Biology subjects

Jones, H.

Publications and source records attributed to Jones, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Sustained Maternal Cortisol Elevation Links Metabolic Stress to Fetal Growth Restriction in a Guinea Pig Model of Undernutrition

Fetal growth restriction (FGR) resulting from maternal undernutrition is commonly attributed to insufficient nutrient substrate delivery to the fetus. However, the contribution of maternal physiological stress responses to this outcome remains poorly characterized. Using the well-established guinea pig maternal nutrient restriction (MNR) model, we conducted a comprehensive retrospective analysis to interrogate the hypothesis that maternal stress physiology actively mediates fetal growth outcomes beyond simple substrate limitation. Maternal salivary and serum cortisol were significantly elevated in MNR dams throughout pregnancy despite no baseline differences at conception, indicating that hypothalamic-pituitary-adrenal (HPA) axis activation was specifically triggered by the combined physiological demands of pregnancy and nutritional constraint. The sustained cortisol elevation was accompanied by acute metabolic perturbations at mid-pregnancy, including hypoglycemia and depleted circulating lipids. While most acute metabolic disturbances resolved by near-term, cortisol remained elevated, and MNR fetuses exhibited parallel cortisol elevation alongside sustained growth restriction. Maternal weight divergence emerged only in late gestation and was driven primarily by reduced conceptus weight. Maternal organ analysis revealed selective hepatic enlargement with apparent lipid accumulation in MNR dams near-term. Overall, these findings help to reframe nutrition-related FGR as a condition in which maternal adaptive stress responses, reduced nutritional components and placental insufficiency are mechanistically intertwined, with important implications for the design of effective interventions beyond simply nutrient supplementation.

physiology↗

bioRxiv2026

N6-methyladenosine (m6A) RNA modifications control the antiviral response to influenza A virus infection by limiting IFITM2/3 expression

N6-methyladenosine (m6A) RNA modifications regulate diverse cellular processes, including the response to virus infection. However, how m6A controls antiviral gene expression and whether effects on viral replication are due to direct modification of viral RNA or regulation of cellular transcripts remain unclear. Herein, we analysed how m6A modifications control the cell-autonomous innate immune response to influenza A virus (IAV) infection. Depletion or inhibition of the m6A writer METTL3 or the m6A reader YTHDF2 restricts IAV replication. However, using a quantitative method to identify m6A sites, we did not detect substantial m6A modification of viral RNA. In contrast, many IAV-induced cellular transcripts were m6A modified in their coding region, including those that encode pattern recognition receptors and direct antiviral proteins. Inhibition of interferon signalling restored IAV replication after METTL3 inhibition, highlighting that m6A controls the antiviral response to infection. METTL3 inhibition increased expression of the paralogous antiviral proteins IFITM2 and IFITM3, which were required for the antiviral activity of the METTL3 inhibitor. We propose that m6A modifications regulate the expression of antiviral proteins to limit the magnitude of their induction and balance antiviral activity with maintaining cellular homeostasis.

microbiology↗

bioRxiv2026

A randomized trial of grant writing coaching groups: Qualitative interviews revealing key elements of intervention efficacy

