Biology subjects

Zoll, J.

Publications and source records attributed to Zoll, J..

4 recordsLinked to original sources

bioRxiv2026

Androgen Receptor mediates beige adipocyte homeostasis and plasticity

Male adipose tissue undergoes profound post-pubertal remodeling characterized by the progressive transition of beige adipocytes toward a white adipocyte phenotype. Although androgen signaling has been implicated in adipose tissue biology, its role in beige adipocyte remodeling and metabolic plasticity remains poorly understood. Here we show that androgen receptor (AR) signaling is dynamically activated in inguinal white adipose tissue during the post-pubertal beige-to-white transition in male mice. Inducible deletion of AR in beige adipocytes impaired this remodeling process, resulting in the persistence of multilocular beige-like adipocytes despite reduced thermogenic competence and marked mitochondrial abnormalities. Transcriptomic and cistromic analyses identified AR as a direct regulator of adipocyte metabolic and differentiation programs, whereas immune-related transcriptional signatures in AR-deficient adipose tissue primarily reflected macrophage infiltration and inflammatory remodeling. Loss of AR promoted mitochondrial dysfunction, mitophagy, and altered glucose handling, while cell-autonomous AR silencing in beige adipocytes recapitulated key defects in mitochondrial organization and adipocyte identity. Longitudinal and metabolic challenge studies further demonstrated that AR signaling is required for age-associated adipose remodeling and adaptive beige adipocyte plasticity during high-fat diet feeding and cold exposure. Together, these findings identify AR as a central regulator of beige adipocyte remodeling, mitochondrial homeostasis, and adaptive metabolic function in male adipose tissue.

physiology↗

bioRxiv2021

Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance

Olorofim (F901318) is a new antifungal currently under clinical development that shows both in vitro and in vivo activity against a number of filamentous fungi including Aspergillus fumigatus. In this study we screened A. fumigatus isolates for intrinsic olorofim-resistant A. fumigatus and evaluated the ability of A. fumigatus to acquire an olorofim-resistant phenotype. No intrinsic resistance was found in 975 clinical A. fumigatus isolates. However, we found that isolates with increased olorofim MICs (> 8 mg/L) could be selected using a high number of conidia and olorofim exposure under laboratory conditions. Assessment of the frequency of acquired olorofim resistance development of A. fumigatus was shown to be higher than for voriconazole but lower than for itraconazole. Sequencing the PyrE gene of isogenic isolates with olorofim MICs of >8 mg/L identified various amino acid substitutions with a hotspot at locus G119. Olorofim was shown to have reduced affinity to mutated target protein dihydroorotate dehydrogenase (DHODH) and the effect of these mutations were proven by introducing the mutations directly in A. fumigatus. We then investigated whether G119 mutations were associated with a fitness cost in A. fumigatus. These experiments showed a small but significant reduction in growth rate for strains with a G119V substitution, while strains with a G119C substitution did not exhibit a reduction in growth rate. These in vitro findings were confirmed in an in vivo pathogenicity model. ImportanceOlorofim represents an important new treatment option for patients with difficult to treat invasive fungal infections, including triazole-resistant A. fumigatus infection. Our study provides insights into one resistance mechanism and the potential dynamics of olorofim resistance, which will help to prevent and manage resistance selection. Such insights are critical to antifungal stewardship and to safeguard its prolonged use in clinical practice.

microbiology↗

bioRxiv2019

Surveillance-embedded genomic outbreak resolution of methicillin-susceptible Staphylococcus aureus in a neonatal intensive care unit

BackgroundWe observed an increase in methicillin-susceptible Staphylococcus aureus (MSSA) infections among neonates at a Dutch third level neonatal intensive care unit. Weekly surveillance data of MSSA carriage among neonates and cross-sectional screenings of health care workers (HCWs) were available for outbreak tracing. While traditional typing of MSSA isolates by staphylococcal protein A gene (spa typing) and Multiple-Locus Variable number tandem repeat Analysis (MLVA) suggested that nosocomial transmission had contributed to the infections, here they lacked the resolution to draw solid conclusions.\n\nMethodsMSSA isolates from neonatal infections, carriage surveillance, and HCWs were subjected to whole-genome sequencing and compared by a series of automated tools including de novo assembly, identification and localization of high-quality single nucleotide polymorphisms, and in-depth analysis of subsets of isolates. Outbreaks were defined as isolates that were more closely related than was to be expected from the genetic diversity in background surveillance.\n\nResultsGenomic analysis identified isolates that had been unjustly assigned to clusters based on MLVA typing, while spa typing was concordant but of insufficient resolution. Detailing particular subsets of isolates further improved resolution and although it provided evidence that HCWs were involved in multiple outbreaks, it alleviated heavy concerns about one particular HCW. Genomic clustering of isolates based on deviations from background surveillance matched epidemiological patient linkage. Compared to MLVA typing, the genomic analysis demonstrated more, shorter, and re-assorted nosocomial transmission chains during this outbreak.\n\nConclusionsIn this study the improved resolution and accuracy of genomic outbreak analyses compared to spa typing and MLVA substantially altered the view on outbreaks, along with apposite outbreak measures. Inclusion of the circulating background population has the potential to overcome current issues in genomic outbreak inference.

microbiology↗

bioRxiv2017

PGC-1β prevents statin-associated myotoxicity in oxidative skeletal muscle

Statins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1{beta} in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1{beta} expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glycolytic, but not in oxidative muscle. In PGC-1{beta} KO mice, atorvastatin induced a shift from oxidative type IIA to glycolytic type IIB myofibers mainly in oxidative muscle and mitochondrial dysfunction was observed in both muscle types. In glycolytic muscle of WT and KO mice and in oxidative muscle of KO mice, atorvastatin suppressed mitochondrial proliferation and oxidative defense, leading to apoptosis. In contrast, mitochondrial function was maintained or improved and apoptosis decreased by atorvastatin in oxidative muscle of WT mice. In conclusion, PGC-1{beta} has an important role in preventing damage to oxidative muscle in the presence of a mitochondrial toxicant such as atorvastatin.

pharmacology and toxicology↗