, Eric M; Patel, Bhaven B; Bahrami-Nejad, Zahra; Travaglini, Kyle J; Ahmed, Yashi; Lee, Ethan; Carette, Jan E; Rohatgi, Rajat
2016-01-01
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. DOI: http://dx.doi.org/10.7554/eLife.21459.001 PMID:27996937
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Kaunhoven, Rebekah Jane; Dorjee, Dusana
2017-03-01
Pre-adolescence is a key developmental period in which complex intrinsic volitional methods of self-regulation are acquired as a result of rapid maturation within the brain networks underlying the self-regulatory processes of attention control and emotion regulation. Fostering adaptive self-regulation skills during this stage of development has strong implications for physical health, emotional and socio-economic outcomes during adulthood. There is a growing interest in mindfulness-based programmes for pre-adolescents with initial findings suggesting self-regulation improvements, however, neurodevelopmental studies on mindfulness with pre-adolescents are scarce. This analytical review outlines an integrative neuro-developmental approach, which combines self-report and behavioural assessments with event related brain potentials (ERPs) to provide a systemic multilevel understanding of the neurocognitive mechanisms of mindfulness in pre-adolescence. We specifically focus on the N2, error related negativity (ERN), error positivity (Pe), P3a, P3b and late positive potential (LPP) ERP components as indexes of mindfulness related modulations in non-volitional bottom-up self-regulatory processes (salience detection, stimulus driven orienting and mind wandering) and volitional top-down self-regulatory processes (endogenous orienting and executive attention). Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.
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Tiered Approach to Resilience Assessment.
Linkov, Igor; Fox-Lent, Cate; Read, Laura; Allen, Craig R; Arnott, James C; Bellini, Emanuele; Coaffee, Jon; Florin, Marie-Valentine; Hatfield, Kirk; Hyde, Iain; Hynes, William; Jovanovic, Aleksandar; Kasperson, Roger; Katzenberger, John; Keys, Patrick W; Lambert, James H; Moss, Richard; Murdoch, Peter S; Palma-Oliveira, Jose; Pulwarty, Roger S; Sands, Dale; Thomas, Edward A; Tye, Mari R; Woods, David
2018-04-25
Regulatory agencies have long adopted a three-tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies. Published 2018. This article is a U.S. government work and is in the public domain in the USA.
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Ouma, Wilberforce Zachary; Pogacar, Katja; Grotewold, Erich
2018-04-01
Understanding complexity in physical, biological, social and information systems is predicated on describing interactions amongst different components. Advances in genomics are facilitating the high-throughput identification of molecular interactions, and graphs are emerging as indispensable tools in explaining how the connections in the network drive organismal phenotypic plasticity. Here, we describe the architectural organization and associated emergent topological properties of gene regulatory networks (GRNs) that describe protein-DNA interactions (PDIs) in several model eukaryotes. By analyzing GRN connectivity, our results show that the anticipated scale-free network architectures are characterized by organism-specific power law scaling exponents. These exponents are independent of the fraction of the GRN experimentally sampled, enabling prediction of properties of the complete GRN for an organism. We further demonstrate that the exponents describe inequalities in transcription factor (TF)-target gene recognition across GRNs. These observations have the important biological implication that they predict the existence of an intrinsic organism-specific trans and/or cis regulatory landscape that constrains GRN topologies. Consequently, architectural GRN organization drives not only phenotypic plasticity within a species, but is also likely implicated in species-specific phenotype.
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Functional autonomy of distant-acting human enhancers
DOE Office of Scientific and Technical Information (OSTI.GOV)
Visel, Axel; Akiyama, Jennifer A.; Shoukry, Malak
2009-02-19
Many human genes are associated with dispersed arrays of transcriptional enhancers that regulate their expression in time and space. Studies in invertebrate model systems have suggested that these elements function as discrete and independent regulatory units, but the in vivo combinatorial properties of vertebrate enhancers remain poorly understood. To explore the modularity and regulatory autonomy of human developmental enhancers, we experimentally concatenated up to four enhancers from different genes and used a transgenic mouse assay to compare the in vivo activity of these compound elements with that of the single modules. In all of the six different combinations of elementsmore » tested, the reporter gene activity patterns were additive without signs of interference between the individual modules, indicating that regulatory specificity was maintained despite the presence of closely-positioned heterologous enhancers. Even in cases where two elements drove expression in close anatomical proximity, such as within neighboring subregions of the developing limb bud, the compound patterns did not show signs of cross-inhibition between individual elements or novel expression sites. These data indicate that human developmental enhancers are highly modular and functionally autonomous and suggest that genomic enhancer shuffling may have contributed to the evolution of complex gene expression patterns in vertebrates« less
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Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.
