Biology subjects

Jeffries, K.

Publications and source records attributed to Jeffries, K..

8 recordsLinked to original sources

bioRxiv2026

DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis

Brain metastasis (BrM) is a devastating complication of triple-negative breast cancer (TNBC), yet how host macroenvironmental conditions influence brain metastatic susceptibility remains poorly understood. Here, we investigated the impact of deep vein thrombosis (DVT), a common complication in patients with cancer, on TNBC brain metastasis. Analysis of a large clinical cohort identified DVT as an independent risk factor for BrM in patients with metastatic breast cancer. Using two syngeneic TNBC models, we demonstrated that DVT selectively enhanced brain metastasis without significantly affecting primary tumor growth or lung metastasis. Mechanistically, DVT increased neutrophil accumulation in the brain metastatic microenvironment, and neutrophil depletion completely abrogated the metastasis-promoting effect of DVT. Single-cell RNA sequencing of CD45+ cells in peripheral blood revealed that DVT reprogrammed circulating neutrophils toward migratory and inflammatory transcriptomic profiles characterized by neutrophil extracellular trap (NET) formation. DVT increased CXCR2 expression on circulating neutrophils and enhanced neutrophil recruitment in brain. Moreover, DVT significantly increased circulating NETs. Collectively, our findings identify DVT as a systemic driver of TNBC brain metastasis and reveal that DVT primes circulating neutrophils toward enhanced vascular recruitment and NET formation, providing a mechanistic link between cancer-associated thrombosis and brain metastatic susceptibility.

molecular biology↗

bioRxiv2026

Mucus transcriptional profiling as a minimally invasive approach to identify thermal stress in a stenothermal salmonid

Global climate change has increased the frequency and severity of stressful temperatures that freshwater fishes experience, necessitating rapid and sensitive methods to monitor wild populations. Tissues used to measure transcriptional responses traditionally involved invasive or lethal sampling, which may be undesirable for imperilled species. Epidermal mucus offers a non-lethal and minimally invasive alternative, but whether thermal thresholds can be detected in mucus to identify fish experiencing thermal stress is unclear. Bull trout (Salvelinus confluentus) are a legally protected salmonid and cold-water specialist, generally occupying waters 12 {degrees}C and below, with higher temperatures resulting in cellular stress. Therefore, we measured a suite of 56 genes using high-throughput qPCR to compare machine learning classifiers developed with transcriptional profiles of epidermal mucus, gill, liver, and muscle to classify laboratory reared juvenile bull trout as below (9 {degrees}C, 12 {degrees}C) or above (15 {degrees}C, 18 {degrees}C) cellular thermal thresholds. Mucus profiles most resembled gills but represented an intermediate transcriptional response to all tissues. A reduced biomarker panel of 10 genes in mucus assigned fish to stress categories with 94.1% (95% CI = 71.3-99.9%) accuracy, which was comparable to gill (100.0%, CI = 82.4- 100%), liver (95.0%, CI = 75.1-99.9%), and muscle (100.0%, CI = 80.5-100.0%). Sex-specific temperature effects were evident in all tissues, but less pronounced in mucus and gill than in liver and muscle. Our findings demonstrate that transcriptional profiling of mucus can reliably identify individuals experiencing thermal stress, highlighting the promise of this non-lethal approach for monitoring at-risk species.

genomics↗

bioRxiv2023

Foot orientation and trajectory variability in locomotion: effects of real-world terrain

