Biology subjects

Young, B. M.

Publications and source records attributed to Young, B. M..

5 recordsLinked to original sources

bioRxiv2024

Stroke and Motor Recovery are Associated with Regional and Age-Specific Changes in Periodic and Aperiodic Cortical Activity

Normal aging is associated with widespread changes in neuronal structure, function, and activity. The consequences of focal brain injury on global neuronal activity in aged individuals are poorly understood. Historically, stroke and aging have been associated with changes in narrow-band periodic neuronal activity, however recent work has highlighted the importance of broad-band aperiodic activity. Aperiodic activity is represented by the 1/f slope of power spectral density generated by cortical activity. Abnormalities in aperiodic activity have been identified in psychiatric disorders and stroke, are associated with cognitive dysfunction in aging, and have been hypothesized to reflect changes in excitation/inhibition balance. Here we sought to further explore changes in both periodic and aperiodic cortical activity in neurotypical intact young and aged healthy individuals and individuals with stroke. We compared "resting state" electroencephalograms from all participants after applying the specparam algorithm, which decomposes the power spectrum into aperiodic and periodic components. We also correlated stroke outcomes using previously obtained tests of motor outcome (box and block) to average whole cortex spectral slopes within the stroke group. Consistent with prior work we found a significant flattening (decrease in exponent) of power spectral slope with normal aging. We also found that both aging and stroke were associated with fewer periodic peaks within the power spectrum. Interestingly, we found that stroke was associated with a significant increase in spectral slope, but age moderated this effect. Younger stroke patients showed minimal difference in slope while older stroke patients had significantly steeper slopes (opposite to the direction in normal aging). Using MRIs from stroke participants we investigated the lesion locations most associated with changes in slope. Interestingly deep lesions were observed to have the greatest influence on cortical spectral slope. Finally, slope in the stroke group was correlated with performance on a test of manual dexterity, however this correlation was much more significant in aged individuals. Our data suggest that stroke in the aged brain has unique effects on aperiodic activity possibly reflecting unique influence of injury on cerebral excitation/inhibition balance in aged individuals and that the degree of these changes may be related to stroke outcomes.

neuroscience↗

bioRxiv2022

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the ER stress sensor IRE1 and its downstream transcription factor XBP1 enhance the upregulation of glycolysis in classically activated macrophages (CAM). The IRE1-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by LPS stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1 activation; while TLR4 supports glycolysis under both conditions, TLR4 is required for activation of IRE1 in response to LPS treatment but not B. abortus infection. Though IRE1 and XBP1 are necessary for maximal induction of glycolysis in CAM, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cells metabolic response and that IRE1 activation may be a way to fine-tune metabolic reprogramming. IMPORTANCEThe immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1 by independent mechanisms. While the IRE1-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1 and XBP1 in innate immunity.

immunology↗

bioRxiv2022

Morphogen Directed Coordination of GPCR Activity Promotes Primary Cilium Function for Downstream Signaling

Sonic Hedgehog (SHH) signaling is an essential driver of embryonic patterning that, when corrupted, leads to developmental disorders and cancers. SHH effector responses are organized through nonmotile primary cilia that grow and retract with the cell cycle and in response to distinct extracellular cues. Destabilization of primary cilium length corrupts SHH pathway regulation, which places significant pressure on SHH to maintain ciliary architecture. Herein, we investigate whether SHH signaling promotes ciliary length control. We reveal a signal crosstalk circuit induced by SHH activation of Phospholipase A2 (cPLA2) that drives ciliary EP4 signaling to stabilize primary cilium length. We demonstrate that chemical or genetic blockade of SHH-EP4 crosstalk leads to destabilized primary cilium cyclic AMP (cAMP) control, reduced ciliary length, and attenuated SHH pathway induction. Accordingly, we find that Ep -/- mice display shortened neuroepithelial primary cilia and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates a signaling crosstalk circuit that maintains primary cilium length for a robust downstream signaling response.

cell biology↗

bioRxiv2020

A Two-Step Bioreactor for Lung Recellularization

Bioreactors for reseeding of decellularized lung scaffolds have evolved with a wide variety of advancements. These include biomimetic mechanical stimulation, constant nutrient flow, multi-output monitoring, and large mammal scaling. Although dynamic bioreactors are not new to the field of bioengineered lungs, ideal conditions during cell seeding have not been extensively studied or controlled. To address the lack of cell dispersal in traditional seeding methods, we have designed a two-step bioreactor. The first step rotates a seeded lung every 20 minutes at different angles to ensure 20 percent of cells are anchored to a particular location based on the known rate of attachment. The second step involves perfusion culture to ensure nutrient dispersion and cellular growth. Compared to statically seeded lungs followed by conventional perfusion, rotationally seeded lungs followed by perfusion had significantly increased dsDNA content and more uniform cellular distribution. This new bioreactor system will aid in recellularizing the lung and other geometrically complex organs for tissue engineering.

bioengineering↗

bioRxiv2019

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

Decellularized tissues offer a unique tool for developing regenerative biomaterials or in vitro platforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen, fibronectin, laminin, and dECM in varying combinations as an in vitro coating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, E- cadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings reveal potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds or edema related pathologies.

bioinformatics↗