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Thompson, J. R.

Publications and source records attributed to Thompson, J. R..

At least 19 recordsLinked to original sources

Overlapping yet distinct spatiomolecular profiles across mood disorders and biological sex in the human prefrontal cortex

Major depressive disorder (MDD) and bipolar disorder (BD) exhibit both overlapping and distinct clinical features, including sex differences in prevalence and symptomatology, but how these similarities and differences are reflected at the molecular and cellular level in the human brain remains poorly understood. Here, we applied spatial transcriptomics to the human dorsolateral prefrontal cortex from individuals with MDD, BD, and neurotypical controls to resolve molecular programs associated with diagnosis and biological sex. Our analysis revealed sex- and diagnosis-specific differences across white matter, the neurovascular unit (NVU), and neuronal compartments. Within white matter, we identified female-specific survival-response programs shared in both MDD and BD, and divergent myelin-related gene expression patterns across disorders (CLDN11, CNDP1). Within the NVU, transcriptional evidence of impaired vascular integrity was accompanied by astrocytic response profiles in females with MDD and males with BD, with inflammatory responses further evident in females with MDD (IFITM3, CEBPD, IL1R1). In donors with BD of both sexes and in females with MDD, inhibitory neurons exhibited impaired neuropeptide expression (SST, CORT, CRH). Integration with donor genotype information highlighted that genetic risk for mood disorders influences MAPK3 expression, implicating altered ERK signaling, which was further supported by disorder-associated changes in Ras/MEK/ERK pathway components in neurons (MAPK3, DUSP6, RASD1, ELK1). Together, these findings reveal coordinated, cell type- and spatial domain-specific molecular programs that distinguish shared and disorder-specific transcriptomic changes across mood disorders in a sex-dependent manner.

neuroscience↗

Distribution and dynamics of Vibrio spp. and pathogen sequences among microhabitats and monsoon seasons in Singapore's coastal waters

Marine infections are rising in temperate regions due in part to a warming climate. However, comparatively little is known about drivers of marine pathogen dynamics in the tropics where temperatures are high year-round. Vibrio bacteria are ubiquitous in both temperate and tropical marine environments, and many are important pathogens of marine organisms and humans. Here, we sampled an equatorial monsoonal site, the Singapore Strait, over 18 months and applied amplicon sequencing (16s rRNA V6-8 region) to three particle size fractions, qPCR quantitation of Vibrio spp., and generalized linear modelling with environmental variables to understand the factors that structure the Vibrio assemblage. We found that Vibrios represented the highest proportion of pathogen-related DNA sequences, with an assemblage composition influenced by microhabitats (size fractions) and monsoon seasons. Vibrio sequences were dominated by ASVs with highest identity to V. xuii, V. rotiferianus and V. caribbeanicus, and including ASVs matching agents of human disease in Singapore - V. parahaemolyticus, V. alginolyticus, and V. furnissii. Vibrio qPCR abundance was lowest in the largest size fraction (10-150 m), following planktonic DNA trends, even though pathogen-related sequences, including Vibrio, were enriched in this fraction. Temperature was a significant predictor of overall Vibrio abundance, but its effect was no longer significant after adjustment for monsoons, suggesting that the temperature association may reflect broader seasonal dynamics. Instead, effects of chlorophyll, ammonia, nitrate and suspended solids were more consistent within seasons. Furthermore, free-living and particle-associated Vibrios responded differently to environmental changes, suggesting that partitioning into microspatial habitats may lead to differences in their environmental sensitivity.

microbiology↗

Particle association and monsoon seasonality influence microbial communities in marine coastal waters of Singapore

