Biology subjects

Williams, S. A.

Publications and source records attributed to Williams, S. A..

14 recordsLinked to original sources

bioRxiv2026

Spatial atlas of the ovary identifies molecular events in primordial follicle activation in humans

The human ovarian reserve is established prenatally, when granulosa cells encapsulate germ cells to form a pool of quiescent primordial follicles, that ultimately determines the female reproductive and endocrine lifespan. From birth to menopause, subsets of these quiescent follicles, located in the thin outer ovarian cortex, are activated and undergo a growth programme with progressive inward migration to the inner cortex, before either undergoing atresia or, during reproductive age, ovulation. Disruption of this process may lead to infertility, metabolic disorders and early menopause, yet early follicle development remains largely poorly understood. Here, we generate the most comprehensive single-cell and spatial multiomics atlas of the human pre- and postnatal ovarian cortex, integrating transcriptomic and chromatin profiles from over four million cells obtained from fetal and newly profiled pediatric and adult donors. We resolve the early granulosa cell trajectory at unprecedented resolution and identify a retinoic acid-associated regulatory switch accompanying follicle activation. We further show that stromal fibroblasts are not homogeneous, but instead form a dynamic scaffold establishing previously unrecognised morphogen and paracrine gradients that organise the cortex into functional niches supporting quiescent, growing, and atretic follicles. Finally, we identify ovarian lipid associated macrophages (oLAMs) that localise around follicles and are likely to support tissue remodelling during folliculogenesis. Together, this atlas provides a foundational blueprint for human ovarian development and homeostasis, and provides a framework for improving strategies in fertility preservation and in vitro follicle maturation.

cell biology↗

bioRxiv2026

A versatile cryopreservation method for peri-gastrulation squamate embryos optimised using the veiled chameleon (C. calyptratus)

Stem cell technologies have become a vital component of conservation efforts around the globe. Biobanks and pluripotent stem cell lines help to ensure species and their genetic diversity are preserved. These efforts have however, focussed mostly on mammals and birds, and the cryopreservation protocols for embryos and cells were developed decades ago laying the basis for artificial reproductive techniques for species conservation. With over 20% of non-avian reptile species facing extinction, it is imperative to establish protocols for reptiles to ensure species preservation and also to facilitate the establishment of new reptile model organisms to match the standard of mammals. Here, we have generated a cryopreservation method for preserving early gastrulating veiled chameleon embryos as a representative squamate species. To this end, we first developed a tissue culture method for maintaining cells extracted from peri-gastrulation chameleon embryos and then tested different cryopreservation methods altering the concentration of the penetrating cryoprotectant DMSO and assessing the effect of the addition of non-penetrating cryoprotectants Trehalose and Sucrose. We then optimised a protocol for whole embryo vitrification in 20% DMSO with added Trehalose or Sucrose that can easily be adapted for fieldwork. Taken together, our method not only provides a protocol for conservation efforts but also lays the basis for mechanistic studies of early squamate embryo development by enabling cryopreservation of whole embryos in a fieldwork setting, which facilitates their live transport back to a laboratory for functional experiments or molecular analyses.

developmental biology↗

bioRxiv2025

Oogenesis and germinal bed morphology of the brown anole (A. sagrei)

BackgroundThe brown anole is a model species of the genus Anolis, a squamate (encompassing lizards and snakes) group widely studied in evolutionary, behavioral, and developmental biology. Full genome annotation, the establishment of gene editing techniques, and comprehensive description of reproductive tract morphology and embryogenesis in this species, has laid the foundation for functional studies. However, analysis of brown anole oogenesis is still required and vital to optimize genome modification, mutant line establishment, and analyses of the evolution of reproductive developmental mechanisms. ResultsHere, we characterize ovary morphology and gametogenesis in the female brown anole, A. sagrei using brightfield imaging, microCT, histology staining, electron microscopy, and confocal imaging. We define 10 stages of oocyte maturation which commences inside the oogonial nest within the germinal bed and concludes with the mature follicle ready to ovulate based on follicle size, yolk-acquisition, and follicular, cellular, and basement membrane architecture. ConclusionsWe describe the complete oogenesis of the brown anole in 10 stages and report that oogenesis is highly conserved within iguanids, a suborder of lizards. With our staging framework, we lay the foundation for functional studies of oogenesis and optimized gene-editing.

