Biology subjects

Cain, J.

Publications and source records attributed to Cain, J..

7 recordsLinked to original sources

bioRxiv2026

Comparison of Automated White Matter Lesion Segmentation Approaches for Use in Large, Multi-Site Data Analyses in Parkinson's Disease

BackgroundParkinsons disease (PD) is the second most common neurodegenerative disorder. PD currently lacks effective disease-modifying treatments, likely due to its diverse clinical features and underlying neuropathology. The vascular role in PD is emerging, with vascular mechanisms increasingly implicated, yet the literature remains conflicted, motivating large-data analyses with greater statistical power. White matter lesions (WML) are an accepted imaging marker of small vessel disease. Accurate automated WML segmentation techniques are crucial for large-scale studies in PD due to the impracticality of manual segmentation for extensive datasets and to ensure consistency. Evaluation of the optimum approach in PD for large-scale analysis is lacking. This study aimed to evaluate various automated WML segmentation algorithms to determine the most accurate and reliable method, among those selected, for assessing WML for multi-site large data analysis in PD. MethodsWe assessed whole-brain volumetric T1-weighted and FLAIR images from 201 PD patients (mean age, 66.6 {+/-} 7.86 years) and 64 healthy controls (HC; mean age, 66.3 {+/-} 8.67) across three datasets: the Parkinsons Progression Markers Initiative (PPMI), the University of Pennsylvania (UPenn) and the Montreal Neurological Institute Biobank: Clinical Biological Imaging and Genetic Repository (C-BIG). The sample included different scanners, imaging parameters and lesion loads, as would be expected for multi-site data. WML were manually segmented to provide the gold standard, and four freely available automated algorithms were evaluated: FSLs BIANCA, FreeSurfer, SPMs LST-LPA and U-Net-pgs using the performance metrics: Dice score, Hausdorff distance, recall, precision, F1 score, log absolute volume difference (LOGAVD) and intraclass correlation coefficient (ICC). Subgroup analyses were performed based on lesion load and lobar regions. The associations of data from these automated approaches with age, and with Fazekas and Wahlund visual rating scales, were assessed through partial correlation analysis. ResultsU-Net-pgs performed best overall, with the highest Dice score (PD: 0.46 {+/-} 0.21; HC: 0.39 {+/-} 0.21), recall (PD: 0.76 {+/-} 0.25; HC: 0.62 {+/-} 0.31), precision (PD: 0.49 {+/-} 0.25; HC: 0.63 {+/-} 0.27), F1 score (PD: 0.54 {+/-} 0.22; HC: 0.56 {+/-} 0.22) and ICC (PD: 0.965; HC: 0.967) and lowest Hausdorff distance (PD: 8.89 {+/-} 3.96; HC: 6.33 {+/-} 2.91). U-Net-pgs achieved the lowest LOGAVD in the PD group (0.31 {+/-} 0.31) whereas BIANCA-LOO with a threshold of 0.9 was lowest in HC (0.27 {+/-} 0.30). U-Net also showed superior performances in all lesion loads for PD and overall across various brain regions in both PD and HC. ConclusionOverall, U-Net-pgs emerged as the best performing automated method, of those we evaluated, for WML segmentation in PD and HC within a dataset collected with various scanner and image acquisition parameters. U-Net-pgs consistently outperformed other automated approaches across lesion loads and brain regions, for most metrics. The accuracy and reliability of U-Net-pgs make it a promising tool for large-scale analyses, facilitating future research investigating WML in PD.

neuroscience↗

bioRxiv2025

Meal timing is a critical factor for maintenance of gut homeostasis around the clock

Gut function exhibits 24 hour (circadian) rhythmicity, in part driven by intrinsic clocks within intestinal epithelial cells (IECs). The gut microbiome also demonstrates circadian rhythms in composition and function, important for maintenance of metabolic, immune and gut health. Here, we determined the influence of feeding behaviour on the colonic circadian landscape using an interval feeding paradigm, whereby food intake was partitioned equally across the 24h day. RNAseq analysis revealed that the IEC intrinsic clock persists in the absence of diurnal feeding rhythms, however a subset of key transcripts lose rhythmicity, demonstrating that cell extrinsic temporal cues contribute significantly to maintenance of the rhythmic gut transcriptome. Furthermore, interval fed mice demonstrated striking loss of rhythms in secretory IgA, a critical regulator of the temporal landscape of the gut microbiome. In keeping, rhythmicity within the microbiota and microbial derived short chain fatty acids was significantly diminished. This work highlights the importance of daily rhythms in feeding behaviour for maintenance of rhythmic processes within the gut, with implications for metabolic and immune health.

