Biology subjects

Watson, B.

Publications and source records attributed to Watson, B..

10 recordsLinked to original sources

bioRxiv2026

Competition among kin generates balancing selection in a wild population

If an individuals niche is determined by its genotype, then competition for limiting resources should be most intense among individuals of the same genotype. Theory predicts this will act to maintain genetic variation, but whether this mechanism operates under natural conditions is unclear. Using long-term observations of a population of free-living Trinidadian guppies, we asked (i) whether competition was strongest between kin, and (ii) whether this process maintained genetic variation. Competition between kin was 1.5-1.8 times stronger than that between non-kin. This contributed to balancing selection: after [~]10 generations, variation was 29% higher than expected under drift. Our results show that relatedness can play a major role in structuring ecological competition, with broader consequences for theories of inclusive fitness. One-sentence summaryHeritable variation is maintained due to resource competition being more intense among kin.

evolutionary biology↗

bioRxiv2026

SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine

Aging is one of the most important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Recently, we demonstrated a critical role for SIRT6, a nuclear NAD- dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether pharmacological activation of SIRT6 improves disc health by examining the spinal phenotype of 24-month-old mice treated with the well-studied agonist MDL-800 for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6, and TGF-{beta}. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels in disc cells, indicating enhanced autophagic flux. Furthermore, plasma LC-MS and nuclear magnetic resonance (NMR) analyses revealed minimal systemic metabolomic changes. ScRNA-sequencing of splenocytes and bone marrow cells and systemic cytokine profiling indicated good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy, cell senescence, and matrix homeostasis in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.

biochemistry↗

bioRxiv2024

SIRT6 loss causes intervertebral disc degeneration in mice by promoting senescence and SASP status

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (AcanCreERT2; Sirt6fl/fl). Histological studies showed a degenerative phenotype in knockout mice compared to Sirt6fl/fl control mice at 12 months which became pronounced at 24 months. RNA-Seq analysis of NP and AF tissues, quantitative histone analysis, and in vitro multiomics employing RNA-seq with ATAC-seq revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues, thereby affecting DNA accessibility and transcriptomic landscape. A decrease in autophagy and an increase in DNA damage were also noted in Sirt6-deficient cells. Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21, {gamma}H2AX, IL-6, and TGF-{beta} abundance. Taken together our study highlights the contribution of SIRT6 in modulating DNA damage, autophagy and cell senescence, and its importance in maintaining disc health during aging thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration.

molecular biology↗

bioRxiv2024

Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution

Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. We next integrated spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), revealing zonally enriched receptor-ligand interactions. Finally, analysis of fibrotic liver samples identified two hepatocyte populations that are not restricted to zonal distribution and expand with injury. Together these spatial maps of the healthy and fibrotic liver provide a deeper understanding of the cellular and spatial remodeling that drives disease which, in turn, could provide new avenues for intervention and further study.

genomics↗

bioRxiv2023

Printing, Characterising, and Assessing Transparent 3D Printed Lenses for Optical Imaging

High-quality lens production has involved subtractive manufacturing methods for centuries. These methods demand specialist equipment and expertise that often render custom high-grade glass optics inaccessible. We aimed to develop a low-cost, accessible, and reproducible method to manufacture high-quality three-dimensional (3D) printed lenses using consumer-grade technology. Various planoconvex lenses were produced using a consumer-grade 3D printer and low-cost spin coating setup, and printed lenses were compared to commercial glass counterparts. A range of mechanical and optical methods are introduced to determine the surface quality and curvature of 3D printed lenses. Amongst others, high-resolution interference reflection microscopy methods were used to reconstruct the convex surface of printed lenses and quantify their radius of curvature. The optical throughput and performance of 3D printed lenses were assessed using optical transmissivity measurements and classical beam characterisation methods. We determined that 3D printed lenses had comparable curvature and performance to commercial glass lenses. Finally, we demonstrated the application of 3D printed lenses for brightfield transmission microscopy, resolving sub-cellular structures over a 2.3 mm field-of-view. The high reproducibility and comparable performance of 3D printed lenses present great opportunities for additive manufacturing of bespoke optics for low-cost rapid prototyping and improved accessibility to high-quality optics in low-resource settings.

biophysics↗

bioRxiv2023

Spatial and temporal profiling of the complement system uncovered novel functions of the alternative complement pathway in brain development

Mounting evidence implicated the classical complement pathway (CP) in normal brain development, and the pathogenesis of neuropsychiatric and neurodegenerative diseases. However the source and regulation of complement in the brain remain unclear. Using MERFISH, a spatial transcriptomic method with single-cell resolution, we established a developmental brain atlas of the complement system. We showed that the brain synthesizes essential building blocks of the complement system locally with remarkable cellular and spatial heterogeneity. We provided transcriptional evidence supporting the presence of the alternative pathway (AP), but lack of lectin pathway (LP) activity in postnatal brain development. Cell type, temporal and spatial expression patterns of genes involved indicate non-redundant functions of the CP and AP. In addition, deficiency in Masp3-driven AP resulted in developmental and cognitive defects, indicating essential functions of the AP, an observation that highlights the necessity to disentangle differential involvement of the three complement activation pathways in development and diseases.

