Systems Biology of the qa Gene Cluster in Neurospora crassa

An ensemble of genetic networks that describe how the model fungal system, Neurospora crassa, utilizes quinic acid (QA) as a sole carbon source has been identified previously. A genetic network for QA metabolism involves the genes, qa-1F and qa-1S, that encode a transcriptional activator and repressor, respectively and structural genes, qa-2, qa-3, qa-4, qa-x, and qa-y. By a series of 4 separate and independent, model-guided, microarray experiments a total of 50 genes are identified as QA-responsive and hypothesized to be under QA-1F control and/or the control of a second QA-responsive transcription factor (NCU03643) both in the fungal binuclear Zn(II)2Cys6 cluster family. QA-1F regulation is not sufficient to explain the quantitative variation in expression profiles of the 50 QA-responsive genes. QA-responsive genes include genes with products in 8 mutually connected metabolic pathways with 7 of them one step removed from the tricarboxylic (TCA) Cycle and with 7 of them one step removed from glycolysis: (1) starch and sucrose metabolism; (2) glycolysis/glucanogenesis; (3) TCA Cycle; (4) butanoate metabolism; (5) pyruvate metabolism; (6) aromatic amino acid and QA metabolism; (7) valine, leucine, and isoleucine degradation; and (8) transport of sugars and amino acids. Gene products both in aromatic amino acid and QA metabolism and transport show an immediate response to shift to QA, while genes with products in the remaining 7 metabolic modules generally show a delayed response to shift to QA. The additional QA-responsive cutinase transcription factor-1β (NCU03643) is found to have a delayed response to shift to QA. The series of microarray experiments are used to expand the previously identified genetic network describing the qa gene cluster to include all 50 QA-responsive genes including the second transcription factor (NCU03643). These studies illustrate new methodologies from systems biology to guide model-driven discoveries about a core metabolic network involving carbon and amino acid metabolism in N. crassa

A framework for evolutionary systems biology

<p>Abstract</p> <p>Background</p> <p>Many difficult problems in evolutionary genomics are related to mutations that have weak effects on fitness, as the consequences of mutations with large effects are often simple to predict. Current systems biology has accumulated much data on mutations with large effects and can predict the properties of knockout mutants in some systems. However experimental methods are too insensitive to observe small effects.</p> <p>Results</p> <p>Here I propose a novel framework that brings together evolutionary theory and current systems biology approaches in order to quantify small effects of mutations and their epistatic interactions <it>in silico</it>. Central to this approach is the definition of fitness correlates that can be computed in some current systems biology models employing the rigorous algorithms that are at the core of much work in computational systems biology. The framework exploits synergies between the realism of such models and the need to understand real systems in evolutionary theory. This framework can address many longstanding topics in evolutionary biology by defining various 'levels' of the adaptive landscape. Addressed topics include the distribution of mutational effects on fitness, as well as the nature of advantageous mutations, epistasis and robustness. Combining corresponding parameter estimates with population genetics models raises the possibility of testing evolutionary hypotheses at a new level of realism.</p> <p>Conclusion</p> <p>EvoSysBio is expected to lead to a more detailed understanding of the fundamental principles of life by combining knowledge about well-known biological systems from several disciplines. This will benefit both evolutionary theory and current systems biology. Understanding robustness by analysing distributions of mutational effects and epistasis is pivotal for drug design, cancer research, responsible genetic engineering in synthetic biology and many other practical applications.</p

Discovering novel biology by in silico archaeology

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Shame and Non-suicidal Self-injury: Conceptualization and Preliminary Test of a Novel Developmental Model among Emerging Adults

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Non-suicidal self-injury (NSSI) is particularly prevalent during adolescence and emerging adulthood. The salience of shame during these developmental periods suggests that shame may be inherently linked to NSSI, and at least partially explain the high rates of NSSI observed among youth. In this article, a theoretical developmental model relating shame and NSSI is proposed, and results from a preliminary test of a sub-set of cross-sectional relationships in this model is presented. In the model tested, it was hypothesized that adverse caregiving experiences in prior development (i.e., childhood to late adolescence) like parental invalidation and child maltreatment, established predictors of NSSI, would be linked to proximal episodes of NSSI (i.e., past year) through current shame-proneness (i.e., experiencing shame in a trait-like manner) and internalizing shame-coping (i.e., responding to shame through attacking one’s self and withdrawing). It was also hypothesized that some key proximal predictors of NSSI during youth development, such as low body esteem, increased loneliness and heightened psychological distress, would be linked to proximal NSSI via shame-proneness and internalizing shame-coping. Using structural equation modelling, it was observed that data, obtained via self-reports completed by 573 emerging adults (age in years: M = 20.7, SD = 2.20, 69.1% female, NSSI history: n = 220, where most recent NSSI episode was within a year of study participation) recruited throughout Australia between June 2013 and June 2014, fit the hypothesized model well. Tests of indirect effects indicated that current shame-proneness and internalizing shame-coping significantly linked perceived parental invalidation and prior experiences of child maltreatment to proximal NSSI, though this relationship was, unexpectedly, an inverse one in relation to child maltreatment. Current shame-proneness was also linked to proximal NSSI via internalizing shame-coping, current loneliness, and current psychological distress, but not through current body esteem. Finally, proximal self-evaluations of body esteem, loneliness and increased psychological distress were linked to recent NSSI through internalizing shame-coping. The theory and findings presented in this article contribute to a deeper developmental understanding of NSSI among youth, highlight crucial pathways between adverse caregiving experiences and NSSI, and illuminate important shame-based mechanisms that potentially warrant clinical attention for at-risk individuals. Future research directions and clinical recommendations are discussed