Background Training in grant proposal writing is an essential component of professional development for academic scientists in the biomedical and behavioral sciences. Despite the expansion of inter- and intra-institutional grant writing coaching groups as an approach to honing these skills, specific features that enhance or limit coaching group effectiveness have not been rigorously studied. Methods Qualitative inerviews were conducted with a subset of early-career investigators (n=204 and coaches (n=36) engaged in a national, U.S. based, group-randomized trial of grant writing coaching groups to test the effects of two variables on submission and funding of national-level proposals: (1) coaching duration (regular/extended dose) and (2) mode of engaging a scientific advisor (someone with content-aligned expertise) in the coaching process. This report focuses on interviews conducted upon completion of the regular coaching dose - 5 months of biweekly, group-based coaching sessions to support active proposal writing. Interviews were designed to identify which coaching group elements were perceived to be the most critical. Transcribed interviews were analyzed using deductive (participants) or open (coaches) coding to identify themes. Results Triangulation of results from participant and coach interviews showed strong concordance that coaches, peers, and scientific advisors all played key roles in supporting intervention efficacy. Sufficient alignment of scientific fields and/or methodologies among group members was important, although breadth of perspectives was also valued. Other critical group features were skilled and well-organized coaches, detailed feedback, peer-to-peer support (technical and psychosocial), and clear expectations for group functioning. Factors attenuating impact included variation in participants' engagement and "readiness to write," within-group mismatches of expertise or grant mechanisms, and limited research support at some participants' home institutions. Conclusion This study identified key elements of successful grant writing coaching groups and potential barriers to their effectiveness, while yielding insights about tailoring this approach for individuals at different stages of proposal development.

scientific communication and education↗

bioRxiv2026

Grant writing coaching groups: A randomized trial to discern the influences of coaching duration and engagement of scientific mentors on participants proposal submission and success rates

IntroductionThe acquisition of National Institutes of Health (NIH) grants is an increasingly competitive undertaking. Many early-career biomedical investigators lack sufficient grant writing skills. This pragmatic, 2x2 factorial, group-randomized trial tested the effects of coaching duration and mode of engagement of participants scientific mentors in a grant writing coaching group intervention on grant application outcomes. MethodsA national US sample of 367 faculty and postdoctoral fellows, organized into 76 coaching groups across 6 cohorts (2020-2022), was randomized to 1 of 4 arms that differed by coaching duration (5 months vs 5 months plus 18 months of access to 1:1 coaching) and mode of scientific mentor engagement (structured vs unstructured). Primary outcomes were national-level grant application submissions and awards, and success rate among submitters, assessed via surveys and verified through award databases 30 months after study initiation. ResultsAmong 271 faculty and 96 postdoctoral fellows, 69% submitted at least 1 national application and 32% were awarded at least 1 grant. Submission rates did not differ by experimental arm. Among faculty, the structured engagement of a mentor in coaching was associated with significantly higher odds of any award (adjusted OR = 1.87) and any NIH mentored career development (K) award (adjusted OR = 3.32), and with higher success rates for these proposal types. Extended coaching duration showed a positive but not statistically significant association with faculty awards after adjustment. Neither factor significantly affected outcomes for postdoctoral fellows. Faculty success rates exceeded national NIH-reported success rates for research project grants equivalent to the R01 mechanism (43% vs 17.6%) and K awards (51% vs 36.5%). ConclusionParticipation in a national, cross-institutional, group coaching model yielded high grant submission outcomes, and award rates were higher relative to NIH benchmarks. Structured integration of scientific mentors with the coaching intervention had a greater effect than extended coaching duration on faculty outcomes.

scientific communication and education↗

bioRxiv2026

Local and biogeographical determinants of the diversity and structure of invertebrate communities in rot holes of ash, Fraxinus excelsior

O_LIVeteran trees are biodiversity hotspots, providing a range of microhabitats, including tree hollows or rot holes in trunks, which support a large diversity of invertebrates including threatened species. Each rot hole is a unique microcosm, with variable biotic and abiotic characteristics enabling their use by many invertebrate taxa. C_LIO_LIMost previous studies describing the invertebrate communities of rot holes and the factors determining their structure focus on a narrow range of invertebrate taxa, and many host tree species remain unexplored. European ash (Fraxinus excelsior L.) is one of Europes most threatened deciduous tree species due to the spread of ash dieback disease, but the potential impact of these losses on the invertebrate communities that inhabit ash is poorly understood. C_LIO_LIInvertebrates were sampled and identified to family level from 14 sites across Wales and western England, and major physical characteristics of each rot hole and sample site were assessed (e.g., habitat type, altitude, maximum site temperature). C_LIO_LIAsh rot hole invertebrate communities were highly diverse with a range of threatened taxa, including some undescribed or new to the region. There was large variation in both measured rot hole characteristics and the invertebrate communities between individual rot holes, sites and habitats. Both tree-specific and biogeographical factors significantly influenced invertebrate diversity and community structure, suggesting that sustaining the heterogeneity of ash rot holes across a range of locations is required to support saproxylic invertebrate diversity. C_LIO_LIWith increasing ash veteran tree vulnerability, sustaining these vital habitats and their associated invertebrate communities is a conservation imperative. This study has demonstrated that considering heterogeneity in both habitat characteristics and landscape context will be crucial when conserving these communities. C_LI