La Rosa, Ruggero; Johansen, Helle Krogh; Molin, Søren
2018-04-10
Evolution by natural selection under complex and dynamic environmental conditions occurs through intricate and often counterintuitive trajectories affecting many genes and metabolic solutions. To study short- and long-term evolution of bacteria in vivo , we used the natural model system of cystic fibrosis (CF) infection. In this work, we investigated how and through which trajectories evolution of Pseudomonas aeruginosa occurs when migrating from the environment to the airways of CF patients, and specifically, we determined reduction of growth rate and metabolic specialization as signatures of adaptive evolution. We show that central metabolic pathways of three distinct Pseudomonas aeruginosa lineages coevolving within the same environment become restructured at the cost of versatility during long-term colonization. Cell physiology changes from naive to adapted phenotypes resulted in (i) alteration of growth potential that particularly converged to a slow-growth phenotype, (ii) alteration of nutritional requirements due to auxotrophy, (iii) tailored preference for carbon source assimilation from CF sputum, (iv) reduced arginine and pyruvate fermentation processes, and (v) increased oxygen requirements. Interestingly, although convergence was evidenced at the phenotypic level of metabolic specialization, comparative genomics disclosed diverse mutational patterns underlying the different evolutionary trajectories. Therefore, distinct combinations of genetic and regulatory changes converge to common metabolic adaptive trajectories leading to within-host metabolic specialization. This study gives new insight into bacterial metabolic evolution during long-term colonization of a new environmental niche. IMPORTANCE Only a few examples of real-time evolutionary investigations in environments outside the laboratory are described in the scientific literature. Remembering that biological evolution, as it has progressed in nature, has not taken place in test tubes, it is not surprising that conclusions from our investigations of bacterial evolution in the CF model system are different from what has been concluded from laboratory experiments. The analysis presented here of the metabolic and regulatory driving forces leading to successful adaptation to a new environment provides an important insight into the role of metabolism and its regulatory mechanisms for successful adaptation of microorganisms in dynamic and complex environments. Understanding the trajectories of adaptation, as well as the mechanisms behind slow growth and rewiring of regulatory and metabolic networks, is a key element to understand the adaptive robustness and evolvability of bacteria in the process of increasing their in vivo fitness when conquering new territories. Copyright © 2018 La Rosa et al.
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Jeanne C. Chambers; Jeremy D. Maestas; David A. Pyke; Chad S. Boyd; Mike Pellant; Amarina Wuenschel
2017-01-01
Conservation of imperiled species often demands addressing a complex suite of threats that undermine species viability. Regulatory approaches, such as the US Endangered Species Act (1973), tend to focus on anthropogenic threats through adoption of policies and regulatory mechanisms. However, persistent ecosystem-based threats, such as invasive species and altered...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-31
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66235; File No. SR-CBOE-2011-114] Self-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Order Approving a Proposed Rule Change Relating to Complex Order Processing in Hybrid 3.0 Classes January 25, 2012. I. Introduction On November 29, 2011, the Chicago Board Options...
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-15
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-65310; File No. SR-CBOE-2011-082] Self-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Notice of Filing and Immediate Effectiveness of Proposed Rule Change Related to Opening and Complex Order Price Check Parameter Features September 9, 2011. Pursuant to Section 19(b)(1)...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-26
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66207; File No. SR-CBOE-2012-004] Self-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Notice of Filing and Immediate Effectiveness of Proposed Rule Change Related to Automatic Execution and Complex Order Price Check Parameter Features January 20, 2012. Pursuant to Sectio...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-22
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-63558; File No. SR-NYSEAmex-2010-100] Self-Regulatory Organizations; NYSE Amex LLC; Order Approving a Proposed Rule Change Relating to Complex Orders December 16, 2010. I. Introduction On October 20, 2010, NYSE Amex LLC (``NYSE Amex'' or the ``Exchange...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-09
... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-66084; File No. SR-ISE-2011-84] Self-Regulatory Organizations; International Securities Exchange, LLC; Notice of Filing and Immediate Effectiveness of Proposed Rule Change Relating to Fees for Certain Complex Orders Executed on the Exchange January 3, 2012. Pursuant to Section 19(b)(1) of the...
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Homeostatic Immunity and the Microbiota.
Belkaid, Yasmine; Harrison, Oliver J
2017-04-18
The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. Here we review the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota. Published by Elsevier Inc.
