Biology subjects

McCormick, A.

Publications and source records attributed to McCormick, A..

3 recordsLinked to original sources

bioRxiv2022

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate

Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimers disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/{beta}-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD4-specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

physiology↗

bioRxiv2022

Crowdsourced EEG Experiments: A proof of concept for remote EEG acquisition using EmotivPRO Builder and EmotivLABS

Online research platforms have enabled mass data collection enabling representative samples for cognitive behavioural studies. However, the benefits of online data collection have not been available for cognitive neuroscience fields such as electroencephalography (EEG). In this study, we introduce an approach for remote EEG data collection. We demonstrate how an experiment can be built via the EmotivPRO Builder and deployed to the EmotivLABS website where it can be completed by participants who own EMOTIV EEG headsets. To demonstrate the data collection technique, we collected EEG while participants engaged in a resting state task where participants sat with their eyes open and then eyes closed for two minutes each. We observed a significant difference in alpha power between the two conditions thereby demonstrating the well-known alpha suppression effect. Thus, we demonstrate that EEG data collection, particularly for frequency domain analysis, can be successfully conducted online with remote users.

neuroscience↗

bioRxiv2021

The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

Defective DNA damage response (DDR) pathways allow cancer cells to accrue genomic aberrations and evade normal cellular growth checkpoints. Defective DDR also determines response to chemotherapy. However, the interaction and overlap between the two double strand repair pathways and the three single strand repair pathways is complex, and has remained poorly understood. Here we show that, in ovarian cancer, a disease hallmarked by chromosomal instability, explant cultures show a range of DDR abrogation patterns. Defective homologous recombination (HR) and non-homologous end joining (NHEJ) are near mutually exclusive with HR deficient (HRD) cells showing increased abrogation of the single strand repair pathways compared to NHEJ defective cells. When combined with global markers of DNA damage, including mitochondrial membrane functionality and reactive oxygen species burden, the pattern of DDR abrogation allows the construction of DDR signatures which are predictive of both ex vivo cytotoxicity, and more importantly, patient outcome. SignificanceHolistic assessment of the DDR is possible, shows improved ability to predict response to chemotherapy over single pathway assessment, and is applicable to a variety of ovarian cancer types. Such an assessment has clinical utility in settings of therapeutic dilemma such as retreatment for relapse.

cell biology↗