Biology subjects

Banks, W. A.

Publications and source records attributed to Banks, W. A..

4 recordsLinked to original sources

bioRxiv2025

Heparan sulfate glycosaminoglycans mediate CXCL4 (PF4) transport across the blood-brain barrier and effects on neurogenesis

CXCL4 (PF4) is a chemokine stored in platelets that has pleiotropic effects across biological settings. These effects include driving of inflammation and fibrosis as well as reversal of the effects of ageing. We have recently demonstrated that CXCL4 function is driven, independently of known chemokine receptors, through binding to glycosaminoglycan (GAG) side chains on proteoglycans within the cell surface glycocalyx. In this study, we have used intravital imaging and radioactive tracer studies, in combination with an exogenous inhibitor and a GAG-binding CXCL4 mutant, to demonstrate that CXCL4 can enter the brain parenchyma of mice by binding to proteoglycans within the cell surface of the endothelial glycocalyx of the blood-brain barrier (BBB). Furthermore, we have also demonstrated that CXCL4 directly promotes neurogenesis in vitro, which is mediated by its ability to oligomerise and bind to GAGs. These findings provide a molecular mechanism for CXCL4 uptake and function within the brain. Furthermore, these data have important implications for understanding CXCL4 during health and disease that may enable development of CXCL4-related therapeutics for inflammatory diseases and ageing.

neuroscience↗

bioRxiv2022

Timing matters: Sex differences in acute and chronic outcomes following repetitive blast mild traumatic brain injury

BackgroundRepetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined acute and chronic outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction. MethodsIn this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. ResultsRepetitive blast exposure resulted in both similar and disparate patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited chronic adverse behavioral outcomes. DiscussionRepresenting a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

neuroscience↗

bioRxiv2021

Effects of ozone on sickness and depressive-like behavioral and biochemical phenotypes and their relations to serum amyloid A and kynurenine in blood

Ozone (O3) is an air pollutant which primarily damages the lungs, but growing evidence supports that O3 exposure can also affect the brain. Serum amyloid A (SAA) and kynurenine have been identified as circulating factors that are upregulated by O3, and both can contribute to depressive-like behaviors in mice. However, little is known about the relations of O3 exposure to sickness and depressive-like behaviors in experimental settings. In this study, we evaluated O3 dose-, time- and sex-dependent changes in circulating SAA in context of pulmonary inflammation and damage, sickness and depressive-like behavioral changes, and systemic changes in kynurenine and indoleamine 2,3-dioxygenase (IDO), an enzyme that regulates kynurenine production and contributes to inflammation-induced depressive-like behaviors. Our results in Balb/c and CD-1 mice showed that 3ppm O3, but not 2 or 1ppm O3, caused elevations in serum SAA and pulmonary neutrophils, and these responses resolved by 48 hours. Sickness and depressive-like behaviors were observed at all O3 doses (1-3ppm), although the detection of certain behavioral changes varied by dose. We also found that Ido1 mRNA expression was increased in the brain and spleen 24 hours after 3ppm O3, and that kynurenine was increased in blood. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors which may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. We also present evidence that the IDO/kynurenine pathway is upregulated systemically following an acute exposure to O3 in mice.

physiology↗

bioRxiv2020

The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation

Evidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 {+/-} 0.024 L/g-min and 0.294 {+/-} 0.032 L/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10th the amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