Biology subjects

Delaney, C.

Publications and source records attributed to Delaney, C..

8 recordsLinked to original sources

bioRxiv2026

Cerebello-basal ganglia networks and behavior across adulthood and aging

The cerebellum contributes to aging, cognition, and reward related processing, but has been relatively understudied in these domains. The cerebello-basal ganglia (CB-BG) circuit may be key to better understanding how the brain ages. Prior work has implicated this circuit in aging in a small sample, though it is also of interest in age-related neurodegenerative disease, particularly Parkinson's Disease. Here, we investigated the CB-BG network, which has been implicated in modulation of cognitive, motor, and reward-related functions. In a sample of 138 participants between the ages of 35 and 86 we looked at network connectivity in cognitive and motor sub-circuits. Participants completed motor and cognitive testing batteries followed by 26 minutes of resting state functional connectivity magnetic resonance imaging (fcMRI). This data was analyzed using the CONN toolbox with an ROI-ROI approach targeting the CB-BG circuit. We replicated the previously mapped cognitive subcircuit and motor subcircuits. When examining connectivity by age group (early and late middle age and older adult hood), we found higher functional connectivity in early middle age compared to older adulthood, with no results related to late middle age. Analysis of connectivity as it relates to performance on the Stroop task showed higher connectivity-behavior associations in early middle-aged adults compared to older adults. We also explored sex differences and found higher functional connectivity in females compared to males. Analysis of steroid hormone levels revealed higher connectivity associated with progesterone in females relative to males. Together, we have replicated motor and cognitive CB-BG subcircuits and further demonstrated that this network has altered connectivity associated with age, sex, progesterone, and cognitive performance. This expanded investigation of CB-BG networks represents an essential new step in increasing our knowledge of age-related cognitive and motor declines and may be particularly relevant for consideration in Parkinson's Disease.

neuroscience↗

bioRxiv2024

A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies

Parkinsons disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy. Such an approach must not only demonstrate target selectivity towards -Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for a next-generation antibody for the treatment of synucleinopathies. SAR446159 (ABL301) is a bispecific antibody composed of an -Syn-binding immunoglobulin (IgG) and an engineered insulin-like growth factor receptor 1 (IGF1R) binding single-chain variable fragment (scFv), acting as a shuttle to transport an antibody across the blood-brain barrier (BBB). SAR446159 binds tightly and preferentially to -Syn aggregates and prevents their seeding capacity in vitro and in vivo. Incubation with SAR446159 reduced -Syn preformed fibrils (PFFs) uptake in neurons and facilitated uptake and clearance by microglia. In wild type mice injected in the striatum with -Syn PFFs, treatment with SAR446159 reduced the spread of aSyn pathology as measured by phosphorylated -Syn staining and lessened the severity of motor phenotypes. Additionally, in 9-month-old transgenic mice overexpressing -Syn (mThy1--Syn, Line 61), repeated treatment with SAR446159 reduced markers of -Syn aggregation in the brain. SAR446159 had significantly higher brain and CSF penetration over a sustained period than its monospecific counterpart (1E4) in rats and monkeys. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent, next-generation immunotherapeutic for treating synucleinopathies.

neuroscience↗

bioRxiv2023

Dry surface biofilm formation by Candida auris facilitates persistence and tolerance to sodium hypochlorite

