Biology subjects

Marshall, C.

Publications and source records attributed to Marshall, C..

13 recordsLinked to original sources

bioRxiv2026

Elucidating Molecular Features of White Matter Hyperintensities in Alzheimer’s Disease through Multimodal Imaging and SHAP Analysis

White matter hyperintensities (WMHs) are a common feature of Alzheimers disease and are associated with cognitive decline, yet their molecular composition and spatial heterogeneity remain incompletely defined. Here, we identify distinct lipid signatures in human AD WMHs compared to matched normal-appearing white matter (NAWM) from the same donors. Using an integrated multimodal approach combining magnetic resonance imaging, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), histological staining, and complementary liquid chromatography-tandem mass spectrometry, we resolve spatially localized lipid alterations within tissue sections while preserving spatial context. This approach reveals region-specific heterogeneity in WMH lipid composition across anterior and posterior brain regions that may be obscured by bulk lipidomics alone. Machine learning-based analysis using Shapley additive explanations (SHAP) identified lipid features that contribute to WMH classification, with sulfatide, hexosylceramide, and phosphatidylinositol species emerging as key discriminators. In anterior brain regions, WMHs were associated with differential abundance and depletion of specific sulfatide and hexosylceramide species (SHexCer 44:2;3O, SHexCer 42:2;3O, HexCer 41:1;3O, SHexCer 42:2;2O), whereas posterior WMHs were characterized by reduced phosphatidylinositol species (PI 36:1), demonstrating that AD-associated white matter pathology is governed by region-specific, heterogeneous lipid remodeling rather than uniform global degradation.

Molecular Biology↗

bioRxiv2025

Integrative Spatial Omics for Systems-Level Mapping of Pathological Niches

Spatial omics technologies are a powerful tool for mapping the relationship between cellular organization and molecular distributions in healthy and diseased tissue microenvironments. Here, we describe a novel multimodal pipeline that represents experimental and computational advances for spatiomolecular analysis of tissue samples across molecular classes. This adaptable method integrates matrix-assisted laser desorption/ionization imaging mass spectrometry spatial lipidomics, spatial transcriptomics, protein imaging via multiplexed immunofluorescence microscopy, and histopathological staining to uncover spatiomolecular profiles associated with unique cellular niches and pathological features. We demonstrate the power of this approach using two different complex human disease systems: Alzheimers disease in human brain tissue and type 2 diabetes mellitus in the human pancreas. This work establishes and demonstrates a generalizable framework for multimodal spatial integration, enabling precise mapping of molecular mechanisms that underlie complex tissue pathologies.

systems biology↗

bioRxiv2025

Hypothalamic deiodinase type-3 establishes the period of circannual interval timing in mammals

Animals respond to environmental cues to time phenological events, but the intrinsic mechanism of circannual timing remains elusive. We used transcriptomic sequencing and frequent sampling of multiple hypothalamic nuclei in Djungarian hamster to examine the neural and molecular architecture of circannual interval timing. Our study identified three distinct phases of transcript changes, with deiodinase type-3 (Dio3) expression activated during the early induction phase. Subsequent work demonstrated that targeted mutation of Dio3 using CRISPR-Cas resulted in a shorter period for circannual interval timing. Hamsters that are non-responsive to short photoperiod and fail to show any winter adaptations do not display changes in Dio3 expression do not show any change in body mass or pelage. Our work demonstrates that changes in Dio3 induction is essential for setting the period of circannual interval timing.

neuroscience↗

bioRxiv2024

SNP assays for DVI: cost, time, and performance information for decision-makers

In mass disaster events, forensic DNA laboratories may be called upon to quickly pivot their operations toward identifying bodies and reuniting remains with family members. Ideally, laboratories have considered this possibility in advance and have a plan in place. Compared with traditional short tandem repeat (STR) typing, single nucleotide polymorphisms (SNPs) may be better suited to these disaster victim identification (DVI) scenarios due to their small genomic target size, resulting in an improved success rate in degraded DNA samples. As the landscape of technology has shifted toward DNA sequencing, many forensic laboratories now have benchtop instruments available for massively parallel sequencing (MPS), facilitating this operational pivot from routine forensic STR casework to DVI SNP typing. Herein, we review the commercially available SNP sequencing assays amenable to DVI, we use data simulations to explore the potential for kinship prediction from SNP panels of varying size, and we give an example DVI scenario as context for presenting the matrix of considerations: kinship predictive potential, cost, and throughput of current SNP assay options. This information is intended to assist laboratories in choosing a SNP system for disaster preparedness. Highlights3 to 5 bullet points (maximum 100 characters per bullet point, including spaces). Each bullet point should be a full sentence and should outline the key contributions of your manuscript and how it impacts forensic science. O_LISingle nucleotide polymorphisms (SNPs) are useful in disaster victim identification (DVI). C_LIO_LISNP panels amenable to human identification and extended kinship are described. C_LIO_LISimulations demonstrate the potential for kinship prediction from SNP panels of varying size. C_LIO_LIKinship predictive potential, cost, and throughput are presented for an example DVI scenario. C_LIO_LIInformation is intended to assist laboratories in choosing a SNP system for disaster preparedness. C_LI

molecular biology↗

bioRxiv2023

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging

LRRK2 mutations are the most common cause of dominantly inherited Parkinsons disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats. LRRK2 mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

neuroscience↗

bioRxiv2022

Single cell, whole embryo phenotyping of pleiotropic disorders of mammalian development