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Engineering scalable biological systems
2010-01-01
Synthetic biology is focused on engineering biological organisms to study natural systems and to provide new solutions for pressing medical, industrial and environmental problems. At the core of engineered organisms are synthetic biological circuits that execute the tasks of sensing inputs, processing logic and performing output functions. In the last decade, significant progress has been made in developing basic designs for a wide range of biological circuits in bacteria, yeast and mammalian systems. However, significant challenges in the construction, probing, modulation and debugging of synthetic biological systems must be addressed in order to achieve scalable higher-complexity biological circuits. Furthermore, concomitant efforts to evaluate the safety and biocontainment of engineered organisms and address public and regulatory concerns will be necessary to ensure that technological advances are translated into real-world solutions. PMID:21468204
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Homeostatic immunity and the microbiota
Belkaid, Yasmine; Harrison, Oliver J.
2017-01-01
The microbiota plays a fundamental role in the induction, education and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. In this review, we will highlight the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota. PMID:28423337
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Williams, Patricia A H
2013-01-01
It is no small task to manage the protection of healthcare data and healthcare information systems. In an environment that is demanding adaptation to change for all information collection, storage and retrieval systems, including those for of e-health and information systems, it is imperative that good information security governance is in place. This includes understanding and meeting legislative and regulatory requirements. This chapter provides three models to educate and guide organisations in this complex area, and to simplify the process of information security governance and ensure appropriate and effective measures are put in place. The approach is risk based, adapted and contextualized for healthcare. In addition, specific considerations of the impact of cloud services, secondary use of data, big data and mobile health are discussed.
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Kogelman, Lisette J A; Cirera, Susanna; Zhernakova, Daria V; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N
2014-09-30
Obesity is a complex metabolic condition in strong association with various diseases, like type 2 diabetes, resulting in major public health and economic implications. Obesity is the result of environmental and genetic factors and their interactions, including genome-wide genetic interactions. Identification of co-expressed and regulatory genes in RNA extracted from relevant tissues representing lean and obese individuals provides an entry point for the identification of genes and pathways of importance to the development of obesity. The pig, an omnivorous animal, is an excellent model for human obesity, offering the possibility to study in-depth organ-level transcriptomic regulations of obesity, unfeasible in humans. Our aim was to reveal adipose tissue co-expression networks, pathways and transcriptional regulations of obesity using RNA Sequencing based systems biology approaches in a porcine model. We selected 36 animals for RNA Sequencing from a previously created F2 pig population representing three extreme groups based on their predicted genetic risks for obesity. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to detect clusters of highly co-expressed genes (modules). Additionally, regulator genes were detected using Lemon-Tree algorithms. WGCNA revealed five modules which were strongly correlated with at least one obesity-related phenotype (correlations ranging from -0.54 to 0.72, P < 0.001). Functional annotation identified pathways enlightening the association between obesity and other diseases, like osteoporosis (osteoclast differentiation, P = 1.4E-7), and immune-related complications (e.g. Natural killer cell mediated cytotoxity, P = 3.8E-5; B cell receptor signaling pathway, P = 7.2E-5). Lemon-Tree identified three potential regulator genes, using confident scores, for the WGCNA module which was associated with osteoclast differentiation: CCR1, MSR1 and SI1 (probability scores respectively 95.30, 62.28, and 34.58). Moreover, detection of differentially connected genes identified various genes previously identified to be associated with obesity in humans and rodents, e.g. CSF1R and MARC2. To our knowledge, this is the first study to apply systems biology approaches using porcine adipose tissue RNA-Sequencing data in a genetically characterized porcine model for obesity. We revealed complex networks, pathways, candidate and regulatory genes related to obesity, confirming the complexity of obesity and its association with immune-related disorders and osteoporosis.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-17
... Effectiveness of Proposed Rule Change Related to the Complex Order Book September 13, 2010. Pursuant to Section... to option classes in which the electronic complex order book (``COB'') is activated. The text of the...
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Deep Reinforcement Learning of Cell Movement in the Early Stage of C. elegans Embryogenesis.
