Biology subjects

Prior, A.

Publications and source records attributed to Prior, A..

5 recordsLinked to original sources

bioRxiv2025

Avoidance of pyroptosis accounts for the relatively high metastatic potential observed in early hybrid EMT states

EMT converts epithelial (E) phenotypes to invasive mesenchymal (M) states. However, analyses of circulating tumor cells (CTCs) indicated that biphenotypic (E+M) CTCs better correlate with metastasis. Similarly, investigations of murine tumors undergoing EMT concluded that early E+M states posses the highest metastatic potential. To explore this, we selected in animals with breast cancer CTCs having progressively increasing intravasation abilities. This revealed that downregulation of arrestin Arrdc4 associates with CTC aggressiveness. In xenografts, depleting Arrdc4 accelerated tumor progression, whereas overexpression hindered progression in immunocompetent, but not in immunocompromised mice. Mechanistically, high Arrdc44 suppresses glucose uptake and enhances gasdermin E, triggering pyroptosis a type of pro-inflammatory cell death. Consistently, Arrdc4s lowest levels characterize the most metastatic biphenotypic states. In patients, both epigenetic and chromosomal aberrations downregulate ARRDC4 and predict poor prognosis. In summary, the uncovered mechanism portrays pyroptosis of biphenotypic EMT cells as a rheostat of CTCs, which may resolve the controversy on the role played by EMT in metastasis.

cancer biology↗

bioRxiv2024

An anatomical investigation of alkaptonuria: Novel insights into ochronosis of cartilage and bone

1Ochronotic pigmentation of connective tissue is the central pathological process in the rare metabolic disease alkaptonuria (AKU). Tissue pigmentation in AKU occurs due to unmetabolized homogentisic acid (HGA) in the circulation, caused by an enzyme deficiency in the liver. Ochronotic pigmentation, derived from HGA, has previously been reported and described in large joints obtained from arthroplasty surgeries, which typically have advanced disease. Many tissues that are affected by ochronosis are not accessible for study during life, including tissues subjected to early and mid-stage disease. Here, the opportunity arose to anatomically examine a 60-year-old AKU female body donor, allowing the investigation of previously understudied tissue, including those undergoing early-stage pathological changes. Dissection of fresh-frozen tissue was carried out and harvested tissues were fixed and examined histologically using H&E and Schmorls stains to aid identification of ochronotic pigment. This work focusses on osteochondral tissues including extra-skeletal cartilage, viscera and eyes. Gross and histological images demonstrating pigmentation in the cartilage and perichondrium of the ear ossicles, tympanic membrane, and the pubic symphysis fibrocartilaginous disc are described for the first time here. We also show the first examination of the temporomandibular joint, which macroscopically appeared unpigmented, with histological analysis of the fibrocartilaginous disc showing no pigmentation. Pigmentation of non-articular hyaline cartilage was observed in the respiratory tract, in both the hyaline cartilage and perichondrium, confirming previous findings. Within smaller joints, pigmentation of chondrons and the surrounding territorial matrix was observed, but was confined to calcified articular cartilage, and was not generally found in the hyaline articular cartilage. Dark pigmentation of the perichondrium adjacent to the articular surface was observed in numerous small joints, which has not been described before. The calcified bone matrix was not pigmented but ochronosis was identified in a small fraction of trabecular osteocytes in the capitate and radius, with substantially more pigmented osteocytes observed in bone of the ear ossicles. Viscera examined were unpigmented. This anatomical examination of tissues from an AKU individual highlights that most osteochondral tissues are susceptible to HGA-derived pigmentation, including the ear ossicles which are the smallest bones in the body. Within joints, calcified cartilage and perichondrium appear to be the earliest affected tissues, however why this is the case is not understood. Furthermore, why the TMJ disc was unaffected by pigmentation is intriguing. The heterogenous appearance of pigmentation both within and between different tissues indicates that factors other than tissue type (i.e. cartilage, perichondrium) and matrix composition (i.e. collagen-rich, calcified) may affect the process of ochronosis, such as oxygen tension, loading patterns and tissue turnover. The effect of nitisinone treatment on the ochronotic disease state is considered, in this case 7 years of treatment, however comparisons could not be made to other cases due to inter-individual variability.