neuroscience↗

bioRxiv2023

Eco-evolutionary feedbacks shape the evolution of constitutive and inducible defences

Organisms have evolved a range of constitutive (always active) and inducible (elicited by parasites) defence mechanisms, but we have limited understanding of what drives the evolution of these orthogonal defence strategies. Bacteria and their phages offer a tractable system to study this: bacteria can acquire constitutive resistance by mutation of the phage receptor (surface mutation, sm) or induced resistance through their CRISPR-Cas adaptive immune system. Using a combination of theory and experiments we demonstrate that the mechanism that establishes first has a strong advantage because it weakens selection for the alternative resistance mechanism. As a consequence, ecological factors that alter the relative frequencies at which the different resistances are acquired have a strong and lasting impact: high growth conditions promote the evolution of sm resistance by increasing the influx of receptor mutation events during the early stages of the epidemic, whereas a high infection risk during this stage of the epidemic promotes the evolution of CRISPR immunity, since it fuels the (infection-dependent) acquisition of CRISPR immunity. This work highlights the strong and lasting impact of the transient evolutionary dynamics during the early stages of an epidemic on the long-term evolution of constitutive and induced defences, which may be leveraged to manipulate phage resistance evolution in clinical and applied settings.

evolutionary biology↗

bioRxiv2022

Understanding prefrontal cortex functions by decoding its molecular, cellular and circuit organization

The prefrontal cortex (PFC) is functionally one of the most complex regions of mammalian brain. Unlike other cortical areas that process single sensory modalities (like vision, touch, smell, etc.), the PFC integrates information across brain regions to regulate diverse functions ranging from cognition, emotion, executive action to even pain sensitivity. However, it is unclear how such diverse functions are organized at the cellular and circuit levels within the anatomical modules of the PFC. Here we employed spatially resolved single-cell transcriptome profiling to decode PFCs organizational heterogeneity. The results revealed that PFC has very distinct cell type composition relative to all neighboring cortical areas. Interestingly, PFC also adopts specialized transcriptional features, different from all neighbors, with differentially expressed genes regulating neuronal excitability. The projections to major subcortical targets of PFC emerge from combinations of neuron subclusters determined in a target-intrinsic fashion. These cellular and molecular features further segregated within subregions of PFC, alluding to the subregion-specific specialization of several PFC functions. Finally, using these unique cellular, molecular and projection properties, we identified distinct cell types and circuits in PFC that engage in pathogenesis of chronic pain. Collectively, we not only present a comprehensive organizational map of the PFC, critical for supporting its diverse functions, but also reveal the cluster and circuit identity of a pathway underlying chronic pain, a rapidly escalating healthcare challenge limited by molecular understanding of maladaptive PFC circuits. Major pointsO_LIPFC adopts unique cellular composition, distinct from other cortical areas C_LIO_LISelective transcriptomic features emerge in PFC to support its divergent functional portfolio C_LIO_LISubcortical projections of PFC assume target-intrinsic specification for innervating clusters C_LIO_LIA molecularly defined L5 projection neuron cluster (to PAG) potentially mediates chronic pain pathogenesis C_LI

neuroscience↗

bioRxiv2022

LabGym: A versatile computational tool for automatic quantification of user-defined animal behaviors

Quantifying animal behavior is important for many branches of biological research. Current computational tools for behavioral quantification typically rely on a few pre-defined, simplified features to identify a behavior. However, such an approach restricts the information used and the tools applicability to a limited range of behavior types or species. Here we report a new tool, LabGym, for quantifying animal behaviors without such limitations. Combining a novel approach for effective evaluation of animal motion with customizable convolutional recurrent networks for capturing spatiotemporal details, LabGym provides holistic behavioral assessment and accurately identify user-defined animal behaviors without restrictions on behavior types or animal species. It then provides quantitative measurements of each behavior, which quantify the behavior intensity and the body kinematics during the behavior. LabGym requires neither any intermediate step for processing features that causes information loss nor programming knowledge from users for post-hoc analysis. It tracks multiple animals simultaneously in various experimental settings for high-throughput and versatile analysis. It also provides users a way to generate visualizable behavioral datasets that are valuable resources for the research community. We demonstrate its efficacy in capturing subtle behavioral changes in animals ranging from soft-bodied invertebrates to mammals.

animal behavior and cognition↗

bioRxiv2021

Distinct ground state and activated state modes of spiking in forebrain neurons

Neuronal firing patterns have significant spatiotemporal variability with no agreed upon theoretical framework. Using a combined experimental and modeling approach, we found that spike interval statistics can be described by discrete modes of activity. Of these, a "ground state" (GS) mode of low-rate spiking is universal among forebrain excitatory neurons and characterized by irregular spiking at neuron-specific rates. In contrast, "activated state" (AS) modes consist of spiking at characteristic timescales and regularity that are specific to neuron populations in a given region and brain state. The majority of spiking is contributed by GS mode, while neurons can transiently switch to AS spiking in response to stimuli or in coordination with population activity patterns. We hypothesize that GS spiking serves to maintain a persistent backbone of neuronal activity while AS modes support communication functions.

neuroscience↗