Biology subjects

Sewell, D.

Publications and source records attributed to Sewell, D..

3 recordsLinked to original sources

bioRxiv2025

A common algorithm for confidence judgements across visual, auditory and audio-visual decisions

Most studies investigating the computational basis of decision confidence have focused on simple visual perceptual tasks, leaving open questions about how confidence is formed in decisions involving other sensory modalities or those requiring the integration of information across modalities. To address these gaps, we used computational modelling to analyse confidence judgements in perceptual decisions involving visual, auditory, and audio-visual stimuli. Drawing on research into visual confidence, we adapted models from the literature to evaluate their fit to our data, comparing three popular classes: unscaled evidence strength, scaled evidence strength, and Bayesian models. Our results show that the scaled evidence strength models consistently outperformed the other model classes across all tasks and could also be used to predict behaviour in the audio-visual task from the unidimensional auditory and visual model fits. These findings suggest that confidence judgements across different perceptual decisions rely on a shared algorithm that dynamically accounts for both sensory uncertainty and evidence strength, without the computation of posterior probabilities. Additionally, we investigated the algorithms used for multidimensional (audio-visual) confidence judgements specifically, showing that participants integrated both the visual and auditory dimensions of the stimulus, rather than relying solely on the most informative modality, and used a modality-independent measure of sensory uncertainty to adjust their confidence. Overall, our findings provide evidence for a common algorithm underlying confidence judgements across modalities and demonstrate the broad applicability of the scaled evidence strength algorithm, even in tasks requiring the integration of distinct sensory information.

neuroscience↗

bioRxiv2023

Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.

A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1{beta} from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1{beta} secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-{kappa}B and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1{beta} in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases. Author SummaryAcute myeloid leukaemia (AML) and myelodysplastic syndromes MDS) are related blood cancers that are associated with frequent infections because the cancers suppress normal immunity. These infections are therefore generally considered as medical complications arising as a result of but separate to the cancer. However, we provide evidence here that infections may promote or drive cancer progression. We and others previously demonstrated that a human protein called NM23-H1 promotes the survival of AML cells by eliciting survival signals from other cells. NM23-H1 belongs to a highly conserved family of proteins that also occur in bacteria and fungi that cause infections in AML and MDS patients. Here we demonstrate that these bacterial and fungal proteins recapitulate the pro-survival effect of NM23-H1 on AML cells. We also determine that these effects are mediated via mechanisms already known to be important in the development and progression of AML and MDS. This study is the first to identify NM23-H1 like proteins from pathogenic microorganisms as novel activators of these pathways. These findings have important implications for how we understand infections in AML and MDS patients and suggest that in addition to being the consequence of these diseases, infections may also drive the cancer process.

microbiology↗

bioRxiv2018

The Landscape of Enteric Pathogen Exposure of Young Children in Public Domains of Low-Income, Urban Kenya: The Influence of Exposure Pathway and Spatial Range of Play on Multi-Pathogen Exposure Risks

BackgroundYoung children are infected by a diverse variety of enteric pathogens in low-income, high-burden countries. Little is known about which conditions pose the greatest risk for enteric pathogen exposure and infection. Young children frequently play in residential public areas around their household, including areas contaminated by human and animal feces, suggesting these exposures are particularly hazardous.\n\nObjectivesThe objective of this study was to examine how the dose of six types of common enteric pathogens, and the probability of exposure to one or multiple enteric pathogens for young children playing at public play areas in Kisumu, Kenya is influenced by the type and frequency of child play behaviors that result in ingestion of soil or surface water, as well as by spatial variability in the number of public areas children are exposed to in their neighborhood.\n\nMethodsA Bayesian framework was employed to obtain the posterior distribution of pathogen doses for a certain number of contacts. First, a multivariate random effects tobit model was used to obtain the posterior distribution of pathogen concentrations, and their interdependencies, in soil and surface water, based upon empirical data of enteric pathogen contamination in three neighborhoods of Kisumu. Then, exposure doses were estimated using behavioral contact parameters from previous studies, and contrasted under different exposure conditions.\n\nResultsMulti-pathogen exposure of children at public play areas was common. Pathogen doses and the probability of multi-pathogen ingestion increased with: higher frequency of environmental contact, especially for surface water; larger volume of soil or water ingested; and with play at multiple sites in the neighborhood versus single site play.\n\nDiscussionChild contact with surface water and soil at public play areas in their neighborhood is an important cause of exposure to enteric pathogens in Kisumu, and behavioral, environmental, and spatial conditions are determinants of exposure.

microbiology↗