developmental biology↗

bioRxiv2025

Early life adversity shapes life history trade-offs between growth and reproduction in free-ranging rhesus macaques

Life history theory predicts that organisms allocate resources across physiological processes to maximize fitness. Under this framework, early life adversity (ELA)--which often limits energetic capital--could shape investment in growth and reproduction, as well as trade-offs between them, ultimately contributing to variation in evolutionary fitness. Using long-term demographic, behavioral, and physiological data for 2,100 females from a non-human primate population, we tested whether naturally-occurring ELA influences investment in the competing physiological demands of growth and reproduction. By analyzing ELA, growth, and reproduction in the same individuals, we also assessed whether adversity intensifies trade-offs between life history domains. We found that ELA influenced life history patterns, and was associated with modified growth, delayed reproductive maturity, and small adult body size. Different types of ELA sometimes had distinct reproductive outcomes--e.g., large group size was linked to faster reproductive rates, while low maternal rank predicted slower ones. Adversity also amplified trade-offs between growth and reproduction: small body size was a stronger predictor of delayed and reduced reproductive output in females exposed to ELA, compared to those not exposed. Finally, we examined how traits modified by ELA related to lifetime reproductive success. Across the population, starting reproduction earlier and maintaining a moderate reproductive rate conferred the greatest number of offspring surviving to reproductive maturity. These findings suggest that ELA impacts key life history traits as well as relationships between them, and can constrain individuals from adopting the most optimal reproductive strategy. Significance StatementEarly life adversity (ELA) can have lasting effects on evolutionary fitness (e.g., the number of surviving offspring an animal produces); however, the paths connecting ELA to fitness--for example by influencing growth, reproductive timing or rate, or trade-offs between these processes--remain unclear. Leveraging long-term behavioral, physiological, and demographic data from 2,100 female rhesus macaques, we found that ELA-exposed females exhibited growth and reproductive schedules associated with less-optimal lifetime fitness outcomes. Further, ELA intensified trade-offs between growth and reproduction, suggesting that affected individuals face steeper energetic constraints. Our findings highlight the long-lasting impacts of ELA on traits of evolutionary and biomedical importance in a non-human primate model with relevance to humans.

evolutionary biology↗

bioRxiv2025

Epiblast Lumenogenesis is not a mammalian-specific trait

Epiblast lumenogenesis, which leads to amniotic cavity formation, is a hallmark of mammalian embryogenesis, and required for crucial developmental processes such as anterior-posterior patterning and gastrulation. Based on avian model-organisms, the epiblast in reptiles is thought to form a monolayered flat disc that undergoes anterior-posterior patterning and gastrulation. Here, we report that the squamate, veiled chameleon (Chameleo calyptratus), exhibits epiblast lumenogenesis and amniogenesis prior to anterior-posterior patterning. Using SEM, immunofluorescence, and histology techniques, we demonstrate that chameleon epiblast lumenogenesis occurs via a purse-string-like mechanism involving the formation of supracellular actin cables in concentric rings around the epiblast followed by constriction that closes the epiblast lumen. Through expression analyses of Nodal1, Nodal2, Cerberus, Lefty, Brachyury, Wnt3A, and Bmp2, and immunostaining for Brachyury, we uncovered a Wnt3a- and Brachyury-positive ring at the edge of the epiblast concomitant with lumenogenesis, and preceding anterior-posterior patterning and gastrulation. Furthermore, we report anterior-posterior patterning in veiled chameleons occurs independently of Cerberus and Lefty. These processes that mediate epiblast lumenogenesis in chameleons, result in a morphology remarkably similar to human embryos, despite 300 million years of evolutionary separation. Taken together, we show that pre-gastrulation epiblast lumenogenesis is not mammalian-specific, but also occurs in some non-avian reptiles.

developmental biology↗

bioRxiv2025

Too little and too much: balanced hippocampal, but not medial prefrontal, neural activity is required for intact novel object recognition in rats