pathology↗

bioRxiv2023

miR-324 mediates bone homeostasis through the regulation of osteoblast and osteoclast differentiation and activity

microRNAs (miRNAs) are non-coding RNAs which modulate the expression of other RNA molecules. One miRNA can target many transcripts, allowing each miRNA to play key roles in many biological pathways. miR-324 is a miRNA previously implicated in bone and cartilage maintenance, defects of which result in common age-related diseases, such as osteoporosis or osteoarthritis (OA). In global miR-324-null mice cartilage damage was increased in both surgically and ageing-induced OA, despite minimal changes to the cartilage transcriptome, with few predicted miR-324 targets dysregulated. However, micro-computed tomography and histology demonstrated that global miR- 324-null the mice had an increase in bone mineral density, trabecular thickness and cortical thickness, with many parameters increasing with age. The bone marrow of miR-324-null mice also had reduced lipid content while and in vivo TRAP staining revealed a decrease in osteoclasts, with histomorphometry demonstrating an increased rate of bone formation in miR-324-null mice. Ex vivo assays revealed that the high bone mass phenotype of the miR-324-null mice resulted from increased osteoblast activity and decreased osteoclastogenesis. RNA-seq and qRT-PCR followed by miR-324 target prediction and validation in osteoblasts, osteoclasts and bone marrow macrophages identified the osteoclast fusion regulator Pin1 as a miR-324 target in the osteoclast lineage and the master osteogenic regulator Runx2 as a target of miR-324-5p in osteoblasts, the in vitro overexpression of which recapitulated the increased osteogenesis and decreased adipogenesis phenotype observed in vivo. These data point to important roles of miR-324 in skeletal biology with altered bone homeostasis in miR-324-null mice potentially causal for the increased cartilage damage observed during OA and ageing. Elucidation of pathways regulated by miR-324 offer promise for the treatment of bone diseases such as osteoporosis.

cell biology↗

bioRxiv2021

Assessing the sensitivity of EEG-based frequency-tagging as a metric for statistical learning

AO_SCPLOWBSTRACTC_SCPLOWStatistical Learning (SL) is hypothesized to play an important role in language development. However, the behavioral measures typically used to assess SL, particularly at the level of individual participants, are largely indirect and often have low sensitivity. Recently, a neural metric based on frequency-tagging has been proposed as an alternative and more direct measure for studying SL. Here we tested the sensitivity of frequency-tagging measures for studying SL in individual participants in an artificial language paradigm, using non-invasive EEG recordings of neural activity in humans. Importantly, we use carefully constructed controls, in order to address potential acoustic confounds of the frequency-tagging approach. We compared the sensitivity of EEG-based metrics to both explicit and implicit behavioral tests of SL, and the correspondence between these presumed converging operations. Group-level results confirm that frequency-tagging can provide a robust indication of SL for an artificial language, above and beyond potential acoustic confounds. However, this metric had very low sensitivity at the level of individual participants, with significant effects found only in 30% of participants. Conversely, the implicit behavior measures indicated that SL has occurred in 70% of participants, which is more consistent with the proposed ubiquitous nature of SL. Moreover, there was low correspondence between the different measures used to assess SL. Taken together, while some researchers may find the frequency-tagging approach suitable for their needs, our results highlight the methodological challenges of assessing SL at the individual level, and the potential confounds that should be taken into account when interpreting frequency-tagged EEG data.

neuroscience↗

bioRxiv2019

Syndecan-3 enhances anabolic bone formation through WNT signalling

Osteoporosis is the most common age-related metabolic bone disorder, which is characterised by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however anabolic therapeutics are few and their use is time-restricted. Here we report that Syndecan-3 (SDC3) increases new bone formation through enhancement of WNT signalling. Young adult Sdc3-/- mice have a low bone volume phenotype associated with reduced bone formation, increased bone marrow adipose tissue (BMAT), increased bone fragility and a blunted anabolic bone formation response to mechanical loading. The premature osteoporosis-like phenotype of Sdc3-/- mice is primarily explained by delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast-mediated bone resorption. Mechanistically, SDC3 enhances canonical WNT signalling in osteoblasts through stabilisation of Frizzled 1, making SDC3 an attractive target for novel anabolic drug development.

cell biology↗