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Biology subjects

Connor, J. P.

Publications and source records attributed to Connor, J. P..

3 recordsLinked to original sources

Population geometry enables fast sampling in spiking neural networks

For animals to navigate an uncertain world, their brains need to estimate uncertainty at the timescales of sensations and actions. Sampling-based algorithms afford a theoretically-grounded framework for probabilistic inference in neural circuits, but it remains unknown how one can implement fast sampling algorithms in biologically-plausible spiking networks. Here, we propose to leverage the population geometry, controlled by the neural code and the neural dynamics, to implement fast samplers in spiking neural networks. We first show that two classes of spiking samplers--efficient balanced spiking networks that simulate Langevin sampling, and networks with probabilistic spike rules that implement Metropolis-Hastings sampling--can be unified within a common framework. We then show that careful choice of population geometry, corresponding to the natural space of parameters, enables rapid inference of parameters drawn from strongly-correlated high-dimensional distributions in both networks. Our results suggest design prin-ciples for algorithms for sampling-based probabilistic inference in spiking neural networks, yielding potential inspiration for neuromorphic computing and testable predictions for neurobiology.

neuroscience↗

Sticker-and-Linker Model for Amyloid BetaCondensation and Fibrillation

A major pathogenic hallmark of Alzheimers disease is the presence of neurotoxic plaques composed of amyloid beta (A{beta}) peptides in patients brains. The pathway of plaque formation remains elusive, though some clues appear to lie in the dominant presence of A{beta}1-42 in these plaques despite A{beta}1-4 making up approximately 90% of the A{beta} pool. We hypothesise that this asymmetry is driven by the hydrophobicity of the two extra amino acids that are incorporated in A{beta}1-42. To investigate this hypothesis at the level of single molecules, we have developed a molecular sticker-and-linker lattice model of unfolded A{beta}. The model protein has a single sticker that may reversibly dimerise and elongate into semi-flexible linear oligomers. The growth is hampered by excluded-volume interactions that are encoded by the hydrophilic linkers but is rendered cooperative by the attractive interactions of hydrophobic linkers. For sufficiently strong hydrophobicity, the chains undergo liquid-liquid phase-separation (LLPS) into condensates that facilitate the nucleation of fibres. We find that a small fraction of A{beta}1-40 in a mixture of A{beta}1-40 and A{beta}1-42 shifts the critical concentration for LLPS to lower values. This study provides theoretical support for the hypothesis that LLPS condensates act as a precursors for aggregation and provides an explanation for the A{beta}1-42-enrichment of aggregates in terms of hydrophobic interactions.

neuroscience↗

Anti-SARS-CoV-2 IgG and IgA antibodies in COVID-19 convalescent plasma do not facilitate antibody-dependent enhance of viral infection.

The novel coronavirus SARS-CoV2, which causes COVID-19, has resulted in the death of nearly 4 million people within the last 18 months. While preventive vaccination and monoclonal antibody therapies have been rapidly developed and deployed, early in the pandemic the use of COVID-19 convalescent plasma (CCP) was a common means of passive immunization, with the theoretical risk of antibody-dependent enhancement (ADE) of viral infection remaining undetermined. Though vaccines elicit a strong and protective immune response, and transfusion of CCP with high titers of neutralization activity are correlated with better clinical outcomes, the question of whether antibodies in CCP can enhance infection of SARS-CoV2 has not been directly addressed. In this study, we analyzed for and observed passive transfer of neutralization activity with CCP transfusion. Furthermore, to specifically understand if antibodies against the spike protein (S) enhance infection, we measured the anti-S IgG, IgA, and IgM responses and adapted retroviral-pseudotypes to measure virus neutralization with target cells expressing the ACE2 virus receptor and the Fc alpha receptor (FcR) or Fc gamma receptor IIA (Fc{gamma}RIIA). Whereas neutralizing activity of CCP correlated best with higher titers of anti-S IgG antibodies, the neutralizing titer was not affected when Fc receptors were present on target cells. These observations support the absence of antibody-dependent enhancement of infection (ADE) by IgG and IgA isotypes found in CCP. The results presented, therefore, support the clinical use of currently available antibody-based treatment including the continued study of CCP transfusion strategies.

immunology↗