Impaired GABAergic inhibition, so-called neural disinhibition, in the prefrontal cortex and hippocampus has been linked to cognitive deficits. The novel object recognition (NOR) task has been used widely to study cognitive deficits in rodents. However, the contribution of prefrontal cortex and hippocampal GABAergic inhibition to NOR task performance has not been established. Here, we investigated NOR task performance in male Lister Hooded rats following regional neural disinhibition or functional inhibition, using intra-cerebral microinfusion of the GABA-A receptor antagonist picrotoxin or agonist muscimol, respectively. Our infusion targets were the medial prefrontal cortex (mPFC), dorsal hippocampus and ventral hippocampus. Using a within-subjects design, we compared NOR task performance (1-min retention delay) following bilateral regional saline, picrotoxin or muscimol infusions made before the acquisition phase. In mPFC, neither functional inhibition nor neural disinhibition affected object recognition memory. However, in both dorsal and ventral hippocampus, neural disinhibition impaired NOR relative to saline control, mainly by reducing novel object exploration time. In addition, functional inhibition of dorsal hippocampus impaired NOR, whereas ventral hippocampal functional inhibition tended to reduce novel object exploration at the highest dose used (alongside substantial non-specific behavioural effects). Overall, our data suggest that hippocampal, but not prefrontal, GABAergic inhibition contributes to NOR at a 1-min retention delay. Moreover, such NOR performance likely requires balanced neural activity in the dorsal hippocampus, with both too little and too much dorsal hippocampal activity impairing NOR memory. Our findings support that the NOR task can be used to investigate hippocampal GABAergic dysfunction in rodent models. Significance statementImpaired GABAergic neural inhibition in the prefrontal cortex and hippocampus has emerged as a key neuropathological feature of cognitive disorders. The novel object recognition (NOR) task is used widely in rodent models to investigate cognitive impairments relevant to cognitive disorders. However, the role of hippocampal and prefrontal GABAergic inhibition in NOR is unclear, limiting interpretations as to how NOR deficits in rodent models may relate to this key pathological feature of many cognitive disorders. Here, we show that impaired hippocampal GABAergic inhibition impairs NOR in rats, whereas prefrontal GABAergic inhibition is not required. Thus, the NOR task may be used to investigate hippocampal GABAergic dysfunction in rodent models.

neuroscience↗

bioRxiv2024

Global diversity of soil-transmitted helminths reveals population-biased genetic variation that impacts diagnostic targets

Soil-transmitted helminths (STHs) are intestinal pathogens affecting over a billion people worldwide. STH control relies on microsopy-based diagnostics to monitor parasite prevalence and enable post-treatment surveillance, however, molecular diagnostics are rapidly being developed due to increased sensitivity, particularly in low-STH-prevalence settings. The genetic diversity of helminths and its potential impact on molecular diagnostics remains unclear. Using low-coverage genome sequencing, we assessed the presence of STHs in worm, faecal and purified egg samples from 27 countries, identifying differences in the genetic connectivity and diversity of STH-positive samples across regions and cryptic diversity between closely related human- and pig-infective species. We defined substancial copy number and sequence variants in current diagnostic targets and validated the impact of genetic variants on qPCR diagnostics using in vitro assays. Our study provides insights into the diversity and genomic epidemiology of STHs, highlighting challenges and opportunities for developing molecular diagnostics needed to support STH control efforts.

genomics↗

bioRxiv2021

Hippocampal disinhibition reduces contextual and elemental fear conditioning while sparing the acquisition of latent inhibition

Hippocampal neural disinhibition, i.e. reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signalling, which play a role in salience modulation. Therefore, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. To test this hypothesis, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response procedure (CER). A flashing light was used as the conditioned stimulus (CS) and conditioned suppression was used to index conditioned fear. In Experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin prior to CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls, but could not be detected in picrotoxin-infused rats due to the low level of fear conditioning to the CS. In Experiment 2, VH picrotoxin infusions prior to CS pre-exposure only did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing within the hippocampus and its projection sites. Significance StatementHippocampal disinhibition, reduced GABAergic inhibition, is a feature of schizophrenia, but how this contributes to psychological deficits remains to be clarified. Here, we focused on impairments patients show on classical-conditioning assays: aberrant salience allocation to stimuli that healthy participants have learnt to ignore and reduced fear conditioning, which have been linked to psychosis and negative symptoms, respectively. These impairments may be related to hippocampal disinhibition because the hippocampus modulates neural substrates of salience allocation and is part of the fear-conditioning neural circuit. Combining selective pharmacological manipulation of the hippocampus with a conditioning assay in rats, we found hippocampal disinhibition disrupted fear conditioning, without evidence for aberrant salience allocation. This suggests hippocampal disinhibition contributes to fear conditioning deficits in schizophrenia.