ecology↗

bioRxiv2026

Striatal activity during contextual word learning is influenced by children's reading ability

Contextual word learning is a fundamental mechanism for vocabulary acquisition during childhood. In adults, successful inference of word meaning from context is intrinsically rewarding, and is associated with greater enjoyment and greater activity in reward-related brain regions. Whether similar reward mechanisms support word learning in children, and whether they differ as a function of ability, remains unknown. We used functional magnetic resonance imaging (fMRI) to examine neural responses during contextual word learning in 25 children aged 11-13 years with typical reading skills and in 20 age-matched children with dyslexia. Neurotypical readers showed enhanced activation in core reward-processing regions, including the ventral striatum, when successfully learning the meanings of novel words. In contrast, children with dyslexia did not exhibit comparable reward-related responses despite performing the same task. Crucially, this group difference was specific to word learning, as no significant group differences were observed in ventral striatal responses during a non-linguistic monetary reward task. In addition, to confirm the behavioural relevance of these neural findings, we examined an age-matched, independent sample of children. We found that stronger reading skills were associated with greater enjoyment during successful word learning. Together, these results suggest that interactions between reward and language systems during contextual word learning is influenced by reading proficiency. Reduced intrinsic reward responses to successful language learning may contribute to differences in reading development and have implications for the design of more engaging and effective reading interventions for struggling readers. Significance statementWe investigated how school-age childrens brains learn new words from context, highlighting the important role of reward systems in this process. We show that ventral striatum, a core region associated with reward processing, is activated when children learn the meaning of new words. This suggests learning the meaning of a new word can be its own reward, driving further learning and engagement. Yet, children with dyslexia showed reduced brain activity in the ventral striatum during language learning, even when they successfully learned words. These findings underscore the importance of understanding the mechanisms through which learning becomes rewarding, with implications for designing more engaging and effective reading interventions

neuroscience↗

bioRxiv2025

The barley ear row-number allele ancestral to the six-row allele vrs1.a1 is found in wild barley from the Fertile Crescent

Barley (Hordeum vulgare L.) exhibits two main inflorescence phenotypes: the wild-type two-row form in which only the central spikelet at each rachis node is fertile, and the six-row form, where mutations in the homeobox gene Six-rowed spike 1 (VRS1) confer fertility to all three spikelets. While the six-row alleles vrs1.a2 and vrs1.a3 arose independently from point mutations in the ancestral Vrs1.b2 and Vrs1.b3 alleles, the origin of the hypothesised wild-type Vrs1.b1 allele ancestral to vrs1.a1 is unclear. To explore the origin and exploitation of VRS1 alleles, we re-sequenced VRS1 in 98 cultivars, 170 landraces and 69 wild barley accessions, identifying 39 haplotypes. Sequence analysis confirmed vrs1.a1 as the most commonly used six-row allele in European cultivars. Subsequent analysis of the landrace and wild barley data identified three occurrences of the haplotype consistent with a vrs1.b1 allele, all from wild barley. These wild barley accessions originated from the eastern Fertile Crescent (Iran) and the Caspian Sea region, suggesting vrs1.a1 arose via mutation of Vrs1.b1 within barleys domestication centre - unlike vrs1.a2 and vrs1.a3, which originated in the Western Mediterranean and East Asia cultivated barley genepools, respectively. In addition, we identified ten novel VRS1 amino acid changes in wild barley accessions, which given the pleiotropic effects of VRS1 on traits such as leaf size, vein number and tiller number, may be of interest for future functional investigation. Overall, this study provides insights into the evolution, domestication and utilisation of genetic variation at VRS1, a key gene influencing barley architecture and agricultural performance.

