Biology subjects

Schaaf, K.

Publications and source records attributed to Schaaf, K..

8 recordsLinked to original sources

bioRxiv2025

Auditory Brainstem Development in Autism: From Childhood Hypo-Responsivity to Adult Hyper-Reactivity

BackgroundAutism Spectrum Disorder (ASD) is characterized by sensory disruptions, including auditory processing differences, which can significantly impact social, emotional, and cognitive development. This study investigates auditory brainstem development in Autistic children and adults using auditory brainstem responses (ABRs) and acoustic startle responses (ASRs), two key measures of auditory processing. We hypothesize that early hypo-responsivity in children, measured with ABRs, may lead to compensatory neural adaptations, resulting in hyper-reactivity in adulthood, measured by ASRs. MethodsThe study included 40 Autistic children, 57 non-Autistic children, 20 Autistic adults, and 21 non-Autistic adults. Participants underwent peripheral hearing screening, ABR testing at slow and fast click-rates, and ASR measurements. ABR wave and ASR amplitude were analyzed. Statistical analyses included mixed-model ANOVAs and Spearmans correlations to examine group differences and associations with age. ResultsAutistic participants showed trending differences in auditory brainstem timing relative to non-autistic participants, with no differences in brainstem amplitude at any wave or rate. Post hoc slope comparisons revealed that non-Autistic participants showed positive developmental trajectories in Wave I latency at both rates, while Autistic participants showed flat trajectories, a pattern directionally consistent with developmental convergence. A sex-specific group difference was observed at Wave I slow rate, with Autistic females showing longer latencies than non-Autistic females (d = 1.69), with no difference in males. In contrast, ASR amplitude showed diverging developmental trajectories between groups, with Autistic participants showing a positive age-related increase and non-Autistic participants showing a negative age-related decrease (slope contrast: t(99) = 2.16, p = .033, 2p = .05), consistent with a group difference emerging in adulthood. ABR amplitude was positively correlated with ASR amplitude in non-Autistic participants (Wave I: rho = +0.30; Wave V: rho = +0.25) but negatively correlated in Autistic participants (Wave I: rho = -0.19; Wave V: rho = -0.20), with the between-group difference in correlation direction surviving FDR correction for both waves (Fishers z padj = .035). ConclusionThe findings are consistent with the hypothesis that Autistic children experience auditory brainstem hypo-responsivity, which may normalize in adulthood but lead to maladaptive hyper-reactivity. These results highlight the role of early auditory disruptions in shaping long-term sensory processing and reactivity in Autism, emphasizing the need for further research into the neural mechanisms underlying these differences.

neuroscience↗

bioRxiv2025

Manipulation of the Extracellular Vesicle Biogenesis Pathway in Paternal Somatic Cells Contributes to the Phenotypic Fate of the Next Generation

Human and animal studies have shown that risk factors for certain diseases are linked to our fathers physiological and psychological condition. So far, mainly in vitro evidence indicates extracellular vesicles (EVs) as one of the potential mediators of these paternal effects. In a full in vivo model system, we demonstrate that targeting the EV biogenesis pathway within somatic cells of the male Drosophila melanogaster reproductive tract induces sex-specific phenotypic changes in the progeny. These findings highlight the critical role of the EV pathway in paternal somatic cells in shaping the phenotypic destiny of the next generation and underscore the necessity for further investigations into the mechanisms of somatic to germline information transfer.

physiology↗

bioRxiv2024

microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism

MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.

physiology↗

bioRxiv2024

Acute exercise increases systemic kynurenine pathway metabolites and activates the AHR in human PBMCs

The kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral mononuclear blood cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise, with effects being dependent on exercise intensity. In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.

immunology↗

bioRxiv2022

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging. HighlightsO_LIPhenotyping at scale defines lifetime trajectories of age-dependent changes in C57BL/6J mice C_LIO_LICentral genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs) influence age-sensitive phenotypes (ASPs) often long before the appearance of age-dependent changes in these ASPs C_LIO_LICorresponding genetic variants in humans also have age-independent effects C_LIO_LIMany PAAI effects shift the baseline of ASPs rather than slowing their rate of change C_LI

physiology↗

bioRxiv2020

Enhancer priming by H3K4 methylation safeguards germline competence

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naive pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1 deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.

genomics↗

bioRxiv2020

An interaction network of RNA-binding proteins involved in Drosophila oogenesis

During Drosophila oogenesis, the localization and translational regulation of maternal transcripts relies on RNA-binding proteins (RBPs). Many of these RBPs localize several mRNAs and may have additional direct interaction partners to regulate their functions. Using immunoprecipitation from whole Drosophila ovaries coupled to mass spectrometry, we examined protein-protein associations of 6 GFP-tagged RBPs expressed at physiological levels. Analysis of the interaction network and further validation in human cells allowed us to identify 26 previously unknown associations, besides recovering several well characterized interactions. We identified interactions between RBPs and several splicing factors, providing links between nuclear and cytoplasmic events of mRNA regulation. Additionally, components of the translational and RNA decay machineries were selectively co-purified with some baits, suggesting a mechanism for how RBPs may regulate maternal transcripts. Given the evolutionary conservation of the studied RBPs, the interaction network presented here provides the foundation for future functional and structural studies of mRNA localization across metazoans.

biochemistry↗

bioRxiv2018

Astroplastic: A start-to-finish process for polyhydroxybutyrate production from solid human waste using genetically engineered bacteria to address the challenges for future manned Mars missions

Space exploration has long been a source of inspiration, challenging scientists and engineers to find innovative solutions to various problems. One of the current focuses in space exploration is to send humans to Mars. However, the challenge of transporting materials to Mars and the need for waste management processes are two major obstacles for these long-duration missions.\n\nTo address these two challenges a process called Astroplastic was developed that produces polyhydroxybutyrate (PHB) from solid human waste, which can be used to 3D print useful items for astronauts. PHB granules are naturally produced by bacteria such as Ralstonia eutropha and Pseudomonas aeruginosa for carbon and energy storage. The phaJ, phaC, and phaCBA genes were cloned from these native PHB-producing bacteria into Escherichia coli. These genes code for enzymes that aid in PHB production by converting products of glycolysis and {beta}-oxidation pathways, such as acetyl-CoA and enoyl-CoA, into PHB. To ensure a continuous PHB production system and to eliminate the need for cell lysis to extract PHB, recombinant E. coli was engineered to use the genes in its natural type I secretion system to secrete PHB. The C-terminal of the HlyA secretion tag was fused to phasin (PhaP), a protein originally from R. eutropha. Phasin-HlyA electrostatically binds PHB granules and transports them outside of the cell.\n\nIn addition to genetically engineering bacteria, a concept for start-to-finish PHB production process was designed. Integrating expert feedback and experimental results, conditions for each step of the process including the collection and storage of waste, volatile fatty acid (VFA) fermentation, VFA extraction, PHB fermentation, and PHB extraction were optimized. The optimized system will provide a sustainable and continuous PHB production system, which will address the problems of transportation costs and waste management for future space missions.\n\nFinancial DisclosureMindfuel Science Alberta Foundation Genome Alberta GenScript Polyferm Canada GeekStarter Alberta Integrated DNA Technologies University of Calgary University of Calgary Cumming School of Medicine University of Calgary Bachelor of Sciences University of Calgary Schulich School of Engineering University of Calgary OBrien Centre for the Bachelor of Health Sciences City of Calgary Alberta Innovates The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting InterestsThe authors have declared that no competing interests exist.\n\nEthics StatementN/A\n\nData AvailabilityAll data are freely available without restriction.

synthetic biology↗