Marine microbial communities vary seasonally and spatially, shaped by physiochemical gradients and biotic interactions. Spatiotemporal variability of seawater microbiomes in tropical coastal regions is comparatively understudied, especially in Southeast Asia with high pressures from development and anthropogenic activities. Here, we examined the microspatial and temporal variability of bacterioplankton in the Singapore Strait, which is a tropical system in Southeast Asia influenced by monsoons. By applying total community amplicon sequencing to three particle size fractions reflecting microspatial habitats of seawater (0.22-1 {micro}m ''free-living'', 1-10 {micro}m ''large cells and small aggregates'' and 10-150 {micro}m ''particle-associated''), we show that the seawater microbial community was structured by their microspatial habitats, monsoon seasons and physiochemical variables. Monsoon-driven alternation of water masses originating from the South China Sea to the East and from off the Sumatran coast to the West resulted in a distinct community during the Southwest monsoon across all three size fractions. Total DNA (biomass) was lowest in the 10-150 {micro}m fraction, but these particle-associated sequences had the highest diversity and were surprisingly enriched with picocyanobacterial and some pathogenic taxa, potentially reflecting aggregate formation and/or host-derived particle association. This fraction also exhibited greater temporal variability than the two smaller fractions, which could be related to a more heterogenous environment in particle microhabitats. Overall, this study demonstrated compositional variability in the bacterioplankton across space and time in an equatorial region influenced by monsoons.

microbiology↗

The tuxedo sea urchin Mespilia globulus: A fast-developing and tractable model for genomic and developmental biology

Sea urchins are pivotal models in cellular and developmental biology, but their biphasic life cycle with an extended larval life limits the ability to study post-metamorphosis and adult characters. Here, we introduce a genomically-enabled model system, the tuxedo urchin Mespilia globulus, which has rapid access to late life stages in sea urchins. We describe how we cultured M. globulus in a landlocked marine facility, raised larvae under artificial conditions and closed their life cycle. We established the experimental tractability of M. globulus: we labelled transcripts by hybridization chain reaction (HCR), and knocked out pigmentation genes to produce albino larvae using CRISPR/Cas9. We generated chromosome-scale genome assemblies for two individuals representing both sexes and two color morphs (red and blue), and compared the organisation of the 21 chromosomes of M. globulus with that of other camarodont echinoid models. We determined that M. globulus showed a conservative gene repertoire lacking the gene family expansions seen in other camarodont sea urchins. We annotated the complement of genes associated with pigmentation, immune and nervous systems and profiled their expressions in tissues and organs. Finally, we surveyed sex-related regions in genomes using genome assemblies and resequencing data, finding no evidence of heteromorphic sex chromosomes in M. globulus. Our findings highlight the accessibility of this new sea urchin model for studying the metamorphosis and adult biology of sea urchins.

evolutionary biology↗

Growth-resolved genome-scale metabolic modeling of Priestia megaterium SR7 validated by chemostat and 13-C flux analysis

Priestia megaterium SR7 is a promising candidate chassis for bioprocess engineering, but its development is limited by the availability of condition-grounded, mechanistic models that can translate experimental measurements into predictive design hypotheses. Here, we present PMSR7, a genome-scale metabolic model for SR7, and evaluate it under a growth-resolved chemostat framework spanning a dilution-rate series. Stable steady states were established across the growth regime, with the highest dilution rate (D = 1.1538 h-{superscript 1}) excluded from growth interpretation due to biomass collapse. Extracellular carbon fluxes were quantified by NMR and reported as mean {+/-} SD, providing an experimental basis for model comparison. PMSR7 was benchmarked using MEMOTE against representative reference reconstructions, supporting structural consistency suitable for constraint-based analyses. Under growth-resolved simulations, ATP demand scaled linearly with growth rate, enabling inference of maintenance-energy behavior across the regime. Growth-dependent feasibility and magnitude of overflow secretion were evaluated for acetate, lactate, and formate using feasible-space analyses, highlighting both agreement and regime-sensitive limitations. Finally, growth-resolved leucine and valine production was assessed in both raw and fold-change space, with experimental means compared against median-based summaries of sampled model distributions to account for feasible-space skew. Together, these results establish PMSR7 as a reproducible, quality-benchmarked platform for SR7 chassis development and provide a framework for iterative experimental integration in non-model organisms, where the dominant challenge is achieving congruence between measured physiology and model-feasible behavior.