molecular biology↗

bioRxiv2025

Aberrant placental structure is corrected with repeated nanoparticle-mediated IGF1 treatments in a guinea pig model of fetal growth restriction

Fetal growth restriction (FGR) is most commonly due to placental insufficiency. There are currently no treatments for placental insufficiency or FGR, and the only intervention is iatrogenic pre-term delivery. We have previously shown efficacy of repeated placental nanoparticle-mediated insulin-like 1 growth factor (IGF1) treatment in improving placental efficiency (increased fetal-placental weight ratio) and correcting fetal growth in a maternal nutrient restriction (MNR) guinea pig model of FGR. Here we investigate the structural remodeling of the placenta following 3 repeated intraplacental injections of nanoparticle-mediated hIGF1 that may underpin the published improvements in placental efficiency and fetal growth. We hypothesize placenta structural changes (reduced exchange area, altered vascular structure) that we and others have previously shown in the FGR/MNR placenta which lead to deficits in placental function are mitigated by our repeated nanoparticle-mediated hIGF1 treatment. Sham-treated MNR placentas displayed disorganized microvasculature labyrinthine exchange areas with a reduction in placental capillary number and maternal blood space areas, and an increase in the volume of the placenta macrovasculature. Repeated nanoparticle-mediated hIGF1 treatment, however, resulted in an improved exchange area with normalized placental capillary number and maternal blood space area, and macrovasculature volume. This data demonstrates repeated nanoparticle-mediated hIGF1 delivery corrects aberrant placenta structure likely leading to improved gas exchange and transfer of nutrients to the fetus restoring fetal growth.

developmental biology↗

bioRxiv2025

Virulence of Naegleria fowleri isolates varies significantly in the mouse model of primary amoebic meningoencephalitis

Naegleria fowleri is a small free-living amoeba that causes an acute, fatal disease called primary amoebic meningoencephalitis (PAM). One persisting question is why few people succumb to disease when so many are potentially exposed. We tested the hypothesis that N. fowleri isolates vary in virulence and in the minimum infectious dose required to induce disease by using a mouse model of PAM and intranasally inoculating dilutions of five clinical isolates of N. fowleri. Results showed significant differences in onset of severe disease and mortality rates between isolates. Remarkably, for isolate V596, 100 amoebae produced 100% mortality within 5 days. In contrast, higher numbers of amoebae were required for other isolates and mice survived for >2 weeks. Concurrently, we developed an in vitro virulence assay by comparing feeding rates between amoebae isolates seeded onto Vero cells. We observed a positive correlation between cytopathic effects in vitro and virulence in vivo. Article Summary LineIsolates of Naegleria fowleri vary in virulence, which results in significant differences in minimal infectious concentrations of amoebae that cause primary amoebic meningoencephalitis.

microbiology↗

bioRxiv2025

A human cytotrophoblast-villous endothelium-fetal organ multi-cell model and the impact on gene and protein expression in placenta cytotrophoblast, fetal hepatocytes and fetal kidney epithelial cells