Candida auris is an enigmatic fungal pathogen, recently elevated to the critical priority group of pathogens by the World Health Organization. Of key concern is its ability to cause outbreaks within intensive and chronic care units, facilitated through its environmental persistence. We investigated the susceptibility of phenotypically distinct C. auris isolates to sodium hypochlorite (NaOCl) disinfection, and the subsequent role of biofilms in surviving disinfection using a dry-surface biofilm (DSB) model and transcriptomic profiling. Planktonic cells were tested for susceptibility to NaOCl in suspension, with biofilm formation using the DSB model consisting of consecutive 48 hr cycles with/without media across a 12-day period, assessed using viable counts, biomass assays, and microscopy. Disinfection efficacy was assessed using clinically relevant protocols of 500-1000ppm for 1-5min. RNA-sequencing was performed on untreated DSBs in comparison to planktonic cells. Isolates were found to be sensitive to NaOCl planktonically at concentrations [≤]62.5 ppm, and grew robust biofilms using the DSB protocol. Biofilms developed tolerance to all NaOCl treatment parameters, with only 2-4 log10-reductions in viable cells observed at highest concentrations. Transcriptomics identified ABC transporters and iron acquisition pathways as strongly upregulated in DSBs relative to planktonic cells. Our novel findings have optimised a DSB protocol in which C. auris biofilms can mediate tolerance to adverse conditions such as NaOCl disinfection, suggesting a lifestyle through which this problematic yeast can environmentally persist and transmit. Mechanistically it has been shown for the first time that upregulation of small-molecule and iron transport pathways are potential facilitators of environmental survival. IMPORTANCECandida auris is a pathogenic yeast that has been responsible for outbreaks in healthcare facilities across the globe, predominantly affecting vulnerable patients. This organism displays a concerning ability to persist within the healthcare environment that is likely facilitated by attaching onto surfaces and developing protective microbial communities knows as biofilms. These communities allow cells to survive and tolerate disinfection with bleach. In this study, we show that C. auris forms robust biofilms on surfaces which promote survival up to 12 days, even with prolonged drying periods. We also demonstrate that development of these biofilms over time significantly reduces the efficacy of hypochlorite disinfection. By investigating the molecular mechanisms of biofilms, we have shown that these biofilms express efflux pumps, which may actively remove hypochlorite molecules from cells, allowing them to tolerate disinfection, and that uptake of iron from the external environment is also important for survival of these communities.

microbiology↗

bioRxiv2023

Differentiation latency and dormancy signatures define fetal liver HSCs at single cell resolution

Decoding the gene regulatory mechanisms and signaling interactions that orchestrate the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. Here, to explore intrinsic and extrinsic regulation of FL-HSC self-renewal at the single cell level, we engineered a culture platform designed to recapitulate the FL endothelial niche, which supports the ex vivo amplification of serially engraftable HSCs. Leveraging this platform in combination with single cell index flow cytometry, live imaging, serial transplantation assays, and single cell RNA-sequencing, we uncovered previously unrecognized heterogeneity within immunophenotypically defined FL-HSCs. Specifically, we demonstrated that differentiation latency, symmetric cell divisions, and transcriptional signatures of biosynthetic dormancy and lipid metabolism are distinguishing properties of rare FL-HSCs capable of serial, long-term multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and extrinsic signals combinatorially facilitate the symmetric self-renewal and expansion of nascent HSCs in the FL niche while delaying their active participation in hematopoiesis. Additionally, our study provides a valuable resource for future investigations into the intrinsic and niche-derived signaling pathways that govern FL-HSC self-renewal.

developmental biology↗

bioRxiv2021

Recurrent Vulvovaginal Candidiasis; a dynamic interkingdom biofilm disease of Candida and Lactobacillus

Vulvovaginal Candidiasis (VVC) is the most prevalent Candida infection in humans affecting 75% of women at least once throughout their lifetime. In its debilitating recurrent form, RVVC is estimated to affect 140 million women annually. Despite this strikingly high prevalence, treatment options for RVVC remain limited with many women experiencing failed clinical treatment with frontline azoles. Further, the cause of onset and recurrence of disease is largely unknown with few studies identifying potential mechanisms of failed treatment. This study aimed to assess a panel of clinical samples from healthy women and those with RVVC to investigate the influence of Candida, vaginal microbiome and antagonism between Candida and Lactobacillus on disease pathology. 16S rRNA sequencing characterised disease by a reduction in specific health-associated Lactobacillus such as L. crispatus, coupled with an increase in L. iners. In vitro analysis showed Candida albicans clinical isolates are capable of heterogeneous biofilm formation and show the presence of hyphae and C. albicans aggregates in vaginal lavage. Additionally, the ability of Lactobacillus to inhibit C. albicans biofilm formation and biofilm-related gene expression was demonstrated. Using RNA sequencing technology, we were able to exploit a possible mechanism by which L. crispatus may aim to re-establish a healthy vaginal environment through amino-acid acquisition from C. albicans. This study suggests RVVC is not entirely due to an arbitrary switch in C. albicans from commensal to pathogen and understanding interactions between the yeast and vaginal Lactobacillus species may be more crucial to elucidating the cause of RVVC and developing appropriate therapies.