Wang, Zi; Wang, Dali; Li, Chengcheng; Xu, Yichi; Li, Husheng; Bao, Zhirong
2018-04-25
Cell movement in the early phase of C. elegans development is regulated by a highly complex process in which a set of rules and connections are formulated at distinct scales. Previous efforts have demonstrated that agent-based, multi-scale modeling systems can integrate physical and biological rules and provide new avenues to study developmental systems. However, the application of these systems to model cell movement is still challenging and requires a comprehensive understanding of regulatory networks at the right scales. Recent developments in deep learning and reinforcement learning provide an unprecedented opportunity to explore cell movement using 3D time-lapse microscopy images. We present a deep reinforcement learning approach within an agent-based modeling system to characterize cell movement in the embryonic development of C. elegans. Our modeling system captures the complexity of cell movement patterns in the embryo and overcomes the local optimization problem encountered by traditional rule-based, agent-based modeling that uses greedy algorithms. We tested our model with two real developmental processes: the anterior movement of the Cpaaa cell via intercalation and the rearrangement of the superficial left-right asymmetry. In the first case, the model results suggested that Cpaaa's intercalation is an active directional cell movement caused by the continuous effects from a longer distance (farther than the length of two adjacent cells), as opposed to a passive movement caused by neighbor cell movements. In the second case, a leader-follower mechanism well explained the collective cell movement pattern in the asymmetry rearrangement. These results showed that our approach to introduce deep reinforcement learning into agent-based modeling can test regulatory mechanisms by exploring cell migration paths in a reverse engineering perspective. This model opens new doors to explore the large datasets generated by live imaging. Source code is available at https://github.com/zwang84/drl4cellmovement. dwang7@utk.edu, baoz@mskcc.org. Supplementary data are available at Bioinformatics online.
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Patel, Malhar P; Schettini, Priscille; O'Leary, Colin P; Bosworth, Hayden B; Anderson, John B; Shah, Kevin P
2018-05-01
Ideally, a referral from a primary care physician (PCP) to a specialist results in a completed specialty appointment with results available to the PCP. This is defined as "closing the referral loop." As health systems grow more complex, regulatory bodies increase vigilance, and reimbursement shifts towards value, closing the referral loop becomes a patient safety, regulatory, and financial imperative. To assess the ability of a large health system to close the referral loop, we used electronic medical record (EMR)-generated data to analyze referrals from a large primary care network to 20 high-volume specialties between July 1, 2015 and June 30, 2016. The primary metric was documented specialist appointment completion rate. Explanatory analyses included documented appointment scheduling rate, individual clinic differences, appointment wait times, and geographic distance to appointments. Of the 103,737 analyzed referral scheduling attempts, only 36,072 (34.8%) resulted in documented complete appointments. Low documented appointment scheduling rates (38.9% of scheduling attempts lacked appointment dates), individual clinic differences in closing the referral loop, and significant differences in wait times and distances to specialists between complete and incomplete appointments drove this gap. Other notable findings include high variation in wait times among specialties and correlation between high wait times and low documented appointment completion rates. The rate of closing the referral loop in this health system is low. Low appointment scheduling rates, individual clinic differences, and patient access issues of wait times and geographic proximity explain much of the gap. This problem is likely common among large health systems with complex provider networks and referral scheduling. Strategies that improve scheduling, decrease variation among clinics, and improve patient access will likely improve rates of closing the referral loop. More research is necessary to determine the impact of these changes and other potential driving factors.
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Code of Federal Regulations, 2010 CFR
2010-04-01
... required of self-regulatory organizations operating pilot trading systems pursuant to § 240.19b-5 of this... (CONTINUED) FORMS, SECURITIES EXCHANGE ACT OF 1934 Forms for Self-Regulatory Organization Rule Changes and... Associations § 249.821 Form PILOT, information required of self-regulatory organizations operating pilot...
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Code of Federal Regulations, 2011 CFR
2011-04-01
... required of self-regulatory organizations operating pilot trading systems pursuant to § 240.19b-5 of this... (CONTINUED) FORMS, SECURITIES EXCHANGE ACT OF 1934 Forms for Self-Regulatory Organization Rule Changes and... Associations § 249.821 Form PILOT, information required of self-regulatory organizations operating pilot...
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Code of Federal Regulations, 2013 CFR
2013-04-01
... required of self-regulatory organizations operating pilot trading systems pursuant to § 240.19b-5 of this... (CONTINUED) FORMS, SECURITIES EXCHANGE ACT OF 1934 Forms for Self-Regulatory Organization Rule Changes and... Associations § 249.821 Form PILOT, information required of self-regulatory organizations operating pilot...
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Code of Federal Regulations, 2012 CFR
2012-04-01
... required of self-regulatory organizations operating pilot trading systems pursuant to § 240.19b-5 of this... (CONTINUED) FORMS, SECURITIES EXCHANGE ACT OF 1934 Forms for Self-Regulatory Organization Rule Changes and... Associations § 249.821 Form PILOT, information required of self-regulatory organizations operating pilot...
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Code of Federal Regulations, 2014 CFR
2014-04-01
... required of self-regulatory organizations operating pilot trading systems pursuant to § 240.19b-5 of this... (CONTINUED) FORMS, SECURITIES EXCHANGE ACT OF 1934 Forms for Self-Regulatory Organization Rule Changes and... Associations § 249.821 Form PILOT, information required of self-regulatory organizations operating pilot...
