Biology subjects

Rausser, S.

Publications and source records attributed to Rausser, S..

6 recordsLinked to original sources

bioRxiv2025

Xylazine and fentanyl co-administration delays wound healing in mice

Xylazine, a veterinary sedative increasingly found in the unregulated drug supply, is associated with severe skin wounds in humans, particularly when co-used with fentanyl. Despite growing concern, the mechanisms underlying these wounds remain unclear. To investigate how xylazine and fentanyl affect wound healing, we administered subcutaneous injections of saline, xylazine (3.2 mg/kg), fentanyl (1.0 mg/kg), or their combination to female C57BL/6J mice for 28 days. After a standardized punch biopsy, wound closure was tracked for 14 days, with continued drug exposure. Mice receiving the xylazine-fentanyl combination exhibited significantly delayed wound healing compared to all other groups, as shown by slower closure rates and increased area under the healing curve. A follow-up study without chronic pretreatment showed that acute xylazine-fentanyl exposure still altered healing dynamics, although it did not significantly delay time to closure. Neither drug alone impaired healing at the tested doses. These findings suggest that prior exposure to xylazine and fentanyl contributes to impaired wound healing and support the hypothesis that xylazine-associated wounds may arise from delayed healing of pre-existing skin injuries rather than spontaneous formation. This is the first preclinical model of xylazine-related wound impairment and provides a foundation for future research into biological mechanisms and potential interventions for these emerging soft tissue injuries.

pharmacology and toxicology↗

bioRxiv2024

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Growth Differentiation Factor 15 (GDF15) is a protein that reflects mitochondrial energetic stress and is linked to physical and mental health symptoms, aging, and mortality. Here, we tested the hypothesis that GDF15 is a stress-responsive biomarker through a series of observational and experimental studies. We report four main findings. First, in the UK Biobank (n=53,026) and Framingham Heart Study (FHS) Offspring (n=3,460) cohorts, plasma GDF15 levels were elevated in individuals with symptoms of depression and anxiety. In the FHS cohort, GDF15 was also higher in participants exposed to chronic psychosocial stressors, including lower educational attainment, lower family income, and higher job strain. Second, plasma GDF15 levels in the FHS cohort correlated positively with epigenetic clocks measuring biological aging and effect sizes of GDF15 associations with psychosocial stressors were comparable to those observed for the clocks. Third, in a two-participant intensive-sampling study (n=112 days), saliva GDF15 showed a robust awakening response similar to established stress-related hormones. However, it exhibited a distinct negative pattern, peaking at waking and declining by 42-92% within 30-45 minutes. Finally, in two laboratory experiments (n=148), acute social-evaluative stress significant increased GDF15 levels in plasma and saliva within minutes. Together, these findings suggest that psychosocial stress may contribute to mitochondrial energetic stress indexed by GDF15, with implications for aging and health. This work opens new avenues for using GDF15 as a non-invasive biomarker to study the biological embedding of stress and its impact on aging trajectories. Significance statementGrowth Differentiation Factor 15 (GDF15) is a circulating protein elevated with mitochondrial energetic stress, aging, and diseases. Our findings show that GDF15 is elevated with depressive and anxiety symptoms and in those exposed to chronic psychosocial stress. Elevated plasma GDF15 also correlates with accelerated biological aging, as measured by epigenetic clocks. The effect sizes linking GDF15 to psychosocial stressors were comparable to those observed for the epigenetic clocks. Saliva GDF15 shows a robust negative awakening response characterized by elevated levels at awakening before declining within 30-45 minutes. Acute social-evaluative stress induced increase in plasma and saliva GDF15. Together, these findings suggest GDF15 can be used to study the energetic mechanisms for the biological embedding of stress across the lifespan.

physiology↗

bioRxiv2023

MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva

Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 {micro}L of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.

molecular biology↗

bioRxiv2021

Dynamic behavior of cell-free mitochondrial DNA in human saliva

Mitochondria contain their own genome that can be released in multiple biofluids such as blood and cerebrospinal fluid, as cell-free mitochondrial DNA (cf-mtDNA). In clinical studies, single measures of blood cf-mtDNA predict mortality, and higher cf-mtDNA levels are associated with mental and physical stress. However, the dynamics of cf-mtDNA has not been defined, and whether it can be measured non-invasively like other neuroendocrine markers in saliva has not been examined. Here we report cf-mtDNA in human saliva and establish its natural within-person dynamic behavior across multiple weeks. In a small proof-of-principle cohort of healthy adults, we first develop an approach to rapidly quantify salivary cf-mtDNA without DNA extraction, and demonstrate the existence of saliva cf-mtDNA. We then deploy this approach to perform an intensive repeated-measures analysis of two healthy men studied at 4 daily timepoints over 53-60 consecutive days (n=212-220 observations each) with parallel measures of steroid hormones, self-reported daily mood, and health-related behaviors. Salivary cf-mtDNA exhibited a robust awakening response reaching up to two orders of magnitude 30-45 minutes after awakening, varied from day-to-day, and moderately correlated with the cortisol awakening response. No consistent association with self-reported daily mood/health-related behaviors were found, although this requires further examination in more extensive studies. Dynamic variation in cf-mtDNA was inversely related with salivary interleukin 6 (IL6), inconsistent with a pro-inflammatory effect of salivary cf-mtDNA. The highly dynamic behavior of salivary cf-mtDNA opens the door to non-invasive studies examining the relevance of mtDNA signaling in relation to human health.

molecular biology↗

bioRxiv2020

Mitochondrial profiling reveals dynamic, sex- and age-specific mitochondrial phenotypes in human immune cell subtypes

Using a high-throughput mitochondrial phenotyping platform to quantify multiple mitochondrial features among molecularly-defined immune cell subtypes, we quantify the natural variation in citrate synthase, mitochondrial DNA copy number (mtDNAcn), and respiratory chain enzymatic activities in human neutrophils, monocytes, B cells, and naive and memory T lymphocyte subtypes. In mixed peripheral blood mononuclear cells (PBMCs) from the same individuals, we show to what extent mitochondrial measures are confounded by both cell type distributions and contaminating platelets. Cell subtype-specific measures among women and men spanning 4 decades of life indicate potential age- and sex-related differences, including an age-related elevation in mtDNAcn, which are masked or blunted in mixed PBMCs. Finally, a proof-of-concept, repeated-measures study in a single individual validates cell type differences and also reveals week-to-week changes in mitochondrial activities. Larger studies are required to validate and mechanistically extend these findings. These mitochondrial phenotyping data build upon established immunometabolic differences among leukocyte sub-populations, and provide foundational quantitative knowledge to develop interpretable blood-based assays of mitochondrial health.

cell biology↗

bioRxiv2020

Human Hair Graying is Naturally Reversible and Linked to Stress

Hair graying is a universal hallmark of aging believed to be linked to psychological stress. Here we develop a novel approach to quantitatively profile natural graying events along individual human hair shafts, resulting in a quantifiable physical timescale of hair pigmentation patterns (HPPs). Using this approach, we quantify rare events of white/gray hairs that naturally regain pigmentation within days to weeks, thereby quantitatively defining the reversibility of graying in healthy, unmedicated individuals. Proteomic analysis shows that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining hair pigmentation profiling and proteomics at the single hair level, we also report hair graying and its reversal occurring in parallel with behavioral and psychological stressors. A computational simulation suggests a threshold-based mechanism for the temporary reversibility of graying. Quantitatively mapping HPPs in humans provides an opportunity to longitudinally examine the influence of life exposures on biological aging.

cell biology↗