Biology subjects

Lawson, A.

Publications and source records attributed to Lawson, A..

10 recordsLinked to original sources

bioRxiv2026

Live-cell imaging of fetal microglia reveals time-dependent sex differences in their responsiveness to prenatal maternal stress

Prenatal maternal stress is increasingly being linked to neurodevelopmental disorders (NDDs), and across diverse maternal stressors, immune dysregulation is emerging as a common feature. This suggests that fetal microglia may influence neurodevelopment by detecting changes in signaling from the intrauterine environment. Using a mouse model of prenatal maternal stress, where pregnant mice were exposed to cold from embryonic day 11.5 (E11.5) to E15.5, we previously demonstrated that fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress using static analyses. Here, we extend these analyses by conducting live-cell imaging on the E15.5 hypothalamic paraventricular nucleus (PVN) to assess microglial morphology, motility, and phagocytic behavior in real-time under homeostatic conditions and in response to prenatal maternal cold stress exposure. Prenatal maternal cold stress induced sex- and time-specific changes in microglial morphology in the PVN, where female microglia showed increased branch complexity across the entire live-cell video recording, while male microglia only showed this response at early time-points. Interestingly, PVN microglia also showed baseline sex differences in phagocytic behavior, with male microglia showing higher phagocytic activity as compared to female microglia. In response to prenatal maternal cold stress, male microglia showed a decrease in completed phagocytic events in the PVN, whereas female microglia showed increased engagement in phagocytic activity with no change in completed phagocytic events. Microglial motility was also altered in the PVN of female embryos at early time-points in response to prenatal maternal cold stress, but no such changes were observed in males. Together, these data demonstrate that fetal microglia show sex differences in key physiologies both at baseline and in response to prenatal maternal cold stress. Through time-resolved assessment of microglial dynamics, our findings also suggest that microglial responsiveness to prenatal maternal cold stress differs between males and females, which may help to provide a cellular basis for sex differences observed across many NDDs.

neuroscience↗

bioRxiv2026

Fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress

The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.

neuroscience↗

bioRxiv2026

MSGPCA: Multi-Slice Graph PCA for replicate-aware Spatial Omics analysis

As spatial transcriptomics (ST) and spatial proteomics (SP) technologies mature, experimental designs are increasingly moving beyond single-slice analyses toward multi-slice studies involving one or more donors and experimental conditions. Although these designs enable the identification of reproducible spatial signals, they also introduce substantial biological heterogeneity, particularly when integrating non-serial slices or anatomically distinct regions. If not modeled carefully, such variation can blur slice-specific tissue structure, mask conserved molecular patterns, and limit the discovery of biologically relevant latent structure. Although dimension reduction is essential for representing high-dimensional molecular data in a lower-dimensional space, existing multi-slice methods typically enforce a globally shared representation that inadequately accommodates slice-level heterogeneity. To address this limitation, we propose Multi-Slice Graph Principal Component Analysis (MSGPCA), which decomposes molecular variation into shared spatial factors conserved across slices and slice-specific factors that capture local tissue microarchitecture. In downstream analyses, MSGPCA-derived representations recover spatial tissue structure, denoise molecular profiles, and reveal biologically interpretable metafeatures associated with shared and slice-specific biology. In a mass spectrometry imaging dataset comprising nonserial slices of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), the shared factors captured broad biological differences across tissue regions, whereas the slice-specific factors revealed intratumoral spatial variation within the IBC microenvironment. In human dorsolateral prefrontal cortex ST data, MSGPCA recovered laminar cortical architecture across adjacent slices, closely aligning with expert pathologist annotations. Together, these findings demonstrate that MSGPCA resolves shared tissue architecture while preserving local microenvironmental variation in complex multi-slice spatial omics datasets.

bioinformatics↗

bioRxiv2026

Plant pathogens cleave 2′cADPR to suppress TIR immune signaling

Small molecules produced by TIR (Toll-interleukin-1 receptor) domains are essential for plant immune signaling. A central TIR-derived signal is 2'cADPR, a cyclic ADP-ribose (ADPR) molecule that is generated by plant TIR-domain proteins upon sensing pathogen infection. Here we show that XopQ, a virulence protein widespread in plant pathogenic bacteria, cleaves 2'cADPR and converts it into an inactive, linear ADPR molecule. Steady-state kinetic analyses revealed that XopQ is a highly efficient enzyme that hydrolyzes 2'cADPR with near diffusion-limited catalytic efficiency, while displaying high specificity and no detectable activity toward closely related molecules such as 3'cADPR. We show that XopQ eliminates 2'cADPR in planta and prevents accumulation of pRib-AMP, a derivative of 2'cADPR that activates the downstream immune complex EDS1-PAD4. Our data demonstrate that XopQ inhibits PAD4-dependent plant immunity and can promote pathogen virulence even when the pathogen carries an avirulence effector that triggers TIR-mediated immune signaling. Finally, we show that XopQ can also inhibit type VI Thoeris, a bacterial anti-phage defense system that relies on 2'cADPR signaling, possibly explaining why XopQ and type VI Thoeris are not observed co-occurring in bacterial genomes. Our findings uncover a widespread and conserved strategy used by plant pathogens to directly target host TIR signaling.