Appropriate fetal growth during pregnancy requires multi-directional communication from the maternal, placental and fetal systems. Disruption in any of these signaling arms can have deleterious consequences for fetal growth and initiate developmental adaptations within fetal tissues and organs that are associated with both short- and long-term morbidities. In this proof-of-concept translational, human cell model study we aimed to identify the impacts of altered trophoblast stress response mechanisms and human insulin-like 1 growth factor (hIGF1) nanoparticle gene therapy on gene and protein expression in fetal liver hepatocytes and fetal kidney epithelial cells. We utilized human cell lines: BeWo choriocarcinoma cells (trophoblast), Human Placental Micro-Vascular Endothelial Cells, and WRL68 (hepatocytes) or HEK293T/17 (kidney epithelium), in a co-culture model designed to mimic cytotrophoblast-villous endothelium-fetal organ communication. Trophoblast stress response mechanisms were increased by culturing BeWo cells in growth media without FBS. Stressed BeWo cells were also treated with a hIGF1 nanoparticle gene therapy known to mitigate cellular stress mechanisms. Stressed BeWo cells had increased expression of cellular stress mechanisms but not when IGF1 was over-expressed with a transient hIGF1 nanoparticle gene therapy. Stressed and Stressed+hIGF1 BeWo cells had increased expression of gluconeogenesis and glycolysis rate-limiting enzymes. Gene and protein expression in fetal liver and kidney cells was not impacted by increased trophoblast stress or hIGF1 nanoparticle gene therapy. In conclusion, our data demonstrated that cytotrophoblast under stress turn on mechanisms involved in glucose production. Whether this is reflected in vivo remains uninvestigated but may represent a placental compensation mechanism in complicated pregnancies.

cell biology↗

bioRxiv2025

Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates fetal sex dependent FGR-associated effects on kidney structure and blood pressure-related signaling pathways

Fetal development in an adverse in utero environment significantly increases the risk of hypertension and cardiovascular disease. The kidneys play a pivotal role in the regulation of blood pressure and cardiovascular function, and perturbations in kidney structure and molecular profile are often demonstrated in offspring born fetal growth restricted (FGR). The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate FGR-associated dysregulation of fetal kidney development. Using the guinea pig maternal nutrient restriction (MNR) model, we improved placenta efficiency and fetal weight following three placental administrations of a non-viral polymer-based nanoparticle gene therapy from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal kidney tissue was collected near-term at gestational day 60. Differences in kidney structure, glomeruli size and gene expression of extracellular matrix (ECM) remodeling and blood pressure regulation-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. We speculate that mitigating the FGR-associated changes in kidney architecture and molecular profiles might confer protection against increased susceptibility to aberrant kidney physiology in later-life. Overall, this work opens avenues for future research to assess the long-term impact of the placental hIGF1 nanoparticle gene therapy on cardiovascular function in offspring.

physiology↗

bioRxiv2025

Bumblebees learn to use peripheral taste to predict the presence of nectar in flowers

Learning cues such as tastes associated with palatable food is an important mechanism animals have for foraging optimally. Insects can use gustatory receptor neurons (GRNs) in their mouthparts to detect nutrients and toxins, but they also taste compounds using sensilla on peripheral organs such as their antennae. Bees are adept at learning to associate floral traits with the presence of nectar rewards, but few studies have examined how they incorporate gustatory information from their antennae with rewards. Here, we characterize the ability of adult worker bumblebees (Bombus terrestris) to taste sugar, salt, and bitter compounds using their antennae and then tested whether they could use this sensory information to associate it with food. We show that bumblebees have antennal GRNs sensitive to sugars, salts, and bitter compounds and that they can use surface chemistry differences detected by their periphery to learn about the presence or absence of flower rewards in a free-flight assay. Naive bumblebees showed no instinctual preferences toward or against any surface chemistry tested. Bumblebees performed best when sucrose surface cues were associated with sucrose reward, but they could learn to associate any cue with the presence or absence of sucrose solution. Interestingly, the bees found it more difficult to associate quinine surface chemistry with the presence of reward than its absence. These results indicate that bees have the potential to learn to associate another floral trait - chemicals on the surfaces of petals - with the quality of floral rewards. Summary statementBehavioural experiments and electrophysiological recordings show bumblebees can detect peripheral taste cues on surfaces of artificial flowers, including bitter toxins, and learn to use these to predict rewards.

animal behavior and cognition↗

bioRxiv2025

Placental Nutrient Transport and Signaling in a Guinea Pig Model of Fetal Growth Restriction with Repeated Placental Nanoparticle-mediated IGF1 Treatment

