A systems biology approach reveals the role of a novel methyltransferase in response to chemical stress and lipid homeostasis

Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors.     

A method to construct confidence interval for expected response to multi-trait selection

Summary Confidence intervals are constructed for the expected responses to three types of multi-trait selection. The influence of numbers of replicates and genotypes used in a progeny test experiment on the precision of response of multi-trait selection is discussed based on the structure of the established intervals. Special attention is paid to the characteristics of the intervals constructed for the conventional least square selection indices.     

Susceptibility of central Red Sea corals during a major bleaching event

A major coral bleaching event occurred in the central Red Sea near Thuwal, Saudi Arabia, in the summer of 2010, when the region experienced up to 10–11 degree heating weeks. We documented the susceptibility of various coral taxa to bleaching at eight reefs during the peak of this thermal stress. Oculinids and agaricids were most susceptible to bleaching, with up to 100 and 80 % of colonies of these families, respectively, bleaching at some reefs. In contrast, some families, such as mussids, pocilloporids, and pectinids showed low levels of bleaching (<20 % on average). We resurveyed the reefs 7 months later to estimate subsequent mortality. Mortality was highly variable among taxa, with some taxa showing evidence of full recovery and some (e.g., acroporids) apparently suffering nearly complete mortality. The unequal mortality among families resulted in significant change in community composition following the bleaching. Significant factors in the likelihood of coral bleaching during this event were depth of the reef and distance of the reef from shore. Shallow reefs and inshore reefs had a higher prevalence of bleaching. This bleaching event shows that Red Sea reefs are subject to the same increasing pressures that reefs face worldwide. This study provides a quantitative, genus-level assessment of the vulnerability of various coral groups from within the Red Sea to bleaching and estimates subsequent mortality. As such, it can provide valuable insights into the future for reef communities in the Red Sea.     

Skeletal records of community-level bleaching in Porites corals from Palau

Tropical Pacific sea surface temperature is projected to rise an additional 2–3 °C by the end of this century, driving an increase in the frequency and intensity of coral bleaching. With significant global coral reef cover already lost due to bleaching-induced mortality, efforts are underway to identify thermally tolerant coral communities that might survive projected warming. Massive, long-lived corals accrete skeletal bands of anomalously high density in response to episodes of thermal stress. These “stress bands” are potentially valuable proxies for thermal tolerance, but to date their application to questions of community bleaching history has been limited. Ecological surveys recorded bleaching of coral communities across the Palau archipelago during the 1998 and 2010 warm events. Between 2011 and 2015, we extracted skeletal cores from living Porites colonies at 10 sites spanning barrier reef and lagoon environments and quantified the proportion of stress bands present in each population during bleaching years. Across Palau, the prevalence of stress bands tracked the severity of thermal stress, with more stress bands occurring in 1998 (degree heating weeks = 13.57 °C-week) than during the less severe 2010 event (degree heating weeks = 4.86 °C-week). Stress band prevalence also varied by reef type, as more corals on the exposed barrier reef formed stress bands than did corals from sheltered lagoon environments. Comparison of Porites stress band prevalence with bleaching survey data revealed a strong correlation between percent community bleaching and the proportion of colonies with stress bands in each year. Conversely, annual calcification rates did not decline consistently during bleaching years nor did annually resolved calcification histories always track interannual variability in temperature. Our data suggest that stress bands in massive corals contain valuable information about spatial and temporal trends in coral reef bleaching and can aid in conservation efforts to identify temperature-tolerant coral reef communities.

     

A cytomic approach reveals population heterogeneity of Cupriavidus necator in response to harmful phenol concentrations

The understanding of functions of cells within microbial populations or communities is certainly needed for existing and novel cytomic approaches which grip the individual scale. Population behaviour results from single cell performances and is caused by the individual genetic pool, history, life cycle states and microenvironmental surroundings. Mimicking natural impaired environments, the paper shows that the Gram-negative Betaproteobacterium Cupriavidus necator dramatically altered its population heterogeneity in response to harmful phenol concentrations. Multiparametric flow cytometry was used to follow variations in structural cellular parameters like chromosome contents and storage materials. The functioning of these different cell types was resolved by ensuing proteomics after the cells' spatial separation by cell sorting, finding 11 proteins changed in their expression profile, among them elongation factor Tu and the trigger factor. At least one third of the individuals clearly underwent starving states; however, simultaneously these cells prepared themselves for entering the life cycle again. Using cytomics to recognise individual structure and function on the microbial scale represents an innovative technical design to describe the complexity of such systems, overcoming the disadvantage of small cell volumes and, thus, to resolve bacterial strategies to survive harmful environments by altering population heterogeneity.     

