Trade-off between Responsiveness and Noise Suppression in Biomolecular System Responses to Environmental Cues

When living systems detect changes in their external environment their response must be measured to balance the need to react appropriately with the need to remain stable, ignoring insignificant signals. Because this is a fundamental challenge of all biological systems that execute programs in response to stimuli, we developed a generalized time-frequency analysis (TFA) framework to systematically explore the dynamical properties of biomolecular networks. Using TFA, we focused on two well-characterized yeast gene regulatory networks responsive to carbon-source shifts and a mammalian innate immune regulatory network responsive to lipopolysaccharides (LPS). The networks are comprised of two different basic architectures. Dual positive and negative feedback loops make up the yeast galactose network; whereas overlapping positive and negative feed-forward loops are common to the yeast fatty-acid response network and the LPS-induced network of macrophages. TFA revealed remarkably distinct network behaviors in terms of trade-offs in responsiveness and noise suppression that are appropriately tuned to each biological response. The wild type galactose network was found to be highly responsive while the oleate network has greater noise suppression ability. The LPS network appeared more balanced, exhibiting less bias toward noise suppression or responsiveness. Exploration of the network parameter space exposed dramatic differences in system behaviors for each network. These studies highlight fundamental structural and dynamical principles that underlie each network, reveal constrained parameters of positive and negative feedback and feed-forward strengths that tune the networks appropriately for their respective biological roles, and demonstrate the general utility of the TFA approach for systems and synthetic biology

Rapid Dopaminergic Modulation of the Fish Hypothalamic Transcriptome and Proteome

Background - Dopamine (DA) is a major neurotransmitter playing an important role in the regulation of vertebrate reproduction. We developed a novel method for the comparison of transcriptomic and proteomic data obtained from in vivo experiments designed to study the neuroendocrine actions of DA. // Methods and Findings - Female goldfish were injected (i.p.) with DA agonists (D1-specific; SKF 38393, or D2-specific; LY 171555) and sacrificed after 5 h. Serum LH levels were reduced by 57% and 75% by SKF 38393 and LY 171555, respectively, indicating that the treatments produced physiologically relevant responses in vivo. Bioinformatic strategies and a ray-finned fish database were established for microarray and iTRAQ proteomic analysis of the hypothalamus, revealing a total of 3088 mRNAs and 42 proteins as being differentially regulated by the treatments. Twenty one proteins and mRNAs corresponding to these proteins appeared on both lists. Many of the mRNAs and proteins affected by the treatments were grouped into the Gene Ontology categorizations of protein complex, signal transduction, response to stimulus, and regulation of cellular processes. There was a 57% and 14% directional agreement between the differentially-regulated mRNAs and proteins for SKF 38393 and LY 171555, respectively. // Conclusions - The results demonstrate the applicability of advanced high-throughput genomic and proteomic analyses in an amendable well-studied teleost model species whose genome has yet to be sequenced. We demonstrate that DA rapidly regulates multiple hypothalamic pathways and processes that are also known to be involved in pathologies of the central nervous system

Mapping differential interactomes by affinity purification coupled with data independent mass spectrometry acquisition

Characterizing changes in protein-protein interactions associated with sequence variants (e.g. disease-associated mutations or splice forms) or following exposure to drugs, growth factors or hormones is critical to understanding how protein complexes are built, localized and regulated. Affinity purification (AP) coupled with mass spectrometry permits the analysis of protein interactions under near-physiological conditions, yet monitoring interaction changes requires the development of a robust and sensitive quantitative approach, especially for large-scale studies where cost and time are major considerations. To this end, we have coupled AP to data-independent mass spectrometric acquisition (SWATH), and implemented an automated data extraction and statistical analysis pipeline to score modulated interactions. Here, we use AP-SWATH to characterize changes in protein-protein interactions imparted by the HSP90 inhibitor NVP-AUY922 or melanoma-associated mutations in the human kinase CDK4. We show that AP-SWATH is a robust label-free approach to characterize such changes, and propose a scalable pipeline for systems biology studies

Coordinated modular functionality and prognostic potential of a heart failure biomarker-driven interaction network

<p>Abstract</p> <p>Background</p> <p>The identification of potentially relevant biomarkers and a deeper understanding of molecular mechanisms related to heart failure (HF) development can be enhanced by the implementation of biological network-based analyses. To support these efforts, here we report a global network of protein-protein interactions (PPIs) relevant to HF, which was characterized through integrative bioinformatic analyses of multiple sources of "omic" information.</p> <p>Results</p> <p>We found that the structural and functional architecture of this PPI network is highly modular. These network modules can be assigned to specialized processes, specific cellular regions and their functional roles tend to partially overlap. Our results suggest that HF biomarkers may be defined as key coordinators of intra- and inter-module communication. Putative biomarkers can, in general, be distinguished as "information traffic" mediators within this network. The top high traffic proteins are encoded by genes that are not highly differentially expressed across HF and non-HF patients. Nevertheless, we present evidence that the integration of expression patterns from high traffic genes may support accurate prediction of HF. We quantitatively demonstrate that intra- and inter-module functional activity may be controlled by a family of transcription factors known to be associated with the prevention of hypertrophy.</p> <p>Conclusion</p> <p>The systems-driven analysis reported here provides the basis for the identification of potentially novel biomarkers and understanding HF-related mechanisms in a more comprehensive and integrated way.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Ecoacoustics and multispecies semiosis: naming, semantics, semiotic characteristics, and competencies

Biosemiotics to date has focused on the exchange of signals between organisms, in line with bioacoustics; consideration of the wider acoustic environment as a semiotic medium is under-developed. The nascent discipline of ecoacoustics, that investigates the role of environmental sound in ecological processes and dynamics, fills this gap. In this paper we introduce key ecoacoustic terminology and concepts in order to highlight the value of ecoacoustics as a discipline in which to conceptualise and study intra- and interspecies semiosis. We stress the inherently subjective nature of all sensory scapes (vivo-, land-, vibro- and soundscapes) and propose that they should always bear an organismic attribution. Key terms to describe the sources (geophony, biophony, anthropophony, technophony) and scales (sonotopes, soundtopes, sonotones) of soundscapes are described. We introduce epithets for soundscapes to point to the degree to which the global environment is implicated in semiosis (latent, sensed and interpreted soundscapes); terms for describing key ecological structures and processes (acoustic community, acoustic habitat, ecoacoustic events) and examples of ecoacoustic events (choruses and noise) are described. The acoustic eco-field is recognized as the semiotic model that enables soniferous species to intercept core resources like food, safety and roosting places. We note that whilst ecoacoustics to date has focused on the critical task of the development of metrics for application in conservation and biodiversity assessment, these can be enriched by advancing conceptual and theoretical foundations. Finally, the mutual value of integrating ecoacoustic and biosemiotics perspectives is considered