physiology↗

bioRxiv2025

The club cell circadian clock regulates temporal patterns in leukocyte trafficking in chronic allergic airways disease

RationaleAsthma displays temporally variable symptoms which worsen overnight, corresponding with a nocturnal increase in airway eosinophils. The molecular clock within the club cell of the bronchial epithelium is a key driver of lung rhythmic processes, however, its role in chronic allergic airways disease (AAD) is not known. Elucidating the role of the club cell clock in regulating rhythmic inflammation in AAD could lead to new therapeutic advances. ObjectivesTo investigate the club cell molecular clock regulation of leukocyte trafficking in chronic AAD. Methodsccsp-bmal1 KO mice (which lack a functional clock in club cells) and littermate control mice underwent a 5-week chronic house dust mite (HDM) model of AAD, following which leukocyte populations and cytokines from blood, lung and airway compartments were quantified in a 24-hour time-course. Airway epithelial cells were cultured and transepithelial electrical resistance measured to explore circadian variability in barrier permeability and impact of pharmacological modulation of the clock. Main ResultsLeukocyte populations accumulate in the blood, lung and airways of HDM exposed mice in a time-of-day dependent manner, with time of peak accumulation dependent on cell type. This temporal gating of leukocyte accumulation is controlled and coordinated by the club cell circadian clock, which also regulates airway barrier integrity. Targeting REVERBa (a component of the molecular circadian clock), was effective at modifying airway barrier permeability achieving reduced transepithelial leukocyte migration. ConclusionsThe club cell clock gates leukocyte trafficking signals and airway barrier integrity by time of day in chronic allergic airway inflammation.

immunology↗

bioRxiv2023

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), are uniformly fatal brain tumors that lack effective pharmacological treatment. Analysis of pooled CRISPR-Cas9 loss-of-function gene deletion screen datasets, identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient derived models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic feedback resulting in increased blood glucose and insulin levels, commensurate with DIPG patients in Phase 1b clinical trials who experienced hyperglycemia/hyperinsulinemia. To exploit genetic dependences, but maintain compliance and benefit, we optimized a paxalisib treatment regimen that employed reduced dosing more frequently, in combination with the anti-hyperglycemic drug, metformin. Combining optimized dosing with metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending the survival of DIPG xenograft models. RNA sequencing and phosphoproteomic profiling of DIPG models treated with paxalisib identified increased calcium-activated PKC signaling. Using the brain penetrant PKC inhibitor, enzastaurin in combination with paxalisib, we synergistically extended the survival of orthotopic xenograft models, benefits further promoted by metformin; thus, identifying a clinically relevant DIPG combinatorial approach. Brief SummaryDiffuse intrinsic pontine glioma is a lethal childhood brain tumor. Here we identify PIK3CA as a genetic dependency targeted by the brain penetrant pan-PI3K-inhibitor paxalisib.

cancer biology↗

bioRxiv2021

Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum

SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A to D) in mammals, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans. sec24d mutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. Using Sec24d KO mice and cultured cells, we show that SEC24A and SEC24B also contribute to ER export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.

cell biology↗

bioRxiv2020

Resistance to platinum chemotherapy in lung adenocarcinoma is driven by a non-genetic, cell-cycle dependent mechanism

We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non- genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

cell biology↗

bioRxiv2020

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve recruitment has not been tested. Using a murine model of ovarian cancer, we show that tumor-infiltrating sensory nerves potentiate tumor growth, decrease survival, and contribute to treatment resistance. Furthermore, matched patient samples show significantly increased tumor innervation following chemotherapy. In vitro analysis of tumor-released extracellular vesicles (sEVs) shows they harbor neurite outgrowth activity. These data suggest that chemotherapy may alter sEV cargo, endowing it with robust nerve recruiting capacity.

cancer biology↗