Plant Biology↗

bioRxiv2026

Human 3D epithelioids enable continuous long-term clonal evolution studies across multiple epithelial tissues

Modeling human epithelia in vitro remains challenging because current systems do not fully preserve the combination of architecture, heterogeneity, clonal composition, and long-term dynamics shown in vivo. While 3D approaches such as organoids and organotypic cultures capture important aspects of lineage differentiation and niche signaling, they often lose stable organization over time, limiting studies of long-lasting processes such as clonal evolution and cell competition. Here, we present human epithelioids as continuous long-term, 3D epithelial cultures efficiently derived from eight adult human epithelia, including trachea, skin, buccal mucosa, esophagus, blader, urethra, submandibular gland and endometrium. Using immunostaining, electron microscopy, single-cell RNA sequencing, functional assays and somatic mutation analyses, we deeply characterized human epithelioids and confirmed that they recapitulate native architecture and cell diversity, sustain regenerative capacity, and preserve donor-specific mutational landscapes, establishing a robust and versatile platform for longitudinal interrogation of clonal evolution, tissue dynamics and responses to clinically relevant perturbations, including radiotherapy and chemotherapy, over extended timescales.

cancer biology↗

bioRxiv2025

Regional adaptation to mosquito vectors shapes Plasmodium falciparum populations

Transmission of Plasmodium falciparum through mosquitoes represents the most severe population bottleneck in the parasites life cycle, yet the genetic basis of parasite-vector compatibility remains poorly understood. Here, we show that mosquito species-specific transmissibility depends on allelic variation in multiple P. falciparum genes expressed during midgut invasion, beyond the well-studied Pfs47. Using an allelic replacement strategy, we targeted highly geographically differentiated SNPs in P. falciparum that match regional variation in vector community composition. Transmissibility was compared across four mosquito species representing distinct geographic ranges (An. gambiae, An. stephensi, An. minimus, and An. albimanus). Two of five tested polymorphisms showed increased oocyst and sporozoite burdens in sympatric parasite-vector combinations compared to allopatric ones. Both substitutions occurred in ookinete micronemal proteins, CTRP and WARP, within von Willebrand factor A domains, suggesting that regional allelic variation modulates Plasmodium-vector compatibility by altering midgut adhesion interactions. These findings reveal that vector compatibility is a polygenic trait shaped by molecular interactions across several loci. Understanding this complexity refines models of parasite adaptation and can inform the design of transmission-blocking interventions effective across diverse vector-parasite combinations.

microbiology↗

bioRxiv2024

Effects of Age and Noise Exposure History on Auditory Nerve Response Amplitudes: A Systematic Review, Study, and Meta-Analysis

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r=-0.407), but noise-exposure effects are weak (r=-0.152). We conclude that noise-exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

neuroscience↗

bioRxiv2022

A wheat resistosome defines common principles of immune receptor channels

Plant intracellular nucleotide-binding leucine-rich repeat (NLRs) receptors detect pathogen effectors to trigger immune responses. Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil (CC) domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity (1-3). Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. We report here a cryogenic electron microscopy (cryo-EM) structure of the wheat CNL Sr35 in complex with the effector AvrSr35 of the wheat stem rust pathogen at 3.0 [A] resolution. Direct effector binding to the leucine-rich repeats (LRRs) of Sr35 results in the formation of a pentameric Sr35-AvrSr35 complex, which we designate the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarity, including a previously unnoticed arginine cluster in the LRR domain that co-occurs and forms intramolecular interactions with the EDVID motif in the CC domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate novel variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement.

plant biology↗

bioRxiv2021

An intrinsic endothelial dysfunction causes cerebral small vessel disease

Small Vessel Disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes(1, 2). The disease is characterised by cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. Classically, the microvascular and tissue damage has been considered secondary to extrinsic factors, such as hypertension, consisting of microvessel stiffening, impaired vasoreactivity and blood-brain barrier dysfunction identified in human sporadic SVDs. However, increasing evidence points to an underlying vulnerability to SVD-related brain damage, not just extrinsic factors. Here, in a novel normotensive transgenic rat model where the phospholipase flippase Atp11b is deleted, we show pathological, imaging and behavioural changes typical of those in human sporadic SVD, but that occur without hypertension. These changes are due to an intrinsic endothelial cell dysfunction, identified in vessels of the brain white matter and the retina, with pathological evidence of vasoreactivity and blood-brain barrier deficits, which precipitate a secondary maturation block in oligodendroglia and myelin disruption around the small vessels. This highlights that an intrinsic endothelial dysfunction may underlie vulnerability to human sporadic SVD, providing alternative therapeutic targets to prevent a major cause of stroke and dementia.

neuroscience↗

bioRxiv2020

The allosteric modulation of Complement C5 by knob domain peptides

To overcome limited germline combinatorial diversity, bovines have evolved a subset of antibodies with ultra-long CDRH3 regions that harbour cysteine-rich knob domains. To produce affinity-maturated peptides, we previously isolated autonomous 3-6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 [A] from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

immunology↗