neuroscience↗

bioRxiv2021

New fossils of Australopithecus sediba reveal a nearly complete lower back

Adaptations of the lower back to bipedalism are frequently discussed but infrequently demonstrated in early fossil hominins. Newly discovered lumbar vertebrae contribute to a near-complete lower back of Malapa Hominin 2 (MH2), offering additional insights into posture and locomotion in Australopithecus sediba. We show that MH2 demonstrates a lower back consistent with human-like lumbar lordosis and other adaptations to bipedalism, including an increase in the width of intervertebral articular facets from the upper to lower lumbar column ("pyramidal configuration"). This contrasts with recent work on lordosis in fossil hominins, where MH2 was argued to demonstrate no appreciable lordosis ("hypolordosis") similar to Neandertals. Our three-dimensional geometric morphometric (3D GM) analyses show that MH2s nearly complete middle lumbar vertebra is human-like in shape but bears large, cranially-directed transverse processes, implying powerful trunk musculature. We interpret this combination of features to indicate that A. sediba used its lower back in both human-like bipedalism and ape-like arboreal positional behaviors, as previously suggested based on multiple lines of evidence from other parts of the skeleton and reconstructed paleobiology of A. sediba.

paleontology↗

bioRxiv2021

Cross-platform proteomics to advance genetic prioritisation strategies

Discovery of protein quantitative trait loci (pQTLs) has been enabled by affinity-based proteomic techniques and is increasingly used to guide genetically informed drug target evaluation. Large-scale proteomic data are now being created, but systematic, bidirectional assessment of platform differences is lacking, restricting clinical translation. We compared genetic, technical, and phenotypic determinants of 871 protein targets measured using both aptamer-(SomaScan(R) Platform v4) and antibody-based (Olink) assays in up to 10,708 individuals. Correlations coefficients for overlapping protein targets varied widely (median 0.38, IQR: 0.08-0.64). We found that 64% of pQTLs were shared across both platforms among all identified 608 cis- and 1,315 trans-pQTLs with sufficient power for replication, but with correlations of effect estimates being lower than previously reported (cis: 0.41, trans: 0.34). We identified technical, protein, and variant characteristics that contributed significantly to platform differences and found contradicting phenotypic associations attributable to those. We demonstrate how integrating phenomic and gene expression data improves genetic prioritisation strategies, including platform-specific pQTLs.

genetics↗

bioRxiv2020

Genetic architecture of host proteins interacting with SARS-CoV-2

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid in silico assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).

genomics↗

bioRxiv2020

The effect of delayed processing on ovarian tissue stored for fertility preservation

BackgroundOvarian tissue cryopreservation (OTC) is important for fertility preservation and conservation. Delay in OTC may be required for transport or workflow management, however little is understood about the effect of processing delay on the tissue. ObjectiveTo determine whether a delay of 24-48 hours to OTC affects primordial follicle (PF) health. MethodsOvaries (n=6 sheep) were processed immediately or after storage at 4{degrees}C (24h, 48h). Tissue was fixed fresh, after cryopreservation or 10-day xenotransplantation. Morphological assessment of follicle health and development was performed. FindingsA total of 1541 follicles were analysed. A 24h processing delay did not impact PF health in fresh or cryopreserved tissue. In fresh tissue a 48h delay had an adverse effect on follicle health (OR=2.47, 95% CI 1.29-4.71). Interestingly, a 48h delay resulted in cryopreserved tissue being less likely to be graded as unhealthy compared to control (OR=0.56, 95% CI 0.36-0.87). There was no difference in PF health or development across groups following xenotransplantation. ConclusionOvarian tissue can be stored for up to 48 hours prior to cryopreservation with no net impact on PF health.

physiology↗

bioRxiv2019

Sex Differences in Age-related Impairments Vary across Cognitive and Physical Assessments in Rats