Roughly 10% of all pregnancies are affected by fetal growth restriction (FGR). The primary etiology of FGR is placental insufficiency: the placenta not providing the appropriate amount of nutrients and oxygen to the fetus. There is currently no treatment for FGR or placental insufficiency. Because of the placentas pivotal role in FGR and supplying nutrients to the fetus, it offers an excellent target for therapeutic intervention. Using a guinea pig maternal nutrient restriction model and a repeated placental nanoparticle-mediated IGF1 treatment, placental IGF1 signaling and nutrient transport pathways were characterized to understand changes with FGR and treatment. This study elucidates the signaling mechanisms in which repeated placental nanoparticle-mediated IGF1 treatment leads to correct fetal growth. Overall, this study resulted in sex-specific kinase signaling and nutrient transporter changes within the placenta in both FGR and treatment groups. Combined with our previous studies using this treatment, we demonstrate the basic molecular signaling of this treatment and recapitulate the plausibility of this therapy for future human translation.

molecular biology↗

bioRxiv2024

Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.

Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N ([~]40% of patients) and p.E815K ([~]25% of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.

neuroscience↗

bioRxiv2024

Placental hIGF1 nanoparticle gene therapy in guinea pigs ameliorates fetal growth restriction-associated changes in hepatic lipid and glucose metabolism-related signaling pathways in a fetal sex-specific manner

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic fatty liver diseases and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency was significantly improved following three administrations of a non-viral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex specific differences in liver gene and protein expression of pro-fibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, and indirect measure of hepatic activity, was also increased with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing Control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later-life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements. NEW AND NOTEWORTHYA placenta-specific non-viral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later-life. This knowledge may have implications towards removing predispositions that increase the risk of metabolic diseases including diabetes, dyslipidemia and non-alcoholic fatty liver disease in later life.

physiology↗

bioRxiv2024

Mid-pregnancy placental transcriptome in a model of placental insufficiency with and without novel intervention

Fetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there are no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver, via a non-viral nanoparticle, human insulin-like 1 growth factor (hIGF1) to the placenta as potential treatment of placenta insufficiency and FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur prior to/at initiation of FGR, and the impact of short-term hIGF1 nanoparticle treatment. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control and MNR dams receiving a sham treatment, and MNR dams receiving hIGF1 nanoparticle treatment. Pathway enrichment analysis comparing differentially expressed genelists in sham-treated MNR placentas to Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. When compared to sham-treated MNR placentas, MNR + hIGF1 placentas demonstrated changes to genelists associated with transmembrane transporter activity including ion, vitamin and solute carrier transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta contributing to placental insufficiency prior to/at initiation of FGR, and increases our understanding of the pathways that our nanoparticle-mediated gene therapy intervention regulates. Statements and DeclarationsO_ST_ABSCompeting InterestsC_ST_ABSAuthors declare no conflicts of interest.

physiology↗

bioRxiv2024

Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

physiology↗

bioRxiv2024

Integrating diverse statistical methods to analyse stage-discriminatory cell interactions in colorectal neoplasia

Spatial biology has the potential to unlock information about the disrupted cellular ecosystems that define human disease. Quantitative analysis of spatially-resolved cell interactions allows mapping of tissue self-organisation and assessment of why cells interact differently in physiological and pathological contexts. However, the complexity of mammalian tissues, that occur across a spectrum of length scales, presents significant challenges for spatial analysis, increasing the gap between our capacity to generate and biologically interpret these datasets. Here, we have adapted a range of mathematical tools to develop a suite of spatial descriptors, and deployed them to determine how cell interactions change as colorectal cancer progresses from benign precursors. We demonstrate that combining mathematical analyses permits insightful examination of tissue organisational structures and identifies variable cell-interaction pathways that underpin disease progression. Mathematical tool triangulation can cross-corroborate spatial biology findings, facilitating development of analysis pipelines that are robust to individual method limitations.

cancer biology↗