Biology subjects

O'Connell, G.

Publications and source records attributed to O'Connell, G..

4 recordsLinked to original sources

bioRxiv2024

Characterization of the murine spine for spaceflight studies

Rodents provide a useful analog for understanding the effects of spaceflight on the human body, offering opportunities for investigations into the relationship between microgravity and the musculoskeletal system. In particular, rodents have often been utilized to improve our understanding of the effects of spaceflight on the spine, including intervertebral disc and vertebral body health. However, there are a number of experimental factors that differ between existing works, including mission duration, animal housing, and anatomical location of interest, making it difficult to draw holistic conclusions. Additionally, the quadrupedal nature of the murine spine results in different biomechanical loading than in a bipedal organism. Thus, the objective of this study was to more fully define the bulk properties of the murine lumbar spine model after 28 days of spaceflight. Additionally, the proximal tibia was analyzed to provide insight into the skeletal site-specificity of gravitational unloading in space. Results indicated that the effects of spaceflight on vertebral body bone microarchitecture, intervertebral disc biochemistry, and intervertebral disc joint mechanics were statistically insignificant, while large and significant bone loss was observed in the proximal tibia of the same animals. We hypothesize that this may be due to site-specific loading changes in space. Specifically, vigorous ambulatory behaviors observed in this experiment after initial acclimation to spaceflight may increase axial load-bearing in the lumbar spine, while maintaining microgravity induced mechanical unloading in the tibia. In total, this work shows that the rodent spine, unlike the weight bearing tibia in the same mice, is not affected by gravitational unloading, suggesting the tissue degenerative effects of spaceflight are site- and load-specific and not systemic. This study also highlights the importance of considering experimental variables such as habitat acclimation, physical activity, and experiment duration as key factors in determining musculoskeletal and spine health outcomes during spaceflight.

bioengineering↗

bioRxiv2023

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is the 5{beta}1 integrin and fibronectin (FN) bond, known for its role in establishing cell adhesion sites for migration. However, upregulation of the 5{beta}1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics of 5{beta}1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (arg-gly-asp) motif, act as active points for structural changes in 5{beta}1 integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite element model is employed to elucidate how the synergy site may promote dynamic 5{beta}1-FN binding, resisting cell contraction. In summary, our study integrates molecular and cellular-level modeling to propose that FNs synergy site reinforces cell adhesion through enhanced binding dynamics and a mechanosensitive pivot-clip mechanism. This work sheds light on the interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts. SIGNIFICANCE5{beta}1 integrin serves as a mediator of cell-matrix adhesion and has garnered attention as a target for impeding cancer metastasis. Despite its importance, the mechanism underlying the formation of a catch bond between 5{beta}1 integrin and its primary ligand, fibronectin, has remained elusive. Our study aims to address this gap by proposing a pivot-clip mechanism. This mechanism elucidates how 5{beta}1 integrin and fibronectin collaboratively reinforce cell adhesion through conformational changes induced by the dynamic interaction of a key binding motif known as the synergy site.

biophysics↗

bioRxiv2021

Brain structural correlates of autistic traits across the diagnostic divide: A grey matter and white matter microstructure study

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental conditions characterised by difficulties in social interaction and communication as well as stereotyped and restricted patterns of interest. Autistic traits exist in a continuum across the general population, whilst the extreme end of this distribution is diagnosed as clinical ASD. While many studies have investigated brain structure in autism using a case-control design, few have used a dimensional approach. To add to this growing body of literature, we investigated the structural brain correlates of autistic traits in a mixed sample of adults (N=91) with and without a clinical diagnosis of autism. We examined regional brain volumes (using voxel-based morphometry and surface-based morphometry) and white matter microstructure properties (using Diffusion Tensor Imaging). Our findings show widespread grey matter differences, including in the social brain regions, and some evidence for white matter microstructure differences related to higher autistic traits. These grey matter and white matter microstructure findings from our study are consistent with previous reports and support the brain structural differences in ASD. These findings provide further support for shared aetiology for autistic traits across the diagnostic divide.

neuroscience↗

bioRxiv2017

Stroke-associated pattern of gene expression previously identified by machine-learning is diagnostically robust in an independent patient population.

PurposeOur group recently identified a ten gene pattern of differential expression in peripheral blood which may have utility for detection of stroke. The objective of this study was to assess the diagnostic capacity and temporal stability of this stroke-associated transcriptional signature in an independent patient population.\n\nMethodsPublically available whole blood microarray data generated from 23 ischemic stroke patients at 3, 5, and 24 hours post-symptom onset, along with 23 cardiovascular disease controls were obtained via the National Center for Biotechnology Information Gene Expression Omnibus. Expression levels of the ten candidate genes were extracted, compared between groups, and evaluated for their discriminatory ability at each time point.\n\nResultsWe observed a largely identical pattern of differential expression between stroke patients and controls across the ten candidate genes as reported in our prior work. Furthermore, the coordinate expression levels of the ten candidate genes were able to discriminate between stroke patients and controls with levels of sensitivity and specificity upwards of 90% across all three time points.\n\nConclusionsThese findings confirm the diagnostic robustness of the previously identified pattern of differential expression in independent patient population, and further suggest that it is temporally stable over the first 24 hours of stroke pathology.

genomics↗