Inclusion of female subjects in biomedical research is imperative for understanding the mechanisms of age-related cognitive decline, as more than half of individuals older than 65 are female. Few behavioral and physical assays, however, have been conducted in both sexes within the same study. In the current experiments young and aged male and female rats underwent a battery of cognitive and physical assessments to examine for potential sex and age differences. Physical performance was measured with a rotarod test of motor coordination, assessment of maximum grip strength and swim speed. While there were differences between males and females in rotarod and grip strength, there was also a clear age-dependent decline in physical performance in both sexes. Cognitive assessment included the Morris watermaze test of hippocampal dependent spatial navigation and a biconditional association task (BAT) with a working memory (WM) component. Notably, a similar BAT has previously been validated as a more sensitive assay of age-related cognitive decline than the watermaze in male rats, which is replicated here in both female and male rats. Furthermore, young and aged female rats both spent a similar percent of time in each estrus cycle phase and phase did not influence WM/BAT performance. In conclusion, robust age differences in biconditional association task performance are observed in both sexes with no need for increased cohort size. Thus, future studies utilizing similar behavioral paradigms should be representative of the human population they intend to model through the inclusion of female subjects.

neuroscience↗

bioRxiv2019

Comparison of multi-parallel qPCR and Kato-Katz for detection of soil-transmitted helminth infection among children in rural Bangladesh

An active area of research investigates whether soil-transmitted helminths (STH) can be locally eliminated in endemic settings. In such settings, highly sensitive diagnostics are needed to detect STH infection. We compared double-slide Kato-Katz, the most commonly used copromicroscopic detection method, to multi-parallel quantitative polymerase chain reaction (qPCR) in 2,800 stool samples from children 2-12 years in rural Bangladesh. We estimated the sensitivity and specificity of each diagnostic using Bayesian latent class analysis. Compared to Kato-Katz, STH prevalence using qPCR was almost 3-fold higher for hookworm species and nearly 2-fold higher for Trichuris trichiura. Ascaris lumbricoides prevalence was lower using qPCR, and 26% of samples classified as A. lumbricoides positive by Kato-Katz were negative by qPCR. Amplicon sequencing of the 18S rDNA from 10 samples confirmed that A. lumbricoides was absent in samples classified as positive by Kato-Katz and negative by qPCR. The sensitivity of Kato-Katz was 49% for A. lumbricoides, 32% for hookworm, and 52% for T. trichiura; the sensitivity of qPCR was 79% for A. lumbricoides, 93% for hookworm, and 90% for T. trichiura. Specificity was [≥] 97% for both tests for all STH except for Kato-Katz for A. lumbricoides (specificity = 68%). There were moderate negative, monotonic correlations between qPCR cycle quantification values and eggs per gram quantified by Kato-Katz. While it is widely assumed that Kato-Katz has few false positives, our results indicate otherwise. Our findings suggest that qPCR is more appropriate than Kato-Katz in low intensity infection settings because of its higher sensitivity and specificity.\n\nAuthor summarySoil-transmitted helminth infections (STH) (e.g., Ascaris, hookworm, Trichuris) contribute to a large burden of disease among children in low- and middle-income countries. There is increasing interest in implementing large-scale deworming programs to eliminate STH in certain settings. Efforts to monitor whether local elimination has occurred require sensitive diagnostic tests that will not miss positive cases. Kato-Katz, a microscopy-based diagnostic test, has commonly been used to identify STH eggs in stool, but in settings where infection intensity is low, this method frequently misses positive samples because it requires visual identification of small numbers of eggs, and eggs may degrade prior to visualization. Quantitative polymerase chain reaction (qPCR) is a molecular diagnostic method that may miss fewer infections because it identifies STH DNA in stool, which can be detected in very small quantities and is less likely to degrade. This study compared the performance of Kato-Katz and qPCR using 2,800 stool samples from children aged 2-12 years in rural Bangladesh. qPCR detected substantially more hookworm and Trichuris infections than Kato-Katz. 26% of samples were classified as Ascaris positive by Kato-Katz and negative by qPCR. We conclude that qPCR is a more appropriate diagnostic method than Kato-Katz in low infection intensity settings.

epidemiology↗