The effect of species and colony size on the bleaching response of reef-building corals in the Florida Keys during the 2005 mass bleaching event

Understanding the variation in coral bleaching response is necessary for making accurate predictions of population changes and the future state of reefs in a climate of increasing thermal stress events. Individual coral colonies, belonging to inshore patch reef communities of the Florida Keys, were followed through the 2005 mass bleaching event. Overall, coral bleaching patterns followed an index of accumulated thermal stress more closely than in situ temperature measurements. Eight coral species (Colpophyllia natans, Diploria strigosa, Montastraea cavernosa, M. faveolata, Porites astreoides, P. porites, Siderastrea siderea, and Stephanocoenia intersepta), representing >90% of the coral colonies studied, experienced intense levels of bleaching, but responses varied. Bleaching differed significantly among species: Colpophyllia natans and Diploria strigosa were most susceptible to thermal stress, while Stephanocoenia intersepta was the most tolerant. For colonies of C. natans, M. faveolata, and S. siderea, larger colonies experienced more extensive bleaching than smaller colonies. The inshore patch reef communities of the Florida Keys have historically been dominated by large colonies of Montastraea sp. and Colpophyllia natans. These results provide evidence that colony-level differences can affect bleaching susceptibility in this habitat and suggest that the impact of future thermal stress events may be biased toward larger colonies of dominant reef-building species. Predicted increases in the frequency of mass bleaching and subsequent mortality may therefore result in significant structural shifts of these ecologically important communities.     

Photophysiological stress in scleractinian corals in response to short-term sedimentation

Effects of short-term sedimentation on common coastal coral species were investigated in laboratory and field experiments on the Great Barrier Reef (GBR) using pulse-amplitude modulated (PAM) chlorophyll fluorometry. In the laboratory, changes in maximal quantum yields of photosystem II (F_v/F_m) in Montipora peltiformis were examined in response to the amount of sedimentation (79-234 mg cm⁻²) and duration of exposure (0-36 h). In control colonies, F_v/F_m ranged from 0.67 to 0.71, and did not show any temporal trend, while maximum yields of sediment-covered fragments declined steadily and reached levels below 0.1 in most colonies after 36 h coverage. Maximal quantum yield in M. peltiformis declined linearly in relation to both the amount of sediment deposited per unit surface area and the duration of exposure. Zooxanthellae densities and chlorophyll concentrations per unit area of sediment-treated corals decreased in the same manner, however, their responses were not quite as strong as the changes in F_v/F_m. Within the ranges measured, sedimentation stress of colonies exposed to large amounts of sediment for short periods of time was similar to that exposed to low amounts of sediments for prolonged periods of time. Colonies were recovered from short-term, or low-level, sedimentation within <36 h, whereas long-term exposure, or high levels of sedimentation, killed exposed colony parts. Field experiments comparing susceptibilities of common coastal coral species towards sedimentation showed significant reductions in effective quantum yields (ΔF/F_m′) in 9 out of 12 common coastal species after 22 h of exposure. Three out of twelve investigated species were not affected by the experimental application of sediments (Galaxea fascicularis, Fungia crassa, and Pectinia lactuca). Our results suggest that anthropogenic sediment deposition can negatively affect the photosynthetic activity of zooxanthellae and thus the viability of corals. However, the results also showed the ability of corals to compartmentalise sedimentation stress, as the photosynthetic activity only from tissues directly underneath the sediment declined, whereas that of adjacent clean tissues did not change measurably.     

Photoinhibition, bleaching susceptibility and mortality in two scleractinian corals, Platygyra ryukyuensis and Stylophora pistillata, in response to thermal and light stresses

