Browsing by Issue Date, starting with "2018-08"
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- Antibodies aggravate the development of ischemic heart failurePublication . Keppner, Lea; Heinrichs, Margarete; Rieckmann, Max; Jocelyne, Demengeot; Frantz, Stefan; Hofmann, Ulrich; Ramos, GustavoHeart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure in agammaglobulinemic mice (AID-/-μS-/-). Although these animals can produce functional B cells, they cannot synthesize secretory IgM (μS-/-) or perform Ig class switching (AID-/-), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that, compared with wild-type infarcted control mice, AID-/-μS-/- mice exhibited improved cardiac function and reduced remodeling on day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AID-/-μS-/- mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as matrix metalloproteinase-9, collagen type I a1, collagen type III a1, and IL-6. An unbiased screening of the heart reactivity potential in the plasma of wild-type MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic heart failure progression and provide novel insights into the mechanisms underlying this phenomenon. NEW & NOTEWORTHY Our study sheds some light on the long-standing debate over the relevance of autoantibodies in heart failure and might stimulate future research in the field. The observation of extracellular matrix-specific antibodies and the detection of Fcγ receptor-expressing cells within the scar provide novel insights into the mechanisms by which antibodies may contribute to adverse remodeling.
- CANA: A python package for quantifying control and canalization in Boolean NetworksPublication . Correia, Rion Brattig; Gates, Alexander J.; Wang, Xuan; Rocha, Luis M.Logical models offer a simple but powerful means to understand the complex dynamics of biochemical regulation, without the need to estimate kinetic parameters. However, even simple automata components can lead to collective dynamics that are computationally intractable when aggregated into networks. In previous work we demonstrated that automata network models of biochemical regulation are highly canalizing, whereby many variable states and their groupings are redundant (Marques-Pita and Rocha, 2013). The precise charting and measurement of such canalization simplifies these models, making even very large networks amenable to analysis. Moreover, canalization plays an important role in the control, robustness, modularity and criticality of Boolean network dynamics, especially those used to model biochemical regulation (Gates and Rocha, 2016; Gates et al., 2016; Manicka, 2017). Here we describe a new publicly-available Python package that provides the necessary tools to extract, measure, and visualize canalizing redundancy present in Boolean network models. It extracts the pathways most effective in controlling dynamics in these models, including their effective graph and dynamics canalizing map, as well as other tools to uncover minimum sets of control variables.
- Alternative Splicing as a Regulator of Early Plant DevelopmentPublication . Szakonyi, Dóra; Duque, PaulaMost plant genes are interrupted by introns and the corresponding transcripts need to undergo pre-mRNA splicing to remove these intervening sequences. Alternative splicing (AS) is an important posttranscriptional process that creates multiple mRNA variants from a single pre-mRNA molecule, thereby enhancing the coding and regulatory potential of genomes. In plants, this mechanism has been implicated in the response to environmental cues, including abiotic and biotic stresses, in the regulation of key developmental processes such as flowering, and in circadian timekeeping. The early plant development steps - from embryo formation and seed germination to skoto- and photomorphogenesis - are critical to both execute the correct body plan and initiate a new reproductive cycle. We review here the available evidence for the involvement of AS and various splicing factors in the initial stages of plant development, while highlighting recent findings as well as potential future challenges.
- The fitness landscape of the codon space across environmentsPublication . Fragata, Inês; Matuszewski, Sebastian; Schmitz, Mark A.; Bataillon, Thomas; Jensen, Jeffrey D.; Bank, ClaudiaFitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and re-estimate selection coefficients of all possible codon mutations across 9 amino acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies.