Biology subjects

Dawson, J.

Publications and source records attributed to Dawson, J..

10 recordsLinked to original sources

bioRxiv2026

Loss of interruption in the HTT CAG repeat is associated with increased somatic expansion and loss of medium spiny neurons in HD

Synonymous loss of interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how CAG expansion in MSNs relates to HD pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD, but accumulate in proportion with duration of disease and inherited CAG repeat length. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased [~]5-fold despite reduced small somatic expansions in blood, and direct caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and hastened onset of HD, but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

neuroscience↗

bioRxiv2025

Finger Type Classification for Fingerprint Image Error Correction in Large Scale Biometric Databases

Large-scale biometric systems, essential for national security and border management, increasingly rely on multimodal databases containing millions of identities. However, operational pressures and insufficient training lead to frequent image classification and labeling errors by human operators. These critical data integrity issues include the mislabeling of rolled vs. flat fingerprints, out-of-sequence captures, and the insertion of incorrect modalities. Such errors render enrollment records unreliable, compromising subsequent identity verification processes. Since manually sorting vast image archives is unfeasible, our study proposes an automated solution. The primary objective was to deploy a Siamese Network to classify fingerprints by their precise finger type and collection methodology (flat or rolled impressions). A secondary, but central, goal was to investigate the influence of varying embedding dimensions (64, 128, 256, 512) and similarity thresholds (0.5, 0.2, 0.1) on the networks performance metrics. Our most significant finding demonstrates a clear trade-off: a lower similarity threshold drastically increases conditional accuracy and precision (e.g., up to 98%) but simultaneously increases the proportion of images categorized as "uncertain" (up to 24%). In a practical, large-scale application, this necessitates balancing superior classification accuracy against a higher volume of images requiring costly manual inspection. This work provides a proof-of-concept tool capable of efficiently quantifying the percentage of images requiring human review across various modalities (fingerprints, face, iris). The eventual goal is a lightweight, efficient tool to establish standard preprocessing procedures for any large biometric dataset, dramatically reducing the time and cost associated with data integrity maintenance.

bioinformatics↗

bioRxiv2024

A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation

The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1{beta} (IL-1{beta}) release in these cells under different stimulation conditions, with the extent of IL-1{beta} inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1{beta} release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1{beta} production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans. HighlightsO_LIIdentification of NK7-902, a CRBN molecular glue degrader of NEK7 C_LIO_LINK7-902 fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1{beta} production C_LIO_LIUnlike most CRBN glue degraders, NK7-902 shows activity in murine systems C_LIO_LIIn vivo oral administration of NK7-902 in non-human primates leads to profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation C_LI

immunology↗

bioRxiv2024

Flight-Scope: microscopy with microfluidics in microgravity

With the European Space Agency (ESA) and NASA working to return humans to the moon and onwards to Mars, it has never been more important to study the impact of altered gravity conditions on biological organisms. These include astronauts but also useful micro-organisms they may bring with them to produce food, medicine, and other useful compounds by synthetic biology. Parabolic flights are one of the most accessible microgravity research platforms but present their own challenges: relatively short periods of altered gravity ([~]20s) and aircraft vibration. Live-imaging is necessary in these altered-gravity conditions to readout any real-time phenotypes. Here we present Flight-Scope, a new microscopy and microfluidics platform to study dynamic cellular processes during the short, altered gravity periods on parabolic flights. We demonstrated Flight-Scopes capability by performing live and dynamic imaging of fluorescent glucose uptake by yeast, S. cerevisiae, on board an ESA parabolic flight. Flight-Scope operated well in this challenging environment, opening the way for future microgravity experiments on biological organisms.

biophysics↗

bioRxiv2024

Root exudation and rhizosphere microbial recruitment are influenced by novel plant trait diversity in carrot genotypes

Root exudate composition can influence rhizosphere microbial recruitment and is tightly controlled by plant genetics. However, little research has profiled root exudate in vegetable crops or determined their role in rhizosphere microbial community and metabolite composition. It is also not well understood how root exudates and resulting rhizosphere dynamics shift across plant trait diversity and with the development of novel crop genotypes. To address these knowledge gaps, this study paired metabolomics and microbiome analyses to evaluate associations between the composition of exudates, soil bacterial and fungal communities, and soil metabolites across four genotypes of organically produced carrot of differential breeding histories, including two experimental genotypes. Plant genotypes modified soil microbial diversity and composition, and differentially recruited bacterial taxa with demonstrated potential for plant-growth related functions including ammonia oxidation, nitrogen fixation, and phytohormone production. Bacterial rhizosphere recruitment from bulk soil was genotype and root exudate-mediated, while fungal recruitment was not. Moreover, root exudate composition was distinct in an heirloom genotype and a novel nematode resistant genotype, compared to other genotypes tested. Root exudate and rhizosphere metabolite composition was decoupled, and soil metabolites strongly associated with fungal, but not bacterial communities. Taken together, the results of this study suggest that novel crop trait diversity and breeding histories hold consequences for the functional potential of soils through the diversification of root exudate mediated plant-microbe interactions.

microbiology↗

bioRxiv2023

Emergent spatiotemporal patterning of synthetic Notch signal transduction in vivo

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of syn-Notch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

biophysics↗

bioRxiv2023

Noise in the direction of motion determines the spatial distribution and proliferation of migrating cell collectives

A variety of living and non-living systems exhibit collective motion. From swarm robotics to bacterial swarms, and tissue wound healing to human crowds, examples of collective motion are highly diverse but all of them share the common necessary ingredient of moving and interacting agents. While collective motion has been extensively studied in non-proliferating systems, how the proliferation of constituent agents affects their collective behavior is not well understood. Here, we focus on growing active agents as a model for cells and study how the interplay between noise in their direction of movement and proliferation determines the overall spatial pattern of collective motion. In this agent-based model, motile cells possess the ability to adhere to each other through cell-cell adhesion, grow in size and divide. Cell-cell interactions influence not only the direction of cell movement but also cell growth through a force-dependent mechanical feedback process. We show that noise in the direction of a cells motion has striking effects on the emergent spatial distribution of cell collectives and proliferation. While higher noise strength leads to a random spatial distribution of cells, we also observe increased cell proliferation. On the other hand, low noise strength leads to a ring-like spatial distribution of cell collectives together with lower proliferation. Our findings provide insight into how noise in the direction of cell motion determines the local spatial organization of cells with consequent mechanical feedback on cell division impacting cell proliferation due to the formation of cell clusters.

biophysics↗

bioRxiv2022

Multisite Phosphorylation and Binding Alter Conformational Dynamics of the 4E-BP2 Protein

Intrinsically disordered proteins (IDPs) play critical roles in regulatory protein interactions, but detailed structural/dynamics characterization of their ensembles remain challenging, both in isolation and they form dynamic fuzzy complexes. Such is the case for mRNA cap-dependent translation initiation, which is regulated by the interaction of the predominantly folded eukaryotic initiation factor 4E (eIF4E) with the intrinsically disordered eIF4E binding proteins (4E-BPs) in a phosphorylation-dependent manner. Single-molecule Forster resonance energy transfer showed that the conformational changes of 4E-BP2 induced by binding to eIF4E are non-uniform along the sequence; while a central region containing both motifs that bind to eIF4E expands and becomes stiffer, the C-terminal region is less affected. Fluorescence anisotropy decay revealed a nonuniform segmental flexibility around six different labelling sites along the chain. Dynamic quenching of these fluorescent probes by intrinsic aromatic residues measured via fluorescence correlation spectroscopy report on transient intra- and inter-molecular contacts on ns-s timescales. Upon hyperphosphorylation, which induces folding of ~40 residues in 4E-BP2, the quenching rates decreased at most labelling sites. The chain dynamics around sites in the C-terminal region far away from the two binding motifs significantly increased upon binding to eIF4E, suggesting that this region is also involved in the highly dynamic 4E-BP2:eIF4E complex. Our time-resolved fluorescence data paint a sequence-level rigidity map of three states of 4E-BP2 differing in phosphorylation or binding status and distinguish regions that form contacts with eIF4E. This study adds complementary structural and dynamics information to recent studies of 4E-BP2, and it constitutes an important step towards a mechanistic understanding of this important IDP via integrative modelling.

biophysics↗

bioRxiv2020

A theoretical framework to study the influence of electrical fields on mesenchymal stem cells

Mesenchymal stem cell dynamics involves cell proliferation and cell differentiation into cells of distinct functional type, such as osteoblasts, adipocytes, or chondrocytes. Electrically active implants influence these dynamics for the regeneration of the cells in damaged tissues. How applied electric field influences processes of individual stem cells is a problem mostly unaddressed. The mathematical approaches to study stem cell dynamics have focused on the stem cell population as a whole, without resolving individual cells and intracellular processes. In this paper, we present a theoretical framework to describe the dynamics of a population of stem cells, taking into account the processes of the individual cells. We study the influence of the applied electric field on the cellular processes. We test our mean-field theory with the experiments from the literature, involving in vitro electrical stimulation of stem cells. We show that a simple model can quantitatively describe the experimentally observed time-course behavior of the total number of cells and the total alkaline phosphate activity in a population of mesenchymal stem cells. Our results show that the stem cell differentiation rate is dependent on the applied electrical field, confirming published experimental findings. Moreover, our analysis supports the cell density-dependent proliferation rate. Since the experimental results are averaged over many cells, our theoretical framework presents a robust and sensitive method for determining the effect of applied electric fields at the scale of the individual cell. These results indicate that the electric field stimulation may be effective in promoting bone regeneration by accelerating osteogenic differentiation.

biophysics↗

bioRxiv2018

Mis-expression of the Alzheimers disease associated gene Ankyrin causes memory loss and shortened lifespan in Drosophila

Alzheimers disease (AD) is the most common form of dementia and is characterized by the accumulation of extracellular amyloid beta (A{beta}) plaques and intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 4R0N isoform. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in AD cortex. Indeed, hypermethylation of the Ankyrin 1 (ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated Drosophila models to allow us to functionally characterize Drosophila Ank2, the ortholog of human ANK1. These models have targeted reduction in the expression of Ank2 in neurons. We find that Drosophila with reduced neuronal Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human mutant APP (that leads to A{beta}42 production) and MAPT (that leads to 0N4R Tau). Therefore, we show that the mis-expression of Ank2 can drive disease relevant processes and phenocopy some features of AD and we propose targeting ANK1 may have therapeutic potential. This represents the first study to characterize a gene implicated in AD, which was nominated from EWAS.\n\nAuthor summaryThe majority (>95%) of Alzheimers disease (AD) cases are sporadic, with their incidence attributed to common genetic mutations, epigenetic variation, aging and the environment. There is no cure for AD and only limited treatment options which only treat the symptoms of AD and only work in some people. Recent epigenome-wide association studies (EWAS) in AD have highlighted hypermethylation of the Ankyrin1 (ANK1) gene in AD cortex. Little is known of the normal role of the gene in the brain. Here, we have demonstrated that Drosophila with reduced neuronal expression of the Drosophila ortholog of human ANK1 (Ank2), can drive AD relevant processes including locomotor difficulties, memory loss and shortened lifespan similar to expression of human amyloid-Beta or tau mutant proteins. Furthermore, increasing Ank2 expression reversed the memory loss caused by expression of human amyloid-Beta or tau mutant proteins, suggesting that targeting ANK1 may have therapeutic potential. This represents the first study to characterize a gene implicated in AD, which was nominated from EWAS.

neuroscience↗