Capturing human locomotion in nearly any environment or context is becoming increasingly feasible with wearable sensors, giving access to commonly encountered walking conditions. While important in expanding our understanding of locomotor biomechanics, these more variable environments present challenges to identify changes in data due to person-level factors among the varying environment-level factors. Our study examined foot-specific biomechanics while walking on terrain commonly encountered with the goal of understanding the extent to which these variables change due to terrain. We recruited healthy adults to walk at self-selected speeds on stairs, flat ground, and both shallow and steep sloped terrain. A pair of inertial measurement units were embedded in both shoes to capture foot biomechanics while walking. Foot orientation was calculated using a strapdown procedure and foot trajectory was determined by double integrating the linear acceleration. Stance time, swing time, cadence, sagittal and frontal orientations, stride length and width were extracted as discrete variables. These data were compared within-participant and across terrain conditions. The physical constraints of the stairs resulted in shorter stride lengths, less time spent in swing, toe-first foot contact, and higher variability during stair ascent specifically (p<0.05). Stride lengths increased when ascending compared to descending slopes, and the sagittal foot angle at initial contact was greatest in the steep slope descent condition (p<0.05). No differences were found between conditions for horizontal foot angle in midstance (p[≥]0.067). Our results show that walking on slopes creates differential changes in foot biomechanics depending on whether one is descending or ascending, and stairs require different biomechanics and gait timing than slopes or flat ground. This may be an important factor to consider when making comparisons of real-world walking bouts, as greater proportions of one terrain feature in a data set could create bias in the outcomes. Classifying terrain in unsupervised walking datasets would be helpful to avoid comparing metrics from different walking terrain scenarios.

bioengineering↗

bioRxiv2023

Differences in the transcriptome response in the gills of sea lamprey acutely exposed to 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide or a TFM:niclosamide mixture

Sea lamprey (Petromyzon marinus) control in the Laurentian Great Lakes of North America makes use of two pesticides: 3-trifluoromethyl-4-nitrophenol (TFM) and niclosamide, which are often co-applied. Sea lamprey appear to be vulnerable to these agents resulting from a lack of detoxification responses with evidence suggesting that lampricide mixtures produce a synergistic effect. However, there is a lack of information pertaining to the physiological responses of sea lamprey to niclosamide and TFM:niclosamide mixtures. Here, we characterized the transcriptomic responses of the sea lamprey to TFM, niclosamide, and a TFM:niclosamide (1.5%) mixture in the gill. Along with a control, larval sea lamprey were exposed to each treatment for 6 h, after which gill tissues were extracted for measuring whole-transcriptome responses using RNA sequencing. Differential gene expression patterns were summarized, which included identifying the broad roles of genes and common expression patterns among the treatments. While niclosamide treatment resulted in no differentially expressed genes, TFM- and mixture-treated fish had several differentially expressed genes that were associated with the cell cycle, DNA damage, metabolism, immune function, and detoxification. However, there was no common differential expression among treatments. For the first time, we characterized the transcriptomic response of sea lamprey to niclosamide and a TFM:niclosamide mixture and identified that these agents impact mRNA transcript abundance of genes associated with the cell cycle and cellular death, and immune function, which are likely mediated through mitochondrial dysregulation. These results may help to inform the production of more targeted and effective lampricides in sea lamprey control efforts.

genomics↗

bioRxiv2023

Transcriptomic impacts and potential routes of detoxification in a lampricide-tolerant teleost exposed to TFM and niclosamide

Sea lamprey (Petromyzon marinus) control in the Laurentian Great Lakes of North America often relies on the application of 3-trifluoromethyl-4-nitrophenol (TFM) and niclosamide mixtures to kill larval sea lamprey. Selectivity of TFM against lampreys appears to be due to differential detoxification ability in these jawless fishes compared to bony fishes, particularly teleosts. However, the proximate mechanisms of tolerance to the TFM and niclosamide mixture and the mechanisms of niclosamide toxicity on its own are poorly understood, especially among non-target fishes. Here, we used RNA sequencing to identify specific mRNA transcripts and functional processes that responded to niclosamide or a TFM:niclosamide mixture in bluegill (Lepomis macrochirus). Bluegill were exposed to niclosamide or TFM:niclosamide mixture, along with a time-matched control group, and gill and liver tissues were sampled at 6, 12, and 24 h. We summarized the whole-transcriptome patterns through gene ontology (GO) term enrichment and through differential expression of detoxification genes. The niclosamide treatment resulted in an upregulation of several transcripts associated with detoxification (cyp, ugt, sult, gst), which may help explain the relatively high detoxification capacity in bluegill. Conversely, the TFM:niclosamide mixture resulted in an enrichment of processes related to arrested cell cycle and growth, and cell death alongside a diverse detoxification gene response. Detoxification of both lampricides likely involves the use of phase I and II biotransformation genes. Our findings strongly suggest that the unusually high tolerance of bluegill to lampricides is due to these animals having an inherently high capacity and flexible detoxification response to such compounds.