systems biology↗

SpatialArtifacts: a computational framework for tissue artifact detection in spatial transcriptomics data

Spatial transcriptomics data are frequently compromised by technical artifacts, such as dry patches, tissue lifting, and uneven reagent coverage, which manifests as regions with low UMI counts, in particular at tissue borders. It can often be challenging to identify these regions using existing quality control methods. Here, we present SpatialArtifacts, a framework that combines median absolute deviation (MAD)-based outlier detection with mathematical morphology operations to identify and classify spatially contiguous tissue artifacts. Focal operations including 3x3 fill, 5x5 outline, and star-pattern connectivity link low-quality spots while preserving true biological domains. We use a hierarchical classification system to distinguish edge versus interior artifacts and large versus small regions, enabling downstream removal or targeted manual review. We demonstrate the performance of our method in human hippocampus, dorsolateral prefrontal cortex, and colorectal cancer tissues using 10x Genomics Visium and VisiumHD platforms. Our SpatialArtifacts package is freely available on Bioconductor at https://bioconductor.org/packages/SpatialArtifacts and on PyPI at https://pypi.org/project/spatial-artifacts/.

bioinformatics↗

Investigating the nicotinic receptor EAT-2 as a novel target to mitigate plant parasitic nematode infections

Plant parasitic nematodes (PPNs) are microscopic soil dwelling pests that infect crops, using a lance-like organ, the stylet, to hatch, invade plant roots, and establish feeding sites. Stylet function is underpinned by pharyngeal muscle contraction and relaxation cycles, making it an attractive route to disrupt the PPN lifecycle. However, knowledge of pharyngeal regulation in PPNs is relatively limited. In the free-living nematode Caenorhabditis elegans, the nicotinic receptor EAT-2 stimulates pharyngeal contraction to facilitate feeding. Here we hypothesize that EAT-2 orthologues may regulate a similar function in PPNs. A phylogenetic analysis reveals that EAT-2 and its orthologues in other nematode species cluster as a distinct group suggesting that EAT-2 is exclusive of other animal species. We identified eat-2 in the genome of the potato cyst nematode Globodera rostochiensis and used in situ hybridization to establish an anterior expression pattern consistent with a pharyngeal function. In vitro pharmacological assays directly compared the response of C. elegans pharynx and G. rostochiensis stylet to cholinergic compounds. Both pharyngeal and stylet activity were stimulated by acetylcholine and nicotine, and these responses were blocked by the nicotinic receptor antagonists, mecamylamine and tubocurarine. These data are consistent with a conserved cholinergic pathway mediated by EAT-2 regulating pharyngeal muscle function. It highlights EAT-2 as a potential determinant of stylet thrusting and a promising pharmacological target to selectively mitigate PPN infections.

pharmacology and toxicology↗

BatchSVG: identifying batch-biased genes in the application of spatially variable gene detection

1A standard task in the analysis of spatially resolved transcriptomics data is to identify spatially variable genes (SVGs). This is most commonly done within one tissue section at a time because the spatial relationships between the tissue sections are typically unknown. However, large-scale spatial atlases are being generated, for example across hundreds of donors, where the goal is to identify a common set of SVGs to use for downstream analyses. One challenge is how to identify and remove SVGs that are associated with a known bias or technical artifact, such as the slide or capture area, which can lead to poor performance in downstream analyses, such as spatial domain detection. Here, we introduce BatchSVG, a tool to identify batch-biased genes in the application of SVG detection. Our approach compares the rank of per-gene deviance under a binomial model (i) with and (ii) without including a covariate in the model that is associated with the known bias or technical artifact. If the rank of a gene changes significantly between these, then we infer that this gene is likely associated with the bias or technical artifact and should be removed from the downstream analysis. We consider two SRT datasets and show how our model can improve the results of downstream analysis.