In the present study, we examined the effect of thermal stress on the photoinhibitory light threshold in a bleaching susceptible (Stylophora pistillata) and a bleaching resistant (Platygyra ryukyuensis) coral. Four light (0, 110, 520, 1015 micromol quantam(-2)s(-1)) and three temperature (26, 32 and 34 degrees C) conditions were used over a 3-h period, followed by 24- and 48-h recovery periods at approximately 21 degrees C under dim light. Dynamic photoinhibition could be detected in both P. ryukyuensis and S. pistillata under 520 and 1015 micromol quantam(-2)s(-1) at 26 degrees C and under 110 micromol quantam(-2)s(-1) at 32 degrees C only in S. pistillata. Chronic photoinhibition was recorded under 520 and 1015 micromol quantam(-2)s(-1) at 34 degrees C in P. ryukyuensis, and under 1015 micromol quantam(-2)s(-1) at 32 degrees C and under all light levels at 34 degrees C in S. pistillata. These results show that high temperature reduced the threshold light intensity for photoinhibition differently in two corals with different bleaching susceptibilities under thermal stress. No visual paling and mortality in P. ryukyuensis was observed at any treatment, even in chronically photoinhibited specimens, while paling and high mortality of S. pistillata was noted in all treatments, apart from samples at 26 degrees C. These observations suggest a potential role of the host in differential bleaching and mortality determination.     

A systems approach to prion disease

Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrP^C) to disease‐causing PrP^Sc isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrP^Sc replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches.     

A systems approach to animal communication

Why animal communication displays are so complex and how they have evolved are active foci of research with a long and rich history. Progress towards an evolutionary analysis of signal complexity, however, has been constrained by a lack of hypotheses to explain similarities and/or differences in signalling systems across taxa. To address this, we advocate incorporating a systems approach into studies of animal communication—an approach that includes comprehensive experimental designs and data collection in combination with the implementation of systems concepts and tools. A systems approach evaluates overall display architecture, including how components interact to alter function, and how function varies in different states of the system. We provide a brief overview of the current state of the field, including a focus on select studies that highlight the dynamic nature of animal signalling. We then introduce core concepts from systems biology (redundancy, degeneracy, pluripotentiality, and modularity) and discuss their relationships with system properties (e.g. robustness, flexibility, evolvability). We translate systems concepts into an animal communication framework and accentuate their utility through a case study. Finally, we demonstrate how consideration of the system-level organization of animal communication poses new practical research questions that will aid our understanding of how and why animal displays are so complex.     

A model management systems approach to manufacturing systems design

Manufacturing systems design involves the solution of a complex series of interrelated problems. This complexity will increase in the future as manufacturing practices change to meet increased global competition. Research within manufacturing systems design has mainly been focused on finding improved models for solving particular problems, or extending existing modeling techniques. This has resulted in numerous modeling tools being available to support manufacturing systems design. However, little research work has been carried out into consolidating the existing theories and models. As a result, a large body of this work has not been applied in industry. Model management has evolved as a research area which investigates methods for storing, modifying, and manipulating models. This article describes a prototype model management system for manufacturing systems design. The objective here is not to develop “another” decision support system for manufacturing design, but to illustrate, through the development of a prototype system, a number of key ideas of how concepts from the area of model management systems can be used to support manufacturing systems design. The prototype model management system utilizes the structured modeling framework and uses an extended version of the structured modeling language. An important aspect of the prototype model management system is the incorporation of the model development task, thus allowing the system to be easily updated and adapted. The prototype system was evaluated using a range of queueing network models for manufacturing systems design.     

Cell biology in model systems as the key to understanding corals

Corals provide the foundation of important tropical reef ecosystems but are in global decline for multiple reasons, including climate change. Coral health depends on a fragile partnership with intracellular dinoflagellate symbionts. We argue here that progress in understanding coral biology requires intensive study of the cellular processes underlying this symbiosis. Such study will inform us on how the coral symbiosis will be affected by climate change, mechanisms driving coral bleaching and disease, and the coevolution of this symbiosis in the context of other host-microbe interactions. Drawing lessons from the broader history of molecular and cell biology and the study of other host-microbe interactions, we argue that a model-systems approach is essential for making effective progress in understanding coral cell biology.     