Mouse models are a critical tool for studying human diseases, particularly developmental disorders, as well as for advancing our general understanding of mammalian biology. However, it has long been suspected that conventional approaches for phenotyping are insufficiently sensitive to detect subtle defects throughout the developing mouse. Here we set out to establish single cell RNA sequencing (sc-RNA-seq) of the whole embryo as a scalable platform for the systematic molecular and cellular phenotyping of mouse genetic models. We applied combinatorial indexing-based sc-RNA-seq to profile 101 embryos of 26 genotypes at embryonic stage E13.5, altogether profiling gene expression in over 1.6M nuclei. The 26 genotypes include 22 mouse mutants representing a range of anticipated severities, from established multisystem disorders to deletions of individual enhancers, as well as the 4 wildtype backgrounds on which these mutants reside. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibited changes in dozens of trajectories (e.g., the pleiotropic consequences of altering the Sox9 regulatory landscape) whereas others showed phenotypes affecting specific subsets of cells. We also identify differences between widely used wildtype strains, compare phenotyping of gain vs. loss of function mutants, and characterise deletions of topological associating domain (TAD) boundaries. Intriguingly, even among these 22 mutants, some changes are shared by heretofore unrelated models, suggesting that developmental pleiotropy might be "decomposable" through further scaling of this approach. Overall, our findings show how single cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

genomics↗

bioRxiv2021

The FORCE panel: An all-in-one SNP marker set for confirming investigative genetic genealogy leads and for general forensic applications

The FORensic Capture Enrichment (FORCE) panel is an all-in-one SNP panel for forensic applications. This panel of 5,422 markers encompasses common, forensically relevant SNPs (identity, ancestry, phenotype, X- and Y-chromosomal SNPs), a novel set of 3,931 autosomal SNPs for extended kinship analysis, and no clinically relevant/disease markers. The FORCE panel was developed as a custom hybridization capture assay utilizing [~]20,000 baits to target the selected SNPs. Five non-probative, previously identified World War II (WWII) cases were used to assess the kinship panel. Each case included one bone sample and associated family reference DNA samples. Additionally, seven reference quality samples, two 200-year-old bone samples, and four control DNAs were processed for kit performance and concordance assessments. SNP recovery after capture resulted in a mean of [~]99% SNPs exceeding 10X coverage for reference and control samples, and 44.4% SNPs for bone samples. The WWII case results showed that the FORCE panel could predict 1st to 5th degree relationships with strong statistical support (likelihood ratios over 10,000 and posterior probabilities over 99.99%). To conclude, SNPs will be important for further advances in forensic DNA analysis. The FORCE panel shows promising results and demonstrates the utility of a 5,000 SNP panel for forensic applications.

genetics↗

bioRxiv2020

Hybridization capture and low-coverage SNP profiling for extended kinship analysis and forensic identification of historical remains

DNA-assisted identification of historical remains requires the genetic analysis of highly degraded DNA, along with a comparison to DNA from known relatives. This can be achieved by targeting single nucleotide polymorphisms (SNPs) using a hybridization capture and next-generation sequencing approach suitable for degraded skeletal samples. In the present study, two SNP capture panels were designed to target ~25,000 (25K) and ~95,000 (95K) nuclear SNPs, respectively, to enable distant kinship estimation (up to 4th degree relatives). Low-coverage SNP data were successfully recovered from 14 skeletal elements 75 years postmortem, with captured DNA having mean insert sizes ranging from 32-170 bp across the 14 samples. SNP comparison with DNA from known family references was performed in the Parabon Fx Forensic Analysis Platform, which utilizes a likelihood approach for kinship prediction that was optimized for low-coverage sequencing data with cytosine deamination. The 25K panel produced 15,000 SNPs on average, which allowed for accurate kinship prediction in 17 of the 21 pairwise comparisons. The 95K panel increased the average SNPs to 42,000 and resulted in two additional pairwise comparisons (19 of 21). This study provides the groundwork for the expansion of research involving compromised samples to include SNP hybridization capture.

genomics↗

bioRxiv2019

A large-scale species level dated angiosperm phylogeny for evolutionary and ecological analyses

Phylogenies are a central and indispensable tool for evolutionary and ecological research. Even though most angiosperm families are well investigated from a phylogenetic point of view, there are far less possibilities to carry out large-scale meta-analyses at order level or higher. Here, we reconstructed a large-scale dated phylogeny including nearly 1/8th of all angiosperm species based on two plastid barcoding genes, matK and rbcL. Novel sequences were generated for several species, while the rest of the data were mined from GenBank. The resulting tree was dated using 56 angiosperm fossils as calibration points. The resulting megaphylogeny is one of the largest dated phylogenetic tree of angiosperms yet, consisting of 36,101 sampled species, representing 8,399 genera, 426 families and all orders. This novel framework will be useful to investigate different broad scale research questions in ecological and evolutionary biology.

