Biology subjects

Klawitter, J.

Publications and source records attributed to Klawitter, J..

4 recordsLinked to original sources

bioRxiv2024

Skeletons in the Forest: Using Entropy-Based Rogue Detection on Bayesian Phylogenetic Tree Distributions

In a phylogenetic analysis, rogue taxa and clades are those that, due to their uncertain placement, contribute disproportionally to the variance in a set of phylogenetics trees. They can obscure clear evolutionary relationships and complicate the interpretation of results. While existing rogue detection algorithms focus on improving the consensus tree for a set of trees, we introduce algorithms based on phylogenetic entropy to improve the analysis in a Bayesian framework. In particular, we introduce a tool that extracts a skeleton distribution of the posterior tree distribution that contains the core relationships by removing a minimal subset of rogues. Additionally, we enable detailed analyses of rogues at both the taxon and clade levels, including the visualisation of different rogue placements.

bioinformatics↗

bioRxiv2024

Priming lymphocyte responsiveness and differential T cell signaling in pediatric IBD patients with Cannabis use.

The prevalence of inflammatory bowel disease (IBD) has increased dramatically in recent years, particularly in pediatric populations. Successful remission with current therapies is limited and often transient, leading patients to seek alternative therapies for symptom relief, including the use of medical marijuana (Cannabis sativa). However, chronic cannabis use among IBD patients is associated with increased risk for surgical interventions. Therefore, determining the direct impact of cannabis use on immune modulation in IBD patients is of critical importance. Peripheral blood mononuclear cells of cannabis using and non-using pediatric IBD patients were phenotyped by flow cytometry and functionally assessed for their cytokine production profile. A phospho-kinase array was also performed to better understand changes in immune responses. Results were then compared with serum phytocannabinoid profiles of each patient to identify cannabinoid-correlated changes in immune responses.Results demonstrated elevated levels of a myriad of pro-inflammatory cytokines in users versus non-users. Differences in signaling cascades of activated T cells between users and non-users were also observed. A number of anti-inflammatory cytokines were inversely correlated with serum phytocannabinoids. These results suggest that cannabis exposure, which can desensitize cannabinoid receptors, may prime pro-inflammatory pathways in pediatric IBD patients. Article SummaryThis observational study examines the impact of chronic cannabis use on peripheral immune cell function in adolescent IBD patients from Childrens Hospital Colorado. Cannabis users displayed altered T cell phenotype, increased pro-inflammatory cytokine release and dephosphorylation of protective protein kinases.

immunology↗

bioRxiv2024

A tractable tree distribution parameterized by clade probabilities and its application to Bayesian phylogenetic point estimation

Bayesian phylogenetic analysis with MCMC algorithms generates an estimate of the posterior distribution of phylogenetic trees in the form of a sample of phylogenetic trees and related parameters. The high dimensionality and non-Euclidean nature of tree space complicates summarizing the central tendency and variance of the posterior distribution in tree space. Here we introduce a new tractable tree distribution and associated point estimator that can be constructed from a posterior sample of trees. Through simulation studies we show that this point estimator performs at least as well and often better than standard methods of producing Bayesian posterior summary trees. We also show that the method of summary that performs best depends on the sample size and dimensionality of the problem in non-trivial ways. Author summaryOur research introduces novel methods to analyse a set of phylogenetic tree topologies, such as those generated by Bayesian Markov Chain Monte Carlo algorithms. We define a new model for a distribution on trees that is based on observed clade frequencies. We study it together with closely related models that are based on observed clade split frequencies. These distributions are easy to work with and, as we show experimentally, provide excellent estimates of the true posterior distribution. Furthermore, we demonstrate that they enable us to find the tree with the highest posterior probability, which acts as a summary tree or point estimate of the distribution. In simulation studies, we show that the new methods performs as least as well or better than existing methods. Additionally, we highlight that choosing the best method for summarizing sets of trees remains challenging, as it depends on the sample size and complexity of the problem in non-trivial ways. This work has the potential to improve the accuracy of phylogenetic studies.

bioinformatics↗

bioRxiv2022

The Tryptophan Metabolizing Enzyme Indoleamine 2,3-Dioxygenase 1 Regulates Polycystic Kidney Disease Progression

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability exceeding genic effects. Dysregulated metabolism and immune cell function are key disease modulators. The tryptophan metabolites, kynurenines, produced through IDO1, are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57Bl/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wildtype. Further, IDO1 levels were increased in ADPKD cell lines and patient cyst cells. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity as measured by %kidney weight/body weight and cystic index. Consistent with a immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Of note, kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition using a tryptophan analog in Pkd1RC/RC animals resulted in less severe PKD versus controls with similar changes in the CME as in the genetic model. Together, our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a novel therapeutic target for ADPKD.

molecular biology↗