Piecewise-Linear Models of Genetic Regulatory Networks: Theory and Example

International audienceThe experimental study of genetic regulatory networks has made tremendous progress in recent years resulting in a huge amount of data on the molecular interactions in model organisms. It is therefore not possible anymore to intuitively understand how the genes and interactions together influence the behavior of the system. In order to answer such questions, a rigorous modeling and analysis approach is necessary. In this chapter, we present a family of such models and analysis methods enabling us to better understand the dynam-ics of genetic regulatory networks. We apply such methods to the network that underlies the nutritional stress response of the bacterium E. coli. The functioning and development of living organisms is controlled by large and complex networks of genes, proteins, small molecules, and their interactions, so-called genetic regulatory networks. The study of these networks has recently taken a qualitative leap through the use of modern genomic techniques that allow for the simultaneous measurement of the expression levels of all genes of an organism. This has resulted in an ever growing description of the interactions in the studied genetic regulatory networks. However, it is necessary to go beyond the simple description of the interactions in order to understand the behavior of these networks and their relation with the actual functioning of the organism. Since the networks under study are usually very large, an intuitive approach for their understanding is out of ques-tion. In order to support this work, mathematical and computer tools are necessary: the unambiguous description of the phenomena that mathematical models provide allows for a detailed analysis of the behaviors at play, though they might not exactly represent the exact behavior of the networks. In this chapter, we will be mostly interested in the modeling of the genetic reg-ulatory networks by means of differential equations. This classical approach allows precise numerical predictions of deterministic dynamic properties of genetic regu-latory networks to be made. However, for most networks of biological interest the application of differential equations is far from straightforward. First, the biochemi-cal reaction mechanisms underlying the interactions are usually not or incompletel

Recovery of a temperate reef assemblage in a marine protected area following the exclusion of towed demersal fishing.

Marine Protected Areas MPA have been widely used over the last 2 decades to address human impacts on marine habitats within an ecosystem management context. Few studies have quantified recovery of temperate rocky reef communities following the cessation of scallop dredging or demersal trawling. This is critical information for the future management of these habitats to contribute towards conservation and fisheries targets. The Lyme Bay MPA, in south west UK, has excluded towed demersal fishing gear from 206 km(2) of sensitive reef habitat using a Statutory Instrument since July 2008. To assess benthic recovery in this MPA we used a flying video array to survey macro epi-benthos annually from 2008 to 2011. 4 treatments (the New Closure, previously voluntarily Closed Controls and Near or Far Open to fishing Controls) were sampled to test a recovery hypothesis that was defined as 'the New Closure becoming more similar to the Closed Controls and less similar to the Open Controls'. Following the cessation of towed demersal fishing, within three years positive responses were observed for species richness, total abundance, assemblage composition and seven of 13 indicator taxa. Definitive evidence of recovery was noted for species richness and three of the indicator taxa (Pentapora fascialis, Phallusia mammillata and Pecten maximus). While it is hoped that MPAs, which exclude anthropogenic disturbance, will allow functional restoration of goods and services provided by benthic communities, it is an unknown for temperate reef systems. Establishing the likely timescales for restoration is key to future marine management. We demonstrate the early stages of successful recruitment and link these to the potential wider ecosystem benefits including those to commercial fisheries

Rapid Global Expansion of Invertebrate Fisheries: Trends, Drivers, and Ecosystem Effects

BACKGROUND: Worldwide, finfish fisheries are receiving increasing assessment and regulation, slowly leading to more sustainable exploitation and rebuilding. In their wake, invertebrate fisheries are rapidly expanding with little scientific scrutiny despite increasing socio-economic importance. METHODS AND FINDINGS: We provide the first global evaluation of the trends, drivers, and population and ecosystem consequences of invertebrate fisheries based on a global catch database in combination with taxa-specific reviews. We also develop new methodologies to quantify temporal and spatial trends in resource status and fishery development. Since 1950, global invertebrate catches have increased 6-fold with 1.5 times more countries fishing and double the taxa reported. By 2004, 34% of invertebrate fisheries were over-exploited, collapsed, or closed. New fisheries have developed increasingly rapidly, with a decrease of 6 years (3 years) in time to peak from the 1950s to 1990s. Moreover, some fisheries have expanded further and further away from their driving market, encompassing a global fishery by the 1990s. 71% of taxa (53% of catches) are harvested with habitat-destructive gear, and many provide important ecosystem functions including habitat, filtration, and grazing. CONCLUSIONS: Our findings suggest that invertebrate species, which form an important component of the basis of marine food webs, are increasingly exploited with limited stock and ecosystem-impact assessments, and enhanced management attention is needed to avoid negative consequences for ocean ecosystems and human well-being

Connectivity and resilience of coral reef metapopulations in marine protected areas : matching empirical efforts to predictive needs

© 2009 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Coral Reefs 28 (2009): 327-337, doi:10.1007/s00338-009-0466-z.Design and decision-making for marine protected areas (MPAs) on coral reefs require prediction of MPA effects with population models. Modeling of MPAs has shown how the persistence of metapopulations in systems of MPAs depends on the size and spacing of MPAs, and levels of fishing outside the MPAs. However, the pattern of demographic connectivity produced by larval dispersal is a key uncertainty in those modeling studies. The information required to assess population persistence is a dispersal matrix containing the fraction of larvae traveling to each location from each location, not just the current number of larvae exchanged among locations. Recent metapopulation modeling research with hypothetical dispersal matrices has shown how the spatial scale of dispersal, degree of advection versus diffusion, total larval output, and temporal and spatial variability in dispersal influence population persistence. Recent empirical studies using population genetics, parentage analysis, and geochemical and artificial marks in calcified structures have improved the understanding of dispersal. However, many such studies report current self-recruitment (locally produced settlement/settlement from elsewhere), which is not as directly useful as local retention (locally produced settlement/total locally released), which is a component of the dispersal matrix. Modeling of biophysical circulation with larval particle tracking can provide the required elements of dispersal matrices and assess their sensitivity to flows and larval behavior, but it requires more assumptions than direct empirical methods. To make rapid progress in understanding the scales and patterns of connectivity, greater communication between empiricists and population modelers will be needed. Empiricists need to focus more on identifying the characteristics of the dispersal matrix, while population modelers need to track and assimilate evolving empirical results.Work by CB Paris was supported by the National Science Foundation grant NSF-OCE 0550732. Work by M-A Coffroth and SR Thorrold was supported by the National Science Foundation grant NSF-OCE 0424688. Work by TL Shearer was supported by an International Cooperative Biodiversity Group grant R21 TW006662-01 from the Fogarty International Center at the National Institutes of Health

Pregnancy and low back pain

Back pain is ubiquitous in today’s society and is particularly common during pregnancy. There are multiple factors contributing to these symptoms during pregnancy including pelvic changes as well as alterations to loading. Potential imaging modalities are limited during pregnancy due to the desire to limit ionizing radiation exposure to the fetus. Treatments are generally conservative, exercise-based interventions and alternative modalities may also be considered. Low back pain associated with pregnancy does generally resolve postpartum

FimL Regulates cAMP Synthesis in Pseudomonas aeruginosa

Pseudomonas aeruginosa, a ubiquitous bacteria found in diverse ecological niches, is an important cause of acute infections in immunocompromised individuals and chronic infections in patients with Cystic Fibrosis. One signaling molecule required for the coordinate regulation of virulence factors associated with acute infections is 3′, 5′-cyclic adenosine monophosphate, (cAMP), which binds to and activates a catabolite repressor homolog, Vfr. Vfr controls the transcription of many virulence factors, including those associated with Type IV pili (TFP), the Type III secretion system (T3SS), the Type II secretion system, flagellar-mediated motility, and quorum sensing systems. We previously identified FimL, a protein with histidine phosphotransfer-like domains, as a regulator of Vfr-dependent processes, including TFP-dependent motility and T3SS function. In this study, we carried out genetic and physiologic studies to further define the mechanism of action of FimL. Through a genetic screen designed to identify suppressors of FimL, we found a putative cAMP-specific phosphodiesterase (CpdA), suggesting that FimL regulates cAMP levels. Inactivation of CpdA increases cAMP levels and restores TFP-dependent motility and T3SS function to fimL mutants, consistent with in vivo phosphodiesterase activity. By constructing combinations of double and triple mutants in the two adenylate cyclase genes (cyaA and cyaB), fimL, and cpdA, we show that ΔfimL mutants resemble ΔcyaB mutants in TM defects, decreased T3SS transcription, and decreased cAMP levels. Similar to some of the virulence factors that they regulate, we demonstrate that CyaB and FimL are polarly localized. These results reveal new complexities in the regulation of diverse virulence pathways associated with acute P. aeruginosa infections