genomics↗

Asymmetric Spring and Autumn Phenology Control Growing Season Length in Temperate Deciduous Forests

Forest phenological responses to climatic variation among species and populations across broad spatial scales remain poorly understood. Here, we quantify four decades of phenological dynamics for 10 major deciduous tree species by compiling a unique dataset that integrates high spatial resolution remote sensing with extensive field inventory data across the Northeastern and Midwestern United States. We found that spring and autumn phenology impose asymmetric controls on growing season length, with spring regulating interannual variation and autumn driving long-term trends. Spring phenology across all species was primarily controlled by temperature, while autumn phenology was influenced by spring phenology and an interacting suite of species-specific environmental factors. Our study demonstrates the promise of combining high resolution remote sensing with forest inventory data to investigate phenological dynamics over large regions. More importantly, our results provide new insights into how species-specific sensitivities to environmental drivers regulate growing season length in temperate forests.

ecology↗

But the clock, tick-tock: the preeminence of relaxed clock models in total-evidence dated phylogenetics

Phylogenetic clock models translate inferred amounts of evolutionary change (calculated from either genotypes or phenotypes) into estimates of elapsed time, providing a mechanism for time scaling phylogenetic trees. Relaxed clock models, which accommodate variation in evolutionary rates across branches, are one of the main components of Bayesian dating, yet their consequences for total-evidence phylogenetics have not been thoroughly explored. Here, we combine morphological, molecular (both transcriptomic and Sanger-sequenced), and stratigraphic datasets for all major lineages of echinoids (sea urchins, heart urchins, sand dollars). We then perform total-evidence dated inference under the fossilized birth-death prior, varying two analytical conditions: the choice between autocorrelated and uncorrelated relaxed clocks, which enforce (or not) evolutionary rate inheritance; and the ability to recover ancestor-descendant relationships. Our results show that the latter has no impact on either topology or node ages and highlight a previously unnoticed interaction between the tree and clock models, with analyses implementing an autocorrelated clock precluding the recovery of direct ancestry. On the other hand, tree topology, fossil placement, divergence times, and downstream macroevolutionary inferences (e.g., ancestral state reconstructions) in sea urchins are all strongly affected by the type of relaxed clock implemented. In regions of the tree where molecular rate variation is pervasive and morphological signal relatively uninformative, fossil tips seem to play little to no role in informing divergence times, and instead passively move in and out of clades depending on the ages imposed upon them by molecular data. Our results highlight the extent to which the phylogenetic and macroevolutionary conclusions of total-evidence dated analyses are contingent on the choice of relaxed clock model, highlighting the need for either careful methodological validation or a thorough assessment of sensitivity. Our efforts continue to illuminate the echinoid tree of life, supporting the erection of the order-level clade Apatopygoida to include three living species last sharing a common ancestor with other extant lineages in the Jurassic. Furthermore, they also illustrate how the phylogenetic placement of extinct clades hinges upon the modelling of molecular data, evidencing the extent to which the fossil record remains subservient to phylogenomics.

evolutionary biology↗

Spatiotemporal Mapping and Molecular Basis of Whole-brain Circuit Maturation

Brain development is highly dynamic and asynchronous, marked by the sequential maturation of functional circuits across the brain. The timing and mechanisms driving circuit maturation remain elusive due to an inability to identify and map maturing neuronal populations. Here we create DevATLAS (Developmental Activation Timing-based Longitudinal Acquisition System) to overcome this obstacle. We develop whole-brain mapping methods to construct the first longitudinal, spatiotemporal map of circuit maturation in early postnatal mouse brains. Moreover, we uncover dramatic impairments within the deep cortical layers in a neurodevelopmental disorders (NDDs) model, demonstrating the utility of this resource to pinpoint when and where circuit maturation is disrupted. Using DevATLAS, we reveal that early experiences accelerate the development of hippocampus-dependent learning by increasing the synaptically mature granule cell population in the dentate gyrus. Finally, DevATLAS enables the discovery of molecular mechanisms driving activity-dependent circuit maturation.

neuroscience↗

Do working forest easements work for conservation?