A nonlinear systems approach to Fechner's Paradox

It is possible to predict the topology of isointensity plots under conditions of extreme imbalance of the stimulus inputs, without making any assumptions specific to the circumstances in which Fechner's Paradox is sometimes observed. This is done by extending a nonlinear model for a sensory channel, by postulating a form of cross-coupling or interference between two channels which represents other phenomena in psychophysics. It is noted that the form in which data are usually reported is not an adequate basis for testing all the predictions of a nonlinear model in sensory psychophysics. The physiologist Panum (1958), and later Fechner (1860) reported that the apparent brightness of an object viewed binocularly could, under conditions where the input to one eye was diminished by filtering, be less than its brightness viewed monocularly by the unfiltered eye. To a first approximation, binocular brightness is more like an averaging of two monocular inputs than a summation of those same inputs. For over 120 years this phenomenon, which came to be called Fechner's Paradox, though Panum should perhaps have had some credit, has been the subject of experimental investigation and associated mathematical modelling. If one consults a dictionary of psychological terms, for example Evans (1978), one may read something like Fechner's Paradox: The name give to the observation that something [which is] viewed binocularly seems to increase in brightness when one eye is closed. And yet we now know that this definition is misleading, because the same phenomenon in pooling two sensory inputs has its analogues in audition (Lehky 1983) and in olfaction (Gregson 1986). Gilchrist and McIver (1985) have now shown an analogue of the paradox exists in ocular contrast sensitivity. The definition also goes awry when the input luminance to one eye is zero, or when the luminance and ocular adaptation are closely matched for the two eyes. It is wiser, in the light of results reporting individual differences in the existence and extent of the paradox, and its sensitivity to stimulus conditions, to side with Blake and Fox (1973) when they observed that it is not unreasonable to suppose that various stimulus conditions might yield varying amounts of summation or even inhibition. Empirical reviews of relevant data in vision have been given by Roelofs and Zeeman (1914), Blake and Fox (1973), and Blake et al. (1981), but a theoretical model of interest as a starting point is that of Lehky (1983).     

A systems biology approach to learning autophagy

With its relevance to our understanding of eukaryotic cell function in the normal and disease state, autophagy is an important topic in modern cell biology; yet, few textbooks discuss autophagy beyond a two- or three-sentence summary. Here, we report an undergraduate/graduate class lesson for the in-depth presentation of autophagy using an active learning approach. By our method, students will work in small groups to solve problems and interpret an actual data set describing genes involved in autophagy. The problem-solving exercises and data set analysis will instill within the students a much greater understanding of the autophagy pathway than can be achieved by simple rote memorization of lecture materials; furthermore, the students will gain a general appreciation of the process by which data are interpreted and eventually formed into an understanding of a given pathway. As the data sets used in these class lessons are largely genomic and complementary in content, students will also understand first-hand the advantage of an integrative or systems biology study: No single data set can be used to define the pathway in full-the information from multiple complementary studies must be integrated in order to recapitulate our present understanding of the pathways mediating autophagy. In total, our teaching methodology offers an effective presentation of autophagy as well as a general template for the discussion of nearly any signaling pathway within the eukaryotic kingdom.     

A systems theoretical approach to biological membranes

Zusammenfassung In der vorliegenden Arbeit wird die Eindeutigkeit der Beschreibung erregbarer Membranen mit Hilfe von Ersatzschaltungen untersucht. Bei Voraussetzung der Existenz verschiedener Membrankanäle für den Ionentransport läßt sich unter Berücksichtigung nichtlinearer Eigenschaften eine weitgehend eindeutige Ersatzschaltung für einen Kanal angeben. Als wesentliches Kriterium erweist sich dabei das Vorhandensein eines konstanten Gleichgewichts-potentials für jeden Kanal. Der lonentransport durch die Membran wird durch ein einfaches Elektrodiffusionsmodell beschrieben. Hierin ist der Potentialverlauf in der Membran durch physiko-chemische Eigenschaften der Membran und nicht durch die transportierten Ionen bestimmt. Die Leitfähigkeit eines bestimmten Kanals verändert eine Steuervariable, deren Wert sich mit Hilfe einer algebraischen Beziehung aus den Zustandsvariablen eines linearen Differentialgleichungssystems ergibt (dessen Koeffizienten vom Potential über der Zellmembran abhängen). Die Zusammenfassung mehrerer Kanäle (passives Transportsystem) und die Einführung von Stromgeneratoren für den aktiven Transport (deren Effektivität von der chemischen Zusammensetzung der an die Membran angrenzenden Lösungen abhängt) führt zu einer allgemeinen Ersatzschaltung für die erregbare Membran. Die so gewonnene Beschreibung ist hinreichend allgemeingültig, um als Grundlage für die Analyse von Problemen der Informationsverarbeitung im Nervensystem bzw. für die weitere Aufklärung der in der erregbaren Membran ablaufenden physikalisch-chemischen Prozesse zu dienen.

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Presented in part at the IV. Intern. Biophysics Congress, Moscow, August 1972.