Biology subjects

Willmann, M.

Publications and source records attributed to Willmann, M..

5 recordsLinked to original sources

bioRxiv2026

Tracking Inflammation and Fibroblast Activation in Hypertensive Heart Failure Across the Cardio-Renal Axis

Hypertension and heart failure are associated with increased risk of chronic kidney disease. Cardiorenal syndrome is characterized by excessive systemic inflammation and progressive fibrosis. We hypothesized that transient hypertension in mice due to infusion of angiotensin II and phenylephrine (Ang/Phe) would induce parallel immune cell and fibroblast activation in both the heart and kidney, where the intensity of inflammation and fibroblast activity would predict decline in function of both organs. Adult male C57Bl/6N mice were randomized to receive 7d infusion of either Ang/Phe (n=41) or vehicle (n=27) by subcutaneous osmotic minipump. Despite removal of minipumps at 7d, Ang/Phe mice displayed persistent myocyte hypertrophy, interstitial fibrosis, and modestly reduced systolic function to 6 weeks. Molecular imaging of chemokine receptor CXCR4 using 68Ga-pentixafor at 3d of Ang/Phe infusion revealed transient inflammation in the left ventricle. Imaging of fibroblast activation protein (FAP) revealed diffuse fibroblast activity in the left ventricle. Both imaging signals predicted subsequent functional decline. Magnetic resonance imaging of the kidney revealed transient prolongation of T1 relaxation in at 2 weeks after Ang/Phe infusion that returned to normal by 6wk, despite a progressive reduction in renal perfusion. CXCR4 and FAP PET displayed no change in kidney inflammation or fibroblast activation. Comparison of imaging data described a direct correlation between cardiac and renal CXCR4 PET signal at 3d and FAP PET signal at 7d. The intensity of cardiac inflammation correlated with subchronic fibrosis in the kidney cortex. Total body molecular imaging enables simultaneous evaluation of the immune-fibrosis network in heart-kidney crosstalk after short term hypertension and may provide valuable guidance of novel therapies.

physiology↗

bioRxiv2019

Human gut mobileome during antibiotic therapy. A trajectory-based approach to analysis of the metagenomic time-series datasets

MotivationAntibiotic resistance is widely recognized as a severe threat to current medical practice. Each antibiotic therapy drives the emergence and subsequent retention of antibiotics resistance genes within the human gut microbiome. However, the details on how the resistance spreads between bacteria within the human gut remain unknown, as does the role of horizontal gene transfer in this process, too.\n\nResultsWe present a novel approach to the analysis of time-series whole-genome metagenomic sequencing data. This involves partitioning the scaffolds from the metagenomic assembly into groups corresponding to bacterial chromosomes, plasmids and those with prophages and transposons. Using specialized sequencing of the bacteriophages we were able to track the flow of ciprofloxacin resistance genes from bacterial chromosomes, through the plasmids, to prophages and phages.\n\nContactanna.gorska@univr.it.

bioinformatics↗

bioRxiv2019

Tracking of antibiotic resistance transfer and rapid plasmid evolution in a hospital setting by Nanopore sequencing

BackgroundInfection of patients with multidrug-resistant (MDR) bacteria often leave very limited or no treatment options. The transfer of antimicrobial resistance genes (ARG) carrying plasmids between bacterial species by horizontal gene transfer represents an important mode of expansion of ARGs. Here, we evaluated the application of Nanopore sequencing technology in a hospital setting for monitoring the transfer and rapid evolution of antibiotic resistance plasmids within and across multiple species.\n\nResultsIn 2009 we experienced an outbreak with an extensively multidrug resistant P. aeruginosa harboring the carbapenemase enzyme blaIMP-8, and in 2012 the first Citrobacter freundii and Citrobacter werkmanii harboring the same enzyme were detected. Using Nanopore and Illumina sequencing we conducted a comparative analysis of all blaIMP-8 bacteria isolated in our hospital over a 6-year period (n = 54). We developed the computational platforms pathoLogic and plasmIDent for Nanopore-based characterization of clinical isolates and monitoring of ARG transfer, comprising de-novo assembly of genomes and plasmids, polishing, QC, plasmid circularization, ARG annotation, comparative genome analysis of multiple isolates and visualization of results. Using plasmIDent we identified a 40 kb plasmid carrying blaIMP-8 in P. aeruginosa and C. freundii, verifying that plasmid transfer had occurred. Within C. freundii the plasmid underwent further evolution and plasmid fusion, resulting in a 164 kb mega-plasmid, which was transferred to C. werkmanii. Moreover, multiple rearrangements of the multidrug resistance gene cassette were detected in P. aeruginosa, including deletions and translocations of complete ARGs.\n\nConclusionPlasmid transfer, plasmid fusion and rearrangement of the multidrug resistance gene cassette mediated the rapid evolution of opportunistic pathogens in our hospital. We demonstrated the feasibility of tracking plasmid evolution dynamics and ARG transfer in clinical settings in a timely manner. The approach will allow for successful countermeasures to contain not only clonal, but also plasmid mediated outbreaks.

genomics↗

bioRxiv2018

Multi-omics approach identifies novel pathogen-derived prognostic biomarkers in patients with Pseudomonas aeruginosa bloodstream infection

Pseudomonas aeruginosa is a human pathogen that causes health-care associated blood stream infections (BSI). Although P. aeruginosa BSI are associated with high mortality rates, the clinical relevance of pathogen-derived prognostic biomarker to identify patients at risk for unfavorable outcome remains largely unexplored. We found novel pathogen-derived prognostic biomarker candidates by applying a multi-omics approach on a multicenter sepsis patient cohort. Multi-level Cox regression was used to investigate the relation between patient characteristics and pathogen features (2298 accessory genes, 1078 core protein levels, 107 parsimony-informative variations in reported virulence factors) with 30-day mortality. Our analysis revealed that presence of the helP gene encoding a putative DEAD-box helicase was independently associated with a fatal outcome (hazard ratio 2.01, p = 0.05). helP is located within a region related to the pathogenicity island PAPI-1 in close proximity to a pil gene cluster, which has been associated with horizontal gene transfer. Besides helP, elevated protein levels of the bacterial flagellum protein FliL (hazard ratio 3.44, p < 0.001) and of a bacterioferritin-like protein (hazard ratio 1.74, p = 0.003) increased the risk of death, while high protein levels of a putative aminotransferase were associated with an improved outcome (hazard ratio 0.12, p < 0.001). The prognostic potential of biomarker candidates and clinical factors was confirmed with different machine learning approaches using training and hold-out datasets. The helP genotype appeared the most attractive biomarker for clinical risk stratification due to its relevant predictive power and ease of detection.

microbiology↗

bioRxiv2016

Rapid and consistent evolution of colistin resistance in Pseudomonas aeruginosa during morbidostat culture

Colistin is a last resort antibiotic commonly used against multidrug-resistant strains of Pseudomonas aeruginosa. To investigate the potential for in-situ evolution of resistance against colistin and map the molecular targets of colistin resistance, we exposed two P. aeruginosa isolates to colistin using a continuous culture device known as morbidostat. Colistin resistance emerged within two weeks along with highly stereotypic yet strain specific mutation patterns. The majority of mutations hit the prmAB two component signaling system and genes involved in lipopolysaccharide synthesis, including lpxC, pmrE, and migA. In seven out of 18 cultures, we observed mutations in mutS along with a mutator phenotype that seemed to facilitate resistance evolution.

microbiology↗