Conservation easements are voluntary legal agreements designed to achieve conservation goals on private land. Extensive public and private funding has been used to establish "working forest" conservation easements (WFCE) that aim to protect conservation values while maintaining commercial timber production. We use variation in the timing and location of easements to estimate the impacts of WFCEs in Maine from a 33-year time-series of forest loss and harvesting. Compared to matched controls, WFCEs reduced forest loss rates by just 0.0004% yr-1, the equivalent of 3ha yr-1, and increased the rate of harvesting by 0.37% yr-1, or 2935ha yr-1 within the 839,000 ha enrolled. More recent easements contained stricter restrictions on harvest practices and these easements reduced harvest by 0.62% yr-1. Overall, WFCEs supported continued harvests, but did not appear to provide substantial ecological benefits. Future easements could be more effective if they include additional provisions for harvest restrictions and monitoring.

ecology↗

An autoinhibited state of 53BP1 revealed by chemical probes and protein engineering

The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1 -- autoinhibited for chromatin binding -- that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

biochemistry↗

Vertex-wise characterization of Non-Human Primate cortical development with prenatal insights.

Characterization of the interwoven complexities of early cortical thickness development has been an ongoing undertaking in neuroscience research. Longitudinal studies of Non-Human Primates (NHP) offer unique advantages to categorizing the diverse patterns of cortical growth trajectories. Here, we used latent growth models to characterize the trajectories of typical cortical thickness development in Japanese macaques at each cortical surface vertex (i.e. grayordinate). Cortical thickness from 4 to 36 months showed regional specific linear and non-linear trajectories and distinct maturation timing across the cortex. Intriguingly, we revealed a "accumulation/ablation phenomenon" of cortical maturation where the most profound development changes in cortical thickness occur in the accumulation or ablation zones surrounding the focal points (i.e., a center of a delineated regions where cortical thickness is thickest or thinnest) throughout the brain. We further examined maternal diet and inflammation in the context of these typical brain trajectories and known network architecture. A well-controlled NHP model of a maternal "Western-style" diet was used alongside measures of inflammatory cytokine interleukin-6 (IL-6) in the mothers during gestation. We observed that these accumulation and ablation zones of variable change might be most susceptible to environmental effects. The maternal factors, diet and inflammation during pregnancy were distinctively associated with different aspects of offspring cortical development reflected in regions related to distinctive functional networks. Our findings characterize the versatile intricacies of typical cortical thickness development and highlight how the maternal environment plays a role in offspring cortical development.

neuroscience↗

Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment

The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to cellular fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive nervous system demyelination, and neurological impairments including the potentially fatal disease X-linked adrenoleukodystrophy (X-ALD). Molecular details underlying substrate recognition and transport by ABCD1 are poorly understood. Here we determined cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 [A] resolution that reveal key details of its transmembrane cavity and ATP dependent conformational transitions. We identify structural elements distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Together, our data support a transport mechanism where only the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane cavity while the acyl chains extend out into the surrounding membrane bilayer, help rationalize disease causing mutations, and provide a framework for ABCD1 targeted structure-based drug design.

biochemistry↗

Phylogenomic analyses of echinoid diversification prompt a re-evaluation of their fossil record

