Biology subjects

Christie, R.

Publications and source records attributed to Christie, R..

5 recordsLinked to original sources

bioRxiv2025

Thiol Scarcity in Cerebrospinal Fluid Renders Leptomeningeal Acute Lymphoblastic Leukaemia Therapeutically Vulnerable to Ferroptosis

The leptomeninges present a challenging tumour microenvironment with cells receiving low levels of nutrients and oxygen from cerebrospinal fluid (CSF), however these metabolic constraints are yet to be exploited therapeutically. Central nervous system (CNS) relapse in acute lymphoblastic leukaemia (ALL) remains a formidable clinical challenge because the leptomeningeal niche restricts drug penetration and immune surveillance. Current CNS-directed treatments rely on neurotoxic intrathecal chemotherapy, underscoring the urgent need for novel targeted strategies. Here, we uncover a profound niche-specific metabolic vulnerability in CNS-resident ALL cells, characterised by an obligate reliance on LRP8-mediated selenium uptake to sustain selenocysteine biosynthesis and GPX4 activity under profound glutathione limitation. We show that scarcity of thiols and cystine in CSF creates an inherently pro-ferroptotic microenvironment. Interference with selenocysteine biosynthesis under these conditions induces synthetic lethality in both in vitro and in vivo CNS-ALL models. This vulnerability is exploitable both by genetic targeting of the selenocysteine biosynthesis pathway and, notably, through repurposing the FDA-approved agent Auranofin, which disrupts selenium utilisation, induces lipid peroxidation, and demonstrates CNS-specific anti-leukaemic eaicacy with excellent tolerability in vivo. These findings identify a novel mechanistically grounded approach, leveraging features of the unique leptomeningeal microenvironment to selectively kill invading cells, with potential implications for all leptomeningeal-tropic malignancies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/693383v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@2303dforg.highwire.dtl.DTLVardef@d357ceorg.highwire.dtl.DTLVardef@129cb26org.highwire.dtl.DTLVardef@d83183_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO The leptomeningeal tumour microenvironment is intrinsically pro-ferroptotic due to low concentrations of free thiols and cystine in cerebrospinal fluid. ALL cells in this niche exhibit disrupted glutathione metabolism and a novel dependency on LRP8-mediated SELENOP uptake to sustain GPX4 levels and thus protect themselves from spontaneous ferroptotic cell death. Perturbation of selenocysteine biosynthesis via genetic inhibition SEPHS2 or LRP8 leads to synthetic lethality in leukaemic cells exposed to CSF in vitro and in vivo - an effect phenocopied by use of Auranofin. C_FIG

cancer biology↗

bioRxiv2023

Mapping the Organization and Morphology of Calcitonin Gene-Related Peptide (CGRP)-IR Axons in the Whole Mouse Stomach

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers [e.g., substance P (SP) and calcitonin gene-related peptide (CGRP)]. We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: 1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. 2) CGRP-IR axons densely innervated the blood vessels. 3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. 4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. 5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. 6) CGRP-IR axons did not colocalize with tyrosine hydroxylase (TH) or vesicular acetylcholine transporter (VAChT) axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. 7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.

neuroscience↗

bioRxiv2021

The SPARC DRC: Building a resource for the autonomic nervous system community

The Data and Resource Center (DRC) of the NIH-funded SPARC program is developing databases, connectivity maps and simulation tools for the mammalian autonomic nervous system. The experimental data and mathematical models supplied to the DRC by the SPARC consortium are curated, annotated and semantically linked via a single knowledgebase. A data portal has been developed that allows discovery of data and models both via semantic search and via an interface that includes Google Map-like 2D flatmaps for displaying connectivity, and 3D anatomical organ scaffolds that provide a common coordinate framework for cross-species comparisons. We discuss examples that illustrate the data pipeline, which includes data upload, curation, segmentation (for image data), registration against the flatmaps and scaffolds, and finally display via the web portal, including the link to freely available online computational facilities that will enable neuromodulation hypotheses to be investigated by the autonomic neuroscience community and device manufacturers.

neuroscience↗

bioRxiv2021

Longer study length, standardized sampling techniques, and broader geographic scope leads to higher likelihood of detecting stable abundance patterns in long term deer tick (Ixodes scapularis) studies

BackgroundUnderstanding how study design and monitoring strategies shape inference within, and synthesis across, studies is critical across biological disciplines. Many biological and field studies are short term and limited in scope. Monitoring studies are critical for informing public health about potential vectors of concern, such as Ixodes scapularis (black-legged ticks). Black-legged ticks are a taxon of ecological and human health concern due to their status as primary vectors of Borrelia burgdorferi, which causes Lyme disease. However, variation in black-legged tick monitoring, and gaps in data, are currently considered major barriers to understanding population trends and in turn, predicting Lyme disease risk. To understand how variable methodology in black-legged tick studies may influence which population patterns researchers find, we conducted a data synthesis experiment. Materials and MethodsWe searched for publicly available black-legged tick abundance datasets that had at least 9 years of data, using keywords about ticks in internet search engines, literature databases, data repositories and public health websites. Our analysis included 289 datasets from 7 surveys from locations throughout the US, ranging in length from 9 to 24 years. We used a moving window analysis, which is a kind of non-random resampling approach, to investigate the temporal stability of black-legged tick population trajectories across the US. We then used t-tests to assess differences in stability time across different study parameters. ResultsAll of our sampled datasets required 4 or more years to reach stability. We also found that several study factors can have an impact on the likelihood of a study reaching stability and of data resulting in misleading results if the study does not reach stability. Specifically, datasets collected via dragging reached stability significantly faster than data collected via opportunistic sampling. Datasets that sampled larva reached stability significantly later than those that sampled adults or nymphs. Additionally, datasets collected at the broadest spatial scale (county) reached stability fastest. ConclusionWe used 289 datasets from 7 long term black-legged tick studies to conduct a non-random data resampling experiment, revealing that sampling design does shape inferences in black-legged tick population trajectories and how many years it takes to find stable patterns. Specifically, our results show the importance of study length, sampling technique, life stage, and geographic scope in understanding black-legged tick populations, in the absence of standardized surveillance methods. Current public health efforts based on existing black-legged tick datasets must take monitoring study parameters into account, to better understand if and how to use monitoring data to inform decision making. We also recommend that potential forecasting initiatives consider these parameters when projecting black-legged tick population trends.

bioinformatics↗

bioRxiv2020

3D single cell scale anatomical map of sex-dependent variability of the rat intrinsic cardiac nervous system

We developed and analyzed a single cell scale anatomical map of the rat intrinsic cardiac nervous system (ICNS) across 4 male and 3 female hearts. We find the ICNS has a reliable structural organizational plan across individuals that may provide the foundation for further analyses of the ICNS in cardiac function and disease. The distribution of the ICNS was evaluated by 3D visualization and using data-driven clustering. The pattern, distribution and clustering of ICNS neurons across all male and female rat hearts is highly conserved, demonstrating a coherent organizational plan in which distinct clusters of neurons are consistently localized. Female hearts had fewer neurons, lower packing density and slightly reduced distribution, but with the same localization. We registered the anatomical data from each heart to a geometric scaffold, normalizing their 3D coordinates for the standardization of common anatomical planes and providing the path where multiple experimental results and data types can be integrated and compared.

neuroscience↗