Contrasting patterns of population structure and gene flow facilitate exploration of connectivity in two widely distributed temperate octocorals

This is the final version of the article. Available from Springer Nature via the DOI in this record.Connectivity is an important component of metapopulation dynamics in marine systems and can influence population persistence, migration rates and conservation decisions associated with Marine Protected Areas (MPAs). In this study, we compared the genetic diversity, gene flow and population structure of two octocoral species, Eunicella verrucosa and Alcyonium digitatum, in the northeast Atlantic (ranging from the northwest of Ireland and the southern North Sea, to southern Portugal), using two panels of thirteen and eight microsatellite loci, respectively. Our results identified regional genetic structure in E. verrucosa partitioned between populations from southern Portugal, northwest Ireland, and Britain/France; subsequent hierarchical analysis of population structure also indicated reduced gene flow between southwest Britain and northwest France. However, over a similar geographical area, A. digitatum showed little evidence of population structure, suggesting high gene flow and/or a large effective population size; indeed, the only significant genetic differentiation detected in A. digitatum occurred between North Sea samples and those from the English Channel/northeast Atlantic. In both species the vast majority of gene flow originated from sample sites within regions, with populations in southwest Britain being the predominant source of contemporary exogenous genetic variants for the populations studied. Unsurprisingly, historical patterns of gene flow appeared more complex, though again southwest Britain appeared an important source of genetic variation for both species. Our findings have major conservation implications, particularly for E. verrucosa, a protected species in UK waters and listed by the IUCN as ‘Vulnerable’, and for the designation and management of European MPAs.We thank Natural England (project No. RP0286, contract No. SAE 03-02-146), the NERC (grant No. NE/L002434/1) and the University of Exeter for funding this research. Additional funding for sample collection, travel and microsatellite development was provided by the EU Framework 7 ASSEMBLE programme, agreement no. 227799, and NERC grant No. NBAF-362

Tensile Properties of the Murine Ventral Vertical Midline Incision

In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type.The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120.After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study

Mycobacterium tuberculosis Rv3586 (DacA) Is a Diadenylate Cyclase That Converts ATP or ADP into c-di-AMP

Cyclic diguanosine monophosphate (c-di-GMP) and cyclic diadenosine monophosphate (c-di-AMP) are recently identified signaling molecules. c-di-GMP has been shown to play important roles in bacterial pathogenesis, whereas information about c-di-AMP remains very limited. Mycobacterium tuberculosis Rv3586 (DacA), which is an ortholog of Bacillus subtilis DisA, is a putative diadenylate cyclase. In this study, we determined the enzymatic activity of DacA in vitro using high-performance liquid chromatography (HPLC), mass spectrometry (MS) and thin layer chromatography (TLC). Our results showed that DacA was mainly a diadenylate cyclase, which resembles DisA. In addition, DacA also exhibited residual ATPase and ADPase in vitro. Among the potential substrates tested, DacA was able to utilize both ATP and ADP, but not AMP, pApA, c-di-AMP or GTP. By using gel filtration and analytical ultracentrifugation, we further demonstrated that DacA existed as an octamer, with the N-terminal domain contributing to tetramerization and the C-terminal domain providing additional dimerization. Both the N-terminal and the C-terminal domains were essential for the DacA's enzymatically active conformation. The diadenylate cyclase activity of DacA was dependent on divalent metal ions such as Mg2+, Mn2+ or Co2+. DacA was more active at a basic pH rather than at an acidic pH. The conserved RHR motif in DacA was essential for interacting with ATP, and mutation of this motif to AAA completely abolished DacA's diadenylate cyclase activity. These results provide the molecular basis for designating DacA as a diadenylate cyclase. Our future studies will explore the biological function of this enzyme in M. tuberculosis

Recruitment Constraints in Singapore's Fluted Giant Clam (Tridacna squamosa) Populations - A Dispersal Model Approach

10.1371/journal.pone.0058819PLoS ONE83