microbiology↗

bioRxiv2020

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize "tumor matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. SummaryUsing single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood.

immunology↗

bioRxiv2020

Candida auris phenotypic heterogeneity determines pathogenicity in vitro

Candida auris is an enigmatic yeast that provides substantial global risk in healthcare facilities and intensive care units. A unique phenotype exhibited by certain isolates of C. auris is their ability to form small clusters of cells known as aggregates, which have been to a limited extent described in the context of pathogenic traits. In this study, we screened several non-aggregative and aggregative C. auris isolates for biofilm formation, where we observed a level of heterogeneity amongst the different phenotypes. Next, we utilised an RNA-sequencing approach to investigate the transcriptional responses during biofilm formation of a non-aggregative and aggregative isolate of the initial pool. Observations from these analyses indicate unique transcriptional profiles in the two isolates, with several genes identified relating to proteins involved in adhesion and invasion of the host in other fungal species. From these findings we investigated for the first time the fungal recognition and inflammatory responses of a three-dimensional skin epithelial model to these isolates. In these models, a wound was induced to mimic a portal of entry for C. auris. We show both phenotypes elicited minimal response in the model minus induction of the wound, yet in the wounded tissue both phenotypes induced a greater response, with the aggregative isolate more pro-inflammatory. This capacity of aggregative C. auris biofilms to generate such responses in the wounded skin highlights how this opportunistic yeast is a high risk within the intensive care environment where susceptible patients have multiple indwelling lines. ImportanceCandida auris has recently emerged as an important cause of concern within healthcare environments due to its ability to persist and tolerate commonly used antiseptics and disinfectants, particularly when surface attached (biofilms). This yeast is able to colonise and subsequently infect patients, particularly those that are critically ill or immunosuppressed, which may result in death. We have undertaken analysis on two different types of this yeast, using molecular and immunological tools to determine whether either of these has a greater ability to cause serious infections. We describe that both isolates exhibit largely different transcriptional profiles during biofilm development. Finally, we show that the inability to form small aggregates (or clusters) of cells has an adverse effect on the organisms immuno-stimulatory properties, suggestive the non-aggregative phenotype may exhibit a certain level of immune evasion.

microbiology↗

bioRxiv2019

Combinatorial prediction of gene-marker panels from single-cell transcriptomic data.

Single-cell transcriptomic studies are identifying novel cell populations with exciting functional roles in various in vivo contexts, but identification of succinct gene-marker panels for such populations remains a challenge. In this work we introduce COMET, a computational framework for the identification of candidate marker panels consisting of one or more genes for cell populations of interest identified with single-cell RNA-seq data. We show that COMET outperforms other methods for the identification of single-gene panels, and enables, for the first time, prediction of multi-gene marker panels ranked by relevance. Staining by flow-cytometry assay confirmed the accuracy of COMETs predictions in identifying marker-panels for cellular subtypes, at both the single- and multi-gene levels, validating COMETs applicability and accuracy in predicting favorable marker-panels from transcriptomic input. COMET is a general non-parametric statistical framework and can be used as-is on various high-throughput datasets in addition to single-cell RNA-sequencing data. COMET is available for use via a web interface (http://www.cometsc.com) or a standalone software package (https://github.com/MSingerlab/COMETSC).

bioinformatics↗