evolutionary biology↗

bioRxiv2019

Genomic interrogation of the burden and transmission of multidrug-resistant pathogens within and across hospital networks

BackgroundMultidrug-resistant organisms (MDROs) disproportionately affect hospitalized patients due to the combination of comorbidities, frequent antimicrobial use, and in-hospital MDRO transmission. Identification of MDRO transmission by hospital microbiology laboratories is difficult due to limitations of existing typing methods.\n\nMethodsWe conducted a prospective multicenter genomics implementation study (8 hospitals, 2800 beds) from 24th April to 18th June 2017 in Melbourne, Australia. Clinical and screening isolates from hospital inpatients were collected for six MDROs (vanA VRE, MRSA, ESBL E. coli [ESBL-Ec] and Klebsiella pneumoniae [ESBL-Kp], and carbapenem-resistant Pseudomonas aeruginosa [CRPa] and Acinetobacter baumannii [CRAb]), sequenced (Illumina NextSeq) and analyzed using open-source tools. MDRO transmission was assessed by genomics (core SNP phylogeny, grouped by species and ST) and compared to epidemiologic data.\n\nResults408 isolates were collected from 358 patients; 47.5% were screening isolates. ESBL-Ec was most common (52.5%), then MRSA (21.6%), vanA VRE (15.7%) and ESBL-Kp (7.6%).\n\nWe define the transmission rate for each MDRO by genomics and epidemiology; 31.6% of all study patients had potential genomic links to other study isolates; 86% of these were confirmed by epidemiologic links (probable or possible transmission). The highest transmission rates occurred with vanA VRE (88.4% of patients).\n\nConclusionsCombining genomics with high-quality epidemiologic data gives substantial insights into the burden and distribution of critical MDROs in hospitals, including in-hospital transmission. By defining transmission rates by genomics, we hope to enable comparisons over time and between sites, and introduce this as a new outcome measure to assess the efficacy of infection control interventions.

genomics↗

bioRxiv2019

Multiomic definition of generalizable endotypes in human acute pancreatitis.

Acute pancreatitis (AP) is sudden onset pancreas inflammation that causes multiple organ dysfunction syndrome (MODS) and death in certain individuals who develop AP yet minimal systemic inflammation in others. Here, we show that this observed diversity in systemic response and outcome is accompagnied by diversity in molecular subtypes that can be identified using computational analysis of clinical and multiomic data. We integrated co-incident whole blood transcriptomic, plasma proteomic, and serum metabolomic data at serial time points from a cohort of patients presenting with AP and systematically evaluated four different metrics for patient similarity, using unbiased mathematical, biological and clinical measures of internal and external validity. Our results identify four distinct and stable AP endotypes that are characterized by pathway and biomarker combination stereotypes into hypermetabolic, hepatopancreaticobiliary, catabolic and innate immune endotypes. The catabolic endotype in AP strikingly recapitulates a disease endotype previously reported in acute respiratory distress syndrome, a recognized complication of AP. Our findings demonstrate that clinically-relevant and generalizable endotypes exist in AP.

systems biology↗

bioRxiv2018

The Pseudomonas aeruginosa Wsp pathway undergoes positive evolutionary selection during chronic infection

Author Contributions Author Contributions Introductory paragraph Results Discussion Materials and Methods References ESG and CWM performed the experimental work. JSH performed the colony PCR. SBC infected and sampled the porcine burn wounds. DS generated the sequence library. MW and GRL quantified the strain frequency in the wounds. ESG, CWM, MW, VSC, and DJW conceptualized the project and wrote the manuscript.\n\nIntroductory paragraph Author Contributions Introductory paragraph Results Discussion Materials and Methods References Pathogens experience pressure in an infection to adapt, with selection favoring mutants that persist. Pseudomonas aeruginosa commonly ad ...

microbiology↗

bioRxiv2017

Anxiety-like but not despair-like behaviors are further aggravated by chronic mild stress in the early stages of APPswe/PS1dE9 transgenic mice

Early Alzheimers disease (AD) and depression share many symptoms, thus it is very difficult to initially distinguish one from the other. Therefore, characterizing the shared and different biological changes between the two disorders will be helpful in making an early diagnosis and planning treatment. In the present study, 8-week-old APPswe/PS1dE9 transgenic mice received chronic mild stress (CMS) for 8 weeks followed by a series of behavioral, biochemical and pathological analyses. APPswe/PS1dE9 mice demonstrated despair- and anxiety-like behaviors, and reduced sociability, accompanied by high levels of soluble beta-amyloid, glial activation, neuroinflammation and brain derived neurotrophic factor signaling disturbance in the hippocampus. Notably, APPswe/PS1dE9 mice exposure to CMS further aggravated anxiety-like behaviors rather than hopelessness and sociability deficits, accompanied with more severe neuroinflammation, and low serum corticosterone increased to the normal level. These results may help to understand the pathogenic mechanism of psychiatric symptoms associated with early AD.

animal behavior and cognition↗