Echinoids are key components of modern marine ecosystems. Despite a remarkable fossil record, the emergence of their crown group is documented by few specimens of unclear affinities, rendering much of their early history uncertain. The origin of sand dollars, one of its most distinctive clades, is also unclear due to an unstable phylogenetic context and discrepancies between molecular divergence times and fossil evidence. We employ seventeen novel genomes and transcriptomes to build a phylogenomic dataset with a near-complete sampling of major lineages. With it, we revise the phylogeny and divergence times of echinoids, and place their history within the broader context of echinoderm evolution. We also introduce the concept of a chronospace--a multidimensional representation of node ages--and use it to explore the effects of using alternative gene samples, models of molecular evolution, and clock priors. We find the choice of clock model to have the strongest impact on divergence times, while the use of site-heterogeneous models shows little effects. The choice of loci shows an intermediate impact, affecting mostly deep Paleozoic nodes, for which clock-like genes recover dates more congruent with fossil evidence. Our results reveal that crown group echinoids originated in the Permian and diversified rapidly in the Triassic, despite the relative lack of fossil evidence for this early diversification. We also clarify the relationships among sand dollars and their close relatives, showing that the genus Apatopygus represents a relict lineage with a deep Jurassic origin. Surprisingly, the origin of sand dollars is confidently dated to the Cretaceous, implying ghost ranges spanning approximately 50 million years, a remarkable discrepancy with their rich fossil record.

evolutionary biology↗

Factors Shaping Young and Mature Bacterial Biofilm Communities in Two Drinking Water Distribution Networks

The presence of biofilms in drinking water distribution systems (DWDS) can affect both water quality and system integrity; yet these systems remain poorly studied due to lack of accessibility. We established two independent full-scale DWDS Testbeds (A and B) on two different campuses situated in a tropical urban environment and equipped them with online sensors. Testbed B experienced higher levels of monochloramine and lower water age than Testbed A within the campus. Based on long amplicon-sequencing of bacterial 16S rRNA genes extracted from the mature biofilms (MPB) growing on pipes and young biofilms (YSB) growing on the sensors, a core community was identified in the two testbeds. The relative abundances of operational taxonomic units at the family level, including Mycobacteriaceae, Methylobacteriaceae, Rhodospirillaceae, Nitrosomonadaceae, and Moraxellaceae, were consistent for MPB and YSB on each campus. The MPB community was found to be influenced by conductivity, sample age, and pipe diameter as determined by both canonical correlation analysis and fuzzy set ordination. MPB displayed higher -diversity based on Hill numbers than YSB; in general, second order Hill numbers correlated positively with conductivity and sample age, but negatively with ORP and nitrite. Pseudomonas spp. together with Bacillus spp. likely initiated biofilm formation of YSB on Testbed A under conditions of reduced monochloramine and high water age. Significant levels of orthophosphate were detected in YSB samples at two stations and associated with higher levels of stagnation based on long-term differential turbidity measurement (DTM). Orthophosphate and DTM may act as indicators of the biofilm growth potential within DWDS. Highlights- Established two testbeds to study biofilms in full-scale distribution system - Biofilms on pipes and sensors had core community - Temporal effect and higher -diversity for biofilms on pipes - Water chemistry was related to biofilm community differences O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/434709v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@c392aforg.highwire.dtl.DTLVardef@1d355eborg.highwire.dtl.DTLVardef@1addf37org.highwire.dtl.DTLVardef@19cc22_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

ecology↗

Cryo-EM structure of lipid embedded human ABCA7 at 3.6 &Aring resolution

Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of the underlying substrate interactions and transport mechanisms remain poorly resolved at the molecular level. Here we report cryo-EM structures of lipid-embedded human ABCA7 in an open state and a nucleotide-bound, closed state at resolutions between 3.6-4.0 [A]. The former reveals an ordered patch of bilayer lipids traversing the transmembrane domain (TMD), while the latter reveals a lipid-free, closed TMD with a small extracellular opening. These structures offer a structural framework for both substrate entry and exit from the ABCA7 TMD and highlight conserved rigid-body motions that underlie the associated conformational transitions. Combined with functional analysis and molecular dynamics (MD) simulations, our data also shed light on lipid partitioning into the ABCA7 TMD and localized membrane perturbations that underlie ABCA7 function and have broader implications for other ABCA family transporters.

biophysics↗