Biology subjects

McCoy, L.

Publications and source records attributed to McCoy, L..

4 recordsLinked to original sources

bioRxiv2024

Mistargeted retinal axons form synaptically segregated subcircuits in the visual thalamus of albino mice

In albino mice and EphB1 knock out mice, mistargeted retinal ganglion cell (RGC) axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity. We conclude that, when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit within the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and for our understanding of the implementation of activity dependent development.

neuroscience↗

bioRxiv2023

Subcellular pathways through VG3 amacrine cells provide regionally tuned object-motion-selective signals in mouse retina.

We combined subcellular calcium imaging and connectomic reconstruction to understand the flow of information through a plexus of excitatory VGluT3-expressing mouse retinal amacrine cells (VG3s). We found that VG3s received inputs from all nearby bipolar cell types but exhibited a strong preference for the fast type 3a bipolar cells. We used our connectivity map and physiological recordings to predict the influence of these bipolar cells on different types of RGCs innervated by VG3s and found that the depth of retinal ganglion cell (RGC) dendritic arbor stratification determined the RGCs view of bipolar cells through the VG3 plexus. We also found that both VG3s and their RGC targets were often innervated by the same bipolar cells. RGCs that extend processes into the middle layers of the inner plexiform layer, therefore, encounter a plexus of small object motion selective glutamatergic excitation that is complementary to the local bipolar cell input.

neuroscience↗

bioRxiv2021

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterised pharmaceuticals for nsp13 inhibitors using a FRET-based high-throughput screening (HTS) approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.

biochemistry↗

bioRxiv2018

Human Nerve-on-a-Chip. Engineering 3D functional human peripheral nerve in vitro

Development of \"organ-on-a-chip\" systems in the space of the nervous system is lagging because of lack of availability of human neuronal & glial cells and the structural complexity of the nervous system. Furthermore, a sizeable challenge in the drug development pipeline and an often-cited reason for failure in a vast number of clinical trials conducted for neuropathological ailments is the lack of translation from animal models. A preclinical in vitro model capable of mimicking the function and structure of the human nervous system is well desired. We present an in vitro biomimetic model of all-human peripheral nerve tissue capable of showing a robust neurite outgrowth (~5mm), myelination of human induced pluripotent stem cells (iPSCs)-derived neurons by primary human Schwann cells and evaluation of nerve conduction velocity (NCV), previously unrealized for any human cell-based in vitro system. This Human Nerve-on-a-chip (HNoaC) system is the first microphysiological system of human peripheral nerve which can be used for evaluating electrophysiological and histological metrics, which are gold-standard assessment techniques previously only possible with in vivo studies.

bioengineering↗