Biology subjects

Ferris, J.

Publications and source records attributed to Ferris, J..

3 recordsLinked to original sources

bioRxiv2025

A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense.

Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the underlying dysfunction remains unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal NETosis via lactate sensing in healthy neutrophils, but this response is defective in SLE. Herein, we show that chronic Toll-like receptor (TLR) 7/9 signaling represses mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and downstream suicidal NETosis. Instead, SLE neutrophils default to vital NET release; a less bactericidal, type I interferon (IFN)-driven process amplified by staphylococcal pore-forming toxins and sustained by elevated systemic IFN levels observed in SLE. Combined treatment with hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restores LDHB expression, NET homeostasis, and bacterial clearance in lupus-prone mice. Neutrophils from SLE patients exhibit similar defects, which are reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings identify a clinically actionable immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE.

immunology↗

bioRxiv2023

Improved cognitive-motor processing speed and decreased functional connectivity after high intensity aerobic exercise in individuals with chronic stroke

After stroke, impaired motor performance is linked to an increased demand for cognitive resources. Aerobic exercise improves cognitive function in healthy populations and may be effective in altering cognitive function post-stroke. We sought to determine if high intensity aerobic exercise paired with motor training in individuals with chronic stroke alters cognitive-motor function and functional connectivity between the dorsolateral prefrontal cortex (DLPFC), a key region for cognitive-motor processes, and the sensorimotor network. Twenty-five participants with chronic stroke were randomly assigned to exercise (n = 14; 66 {+/-} 11 years; 4 females), or control (n = 11; 68 {+/-} 8 years; 2 females) groups. Both groups performed five-days of paretic upper limb motor training after either high intensity aerobic exercise (3 intervals of 3 minutes each, total exercise duration of 23-minutes) or watching a documentary (control). Resting-state fMRI, and TMT-A and B were recorded pre- and post-intervention. Both groups showed implicit motor sequence learning (p < .001), but there was no added benefit of exercise (p = .738). Regardless of group, the changes in task score (p = .025), and dwell time (p = .043) were correlated with a decrease in DLPFC-sensorimotor network functional connectivity (p = .024), which is thought to reflect a reduction in the cognitive demand and increased automaticity. The exercise group experienced greater overall cognitive-motor improvements measured with the trail making test part A (TMT-A: task score: p = .012; dwell time: p = .024; movement time: p = .567). Aerobic exercise may improve cognitive-motor processing speed post-stroke. Significance statementAfter stroke, impaired motor performance is linked to an increased demand for cognitive resources. In our work we show that high intensity aerobic exercise paired with an implicit motor learning task improves cognitive-motor processing speed and reduces resting-state functional connectivity between the dorsolateral prefrontal cortex and the sensorimotor network in individuals living with chronic stroke. These data likely reflect a reduction in cognitive resource dependence during a cognitive-motor task after stroke and a shift towards cognitive-motor automaticity.

neuroscience↗

bioRxiv2019

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCFSkp2 Ubiquitin Ligase Complex

Depending on its expression levels, the long splice form of the pseudo-caspase FLIP (FLIP(L)) can act as an inhibitor (high expression) or activator (low expression) of apoptosis induction by the TRAIL-R2 death-inducing signalling complex (DISC); its expression levels are therefore tightly regulated. Here, we demonstrate that the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCFSkp2) regulates the stability of FLIP(L) (but not the short splice form FLIP(S)), and, unusually, this is mediated by direct binding of FLIP(L) to Cullin-1 rather than via Skp2. By fine mapping the interaction of FLIP(L) with Cullin-1 to the large subunit of its pseudo-caspase domain, we found that the interaction is significantly stronger with FLIP(L)s DISC-processed p43-form. Importantly, this interaction disrupts the ability of p43-FLIP to interact with FADD, caspase-8 and another DISC component, TRAF2. Moreover, we find that SCFSkp2 associates with TRAIL-R2 constitutively and does so independently of FLIP(L) and other canonical DISC components. Inhibition of Cullin-1 expression (using siRNA) or activity (using a NEDDylation inhibitor, MLN4924) enhanced FLIP(L) and TRAF2 levels at the TRAIL-R2 DISC and enhanced caspase-8 processing. This suggests that processing of FLIP(L) to p43-FLIP at the TRAIL-R2 DISC enhances its interaction with co-localised SCFSkp2, leading to disruption of p43-FLIPs association with the DISC thereby altering caspase-8 processing. These findings provide important new insights into how FLIP(L) expression and TRAIL-R2 signaling is controlled.

molecular biology↗