Biology subjects

Butler, T.

Publications and source records attributed to Butler, T..

6 recordsLinked to original sources

bioRxiv2026

Hypertension is related to a slower radiotracer removal from lateral ventricles

BackgroundImpairment of brain waste removal contributes to Alzheimers disease etiology and progression. Although hypertension is a risk factor for dementia, little is known about how it affects measures of clearance in human brain. MethodsCross-sectional (n=159) and longitudinal (n=94) analysis of the relationship between blood pressure (BP) and brain clearance. The estimate of brain clearance was measured using positron emission tomography (PET) as the rate of radiotracer (MK-6240) efflux from the lateral ventricles in the 10-30-minute window after tracer injection. We also examined cerebral blood flow, PET-derived tau deposition in the medial temporal lobe, cognition and plasma biomarkers of neurodegeneration. At baseline we compared participants with (n=88) and without (n=71) hypertension. For longitudinal analyses we defined two groups based on systolic BP trajectories from baseline to follow-up: as long-term controlled (n=76) or uncontrolled BP (n=18). ResultsAt baseline, subjects with hypertension had lower ventricular clearance than normotensive controls (Cohens d=0.53, p=0.001). Over the course of the observation period (median 1.85 years) subjects in the uncontrolled BP group experienced a steeper reduction in clearance rates ({beta}=-5.88) than subjects in the controlled BP group ({beta}=-0.81, interaction p=0.039). ConclusionsOur study suggests that hypertension impairs brain clearance of fluids.

neuroscience↗

bioRxiv2025

Diverse activity in prefrontal projections promotes temporal control of action

Prefrontal neurons can have diverse activity during cognitive functions like working memory, attention, and timing; however, the importance of this heterogeneity is unclear. Our goal was to better understand the diversity of prefrontal activity through connectivity. We harnessed circuit-specific tools to capture activity within prefrontal projections during interval timing, an elementary cognitive process that requires working memory for temporal rules and attention to the passage of time to estimate a temporal interval of several seconds. We used human electroencephalography and single neuronal recordings in mice to capture prefrontal activity during interval timing, with major patterns characterized by time-dependent ramping (monotonic changes) over a temporal interval. We then leveraged retrograde viruses to interrogate prefrontal cortex (PFC) projections to the mediodorsal thalamus (PFC-MD) and to the dorsomedial striatum (PFC-DMS). We report three novel results. First, circuit-specific calcium fiber photometry revealed that PFC-MD and PFC-DMS activity encoded distinct temporal signals, with PFC-MD projections ramping down and PFC-DMS ramping up to interval timing response times. Second, circuit-specific inactivation revealed that PFC-DMS inactivation disrupted animals internal estimates of time. Third, circuit-specific single-nucleus RNA sequencing of prefrontal projections revealed distinct transcriptomic profiles between PFC-MD and PFC-DMS projections, with enriched genes for cortical layers and neuromodulators, and specific genes such as Cux2, Camk2n1, Htr4, and Foxp2. These data suggest differences in gene expression and connectivity give rise to the diversity of prefrontal activity during interval timing. These findings advance our fundamental understanding of prefrontal function and dysfunction in human disease.

neuroscience↗

bioRxiv2025

Colonic inflammation modulates the intestinal circadian landscape

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that carries significant morbidity. The circadian (24h) clock regulates many aspects of immunity and circadian disruption is implicated in inflammatory disease. We examined the impact of acute dextran sulphate sodium-induced colitis on the intestinal circadian landscape and investigated consequences of intestinal epithelial cell (IEC) clock disruption on immune function in health and under inflammatory stress. Within the inflamed colon, we observed attenuated IEC clock function. Furthermore, de novo oscillations in numbers of colonic regulatory T cells emerged, associated with diurnal variation in proliferation and activation markers. IEC-specific deletion of core clock gene Bmal1 drove alterations in the rhythmic colonic transcriptome (impacting key immune pathways) and marked damping of microbiota rhythmicity. IEC-specific Bmal1 deletion did not impact colitis severity. These results highlight the impact of colonic inflammation on circadian processes and suggest that circadian logic could be applied in IBD treatment.

immunology↗

bioRxiv2022

MS2Prop: A machine learning model that directly predicts chemical properties from mass spectrometry data for novel compounds

Mass spectrometry (MS) is a fundamental analytical tool for the study of complex molecular mixtures and in natural products drug discovery and metabolomics specifically, due to its high sensitivity, specificity, and throughput. A major challenge, however, is the lack of structurally annotated mass spectra for these applications. This deficiency is particularly acute for analyses conducted on extracts or fractions that are largely chemically undefined. This work describes the use of mass spectral data in a fundamentally different manner than structure determination; to predict properties or activities of structurally unknown compounds without the need for defined or deduced chemical structure using a machine learning (ML) model, MS2Prop. The models predictive accuracy and scalability is benchmarked against commonly used methods and its performance demonstrated in a natural products drug discovery setting. A new cheminformatic subdiscipline, quantitative spectra-activity relationships (QSpAR), using spectra rather than chemical structure as input, is proposed to describe this approach and to distinguish it from structure based quantitative methods.

bioinformatics↗

bioRxiv2020

Lineage tracing of human embryonic development and foetal haematopoiesis through somatic mutations

To date, ontogeny of the human haematopoietic system during foetal development has been characterized mainly through careful microscopic observations. Here we used whole-genome sequencing (WGS) of 511 single-cell derived haematopoietic colonies from healthy human foetuses of 8 and 18 post-conception weeks (pcw) coupled with deep targeted sequencing of tissues of known embryonic origin to reconstruct a phylogenetic tree of blood development. We found that in healthy foetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 pcw. Using these mutations as barcodes, we timed the divergence of embryonic and extra-embryonic tissues during development and estimated the number of blood antecedents at different stages of embryonic development. Our analysis has shown that ectoderm originates from a smaller set of blood antecedents compared to endoderm and mesoderm. Finally, our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.

genomics↗

bioRxiv2020

Transient Commensal Clonal Interactions Can Drive Tumor Metastasis

To interrogate functional heterogeneity and crosstalk between tumor cells, we generated clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations were engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grew robustly, generating exclusively malignant ascites. However, multiclonal mixtures formed large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions were sufficient to promote metastasis of CL31. CL31 uniquely harbored ERBB2 amplification, and its acquired metastatic trait was dependent on transient exposure to amphiregulin, which was exclusively secreted by non-tumorigenic clones. Amphiregulin enhanced CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit- and-run" commensal interactions.

cancer biology↗