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Competitive Electricity Market Regulation in the United States: A Primer
DOE Office of Scientific and Technical Information (OSTI.GOV)
Flores-Espino, Francisco; Tian, Tian; Chernyakhovskiy, Ilya
The electricity system in the United States is a complex mechanism where different technologies, jurisdictions and regulatory designs interact. Today, two major models for electricity commercialization operate in the United States. One is the regulated monopoly model, in which vertically integrated electricity providers are regulated by state commissions. The other is the competitive model, in which power producers can openly access transmission infrastructure and participate in wholesale electricity markets. This paper describes the origins, evolution, and current status of the regulations that enable competitive markets in the United States.
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Keyamura, Kenji; Katayama, Tsutomu
2011-08-19
Chromosomal replication is initiated from the replication origin oriC in Escherichia coli by the active ATP-bound form of DnaA protein. The regulatory inactivation of DnaA (RIDA) system, a complex of the ADP-bound Hda and the DNA-loaded replicase clamp, represses extra initiations by facilitating DnaA-bound ATP hydrolysis, yielding the inactive ADP-bound form of DnaA. However, the mechanisms involved in promoting the DnaA-Hda interaction have not been determined except for the involvement of an interaction between the AAA+ domains of the two. This study revealed that DnaA Leu-422 and Pro-423 residues within DnaA domain IV, including a typical DNA-binding HTH motif, are specifically required for RIDA-dependent ATP hydrolysis in vitro and that these residues support efficient interaction with the DNA-loaded clamp·Hda complex and with Hda in vitro. Consistently, substitutions of these residues caused accumulation of ATP-bound DnaA in vivo and oriC-dependent inhibition of cell growth. Leu-422 plays a more important role in these activities than Pro-423. By contrast, neither of these residues is crucial for DNA replication from oriC, although they are highly conserved in DnaA orthologues. Structural analysis of a DnaA·Hda complex model suggested that these residues make contact with residues in the vicinity of the Hda AAA+ sensor I that participates in formation of a nucleotide-interacting surface. Together, the results show that functional DnaA-Hda interactions require a second interaction site within DnaA domain IV in addition to the AAA+ domain and suggest that these interactions are crucial for the formation of RIDA complexes that are active for DnaA-ATP hydrolysis.
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Keyamura, Kenji; Katayama, Tsutomu
2011-01-01
Chromosomal replication is initiated from the replication origin oriC in Escherichia coli by the active ATP-bound form of DnaA protein. The regulatory inactivation of DnaA (RIDA) system, a complex of the ADP-bound Hda and the DNA-loaded replicase clamp, represses extra initiations by facilitating DnaA-bound ATP hydrolysis, yielding the inactive ADP-bound form of DnaA. However, the mechanisms involved in promoting the DnaA-Hda interaction have not been determined except for the involvement of an interaction between the AAA+ domains of the two. This study revealed that DnaA Leu-422 and Pro-423 residues within DnaA domain IV, including a typical DNA-binding HTH motif, are specifically required for RIDA-dependent ATP hydrolysis in vitro and that these residues support efficient interaction with the DNA-loaded clamp·Hda complex and with Hda in vitro. Consistently, substitutions of these residues caused accumulation of ATP-bound DnaA in vivo and oriC-dependent inhibition of cell growth. Leu-422 plays a more important role in these activities than Pro-423. By contrast, neither of these residues is crucial for DNA replication from oriC, although they are highly conserved in DnaA orthologues. Structural analysis of a DnaA·Hda complex model suggested that these residues make contact with residues in the vicinity of the Hda AAA+ sensor I that participates in formation of a nucleotide-interacting surface. Together, the results show that functional DnaA-Hda interactions require a second interaction site within DnaA domain IV in addition to the AAA+ domain and suggest that these interactions are crucial for the formation of RIDA complexes that are active for DnaA-ATP hydrolysis. PMID:21708944
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Dynamic integration of splicing within gene regulatory pathways
Braunschweig, Ulrich; Gueroussov, Serge; Plocik, Alex; Graveley, Brenton R.; Blencowe, Benjamin J.
2013-01-01
Precursor mRNA splicing is one of the most highly regulated processes in metazoan species. In addition to generating vast repertoires of RNAs and proteins, splicing has a profound impact on other gene regulatory layers, including mRNA transcription, turnover, transport and translation. Conversely, factors regulating chromatin and transcription complexes impact the splicing process. This extensive cross-talk between gene regulatory layers takes advantage of dynamic spatial, physical and temporal organizational properties of the cell nucleus, and further emphasizes the importance of developing a multidimensional understanding of splicing control. PMID:23498935