genomics↗

bioRxiv2022

Spatiotemporal changes in genetic diversity and structure of a recent fish invasion in eastern North America

Introduced and geographically expanding populations experience similar eco-evolutionary challenges, including founder events, genetic bottlenecks, and novel environments. Theory predicts that reduced genetic diversity resulting from such genetic phenomena limits the colonization success of introduced populations. We examined an invasive population of a Eurasian freshwater fish, Tench (Tinca tinca), that has been expanding geographically in eastern North America for three decades. Using genomic data, we evaluated evidence for single versus multiple introductions and the connectivity of the population across the entire range in which it has been spreading. Tench exhibited low levels of genetic diversity, a lack of marked population subdivision across time and space, and evidence of a recent genetic bottleneck. These results suggest that the invasion stemmed from a single introduction, consistent with the reported invasion history. Furthermore, the large genetic neighbourhood size and weak within-population genetic substructure suggest high connectivity across the invaded range, despite the large area occupied, and no evidence of substantial diminution of genetic diversity from the invasion core to the margins. As eradicating the species within a ~112 km radius would be necessary to prevent recolonization, eradicating Tench is likely not feasible at watershed--and possibly local--scales. Management should instead focus on reducing abundance in priority conservation areas to mitigate adverse impacts. Our study supports the argument that introduced populations can thrive despite recent bottlenecks and low levels of genetic diversity, and it suggests that landscape heterogeneity and population demographics can generate variability in spatial patterns of genetic diversity within a single range expansion.

genomics↗

bioRxiv2021

Variation in the transcriptome response and detoxification gene diversity drives pesticide tolerance in fishes

Pesticides are critical for invasive species management, but often have negative effects on non-target native biota. Tolerance to pesticides should have an evolutionary basis, but this is poorly understood. Invasive sea lamprey (Petromyzon marinus) populations in North America have been controlled with a pesticide lethal to them at lower concentrations than native fishes. We addressed how interspecific variation in gene expression and detoxification gene diversity confer differential pesticide sensitivity in two fish species. We exposed sea lamprey and bluegill (Lepomis macrochirus), a tolerant native species, to TFM, a pesticide commonly used in sea lamprey control, and used whole-transcriptome sequencing of gill and liver to characterize the cellular response. Comparatively, bluegill exhibited a larger number of detoxification genes expressed and a larger number of responsive transcripts overall, which likely contributes to greater tolerance to TFM. Understanding the genetic and physiological basis for pesticide tolerance is crucial for managing invasive species.

genomics↗

bioRxiv2021

A chromosomal inversion may facilitate adaptation despite periodic gene flow in a freshwater fish

Differences in genomic architecture between populations, such as chromosomal inversions, may play an important role in facilitating adaptation despite opportunities for gene flow. One system where chromosomal inversions may be important for eco-evolutionary dynamics are in freshwater fishes, which often live in heterogenous environments characterized by varying levels of connectivity and varying opportunities for gene flow. In the present study, reduced representation sequencing was used to study possible adaptation in n = 345 walleye (Sander vitreus) from three North American waterbodies: Cedar Bluff Reservoir (Kansas, USA), Lake Manitoba (Manitoba, Canada), and Lake Winnipeg (Manitoba, Canada). Haplotype and outlier-based tests revealed a putative chromosomal inversion that contained three expressed genes and was nearly fixed for alternate genotypes in each Canadian lake. These patterns exist despite several opportunities for gene flow between these proximate Canadian lakes, suggesting that the inversion may be important for facilitating adaptive divergence between the two lakes despite gene flow. Our study illuminates the importance of genomic architecture for facilitating local adaptation in freshwater fishes. Furthermore, our results provide additional evidence that inversions may facilitate local adaptation in many organisms that inhabit connected but heterogenous environments.

evolutionary biology↗