Biology subjects

Scott, H.

Publications and source records attributed to Scott, H..

16 recordsLinked to original sources

bioRxiv2026

In vitro pathogenicity evaluation of deep intronic variants for recessive genetic retinal diseases

Non-coding variants altering mRNA splicing are increasingly recognized as important cause of Mendelian disorders. Deep intronic variants (DIV) that activate cryptic exons (CEs) cause ~20% inherited retinal diseases (IRD) cases, yet it remains challenging to predict intronic variant pathogenicity accurately, thus we used a high throughput splicing assay (HTSA) to measure the effects of rare deep intronic variants in recessive IRDs with one confirmed pathogenic variant. 640 very rare deep intronic variants were chosen in trans-position with known mutation from 76 patients. We tested them with HTSA, which consists of a split-GFP minigene, separated by an SMN1 gene intron into which the 270bp sequences flanking the DIVs were cloned. The plasmid library was transfected into 293HEK cells, and 48 hours later total RNA was extracted from the transfected cells. RNA transcripts produced by HTSA minigene were amplified by RT-PCR and sequenced. The intron sequences spliced between the two GFP exons were identified and quantified. 98 variants activated CE >100 times more in altered oligo compared to reference oligo and were classified as pathogenic in this experimental setting, validated in longer context, 26 variants were classified as VUS. Interestingly, only 6 from 90 variants (6,6%) were predicted to be pathogenic by in silico algorithms (Splice AI) which leaves room for significant improvement of prediction algorithms. The results of this experiment confirmed diagnosis for 50 of 78 patients (64%). So, 19,4% of deep intronic variants were shown to cause CE activation. This can lead to conclusion that significant portion of undiagnosed patients with recessive IRDs carry pathogenic intronic mutation which causes the disease.

genetics↗

bioRxiv2026

Organizing principles in the Nitrogen-Carbon Landscape of Marine Heterotrophic Bacteria

Marine microbes metabolize a wide range of carbon and nitrogen sources, shaping global biogeochemical cycles. Despite being crucial at the global scale, the coupling between carbon and nitrogen remains poorly understood at the level of individual metabolites and bacteria. By phenotyping a library of marine heterotrophic bacteria across increasingly complex carbon and nitrogen sources, we generated a snapshot of this coupling. Growth phenotypes were weakly explained by phylogeny, but could be organized around substrate properties, including C:N stoichiometry and degree of reduction. Beyond explainable average trends along these axes, different strains displayed significant variability. For some bacteria, nitrogen use efficiency was associated with ammonium secretion, consistent with their role in ecological interactions. Furthermore, nonlinearities emerged in how yields depend on combinations of resources, such as mixtures of amino acids and dipeptides. These organizing principles may help understand the ecological role of marine heterotrophic bacteria and parametrize models of biogeochemical cycles.

systems biology↗

bioRxiv2026

Time-dependent Glucocorticoid-Induced Transcriptomic Changes in Human Trabecular Meshwork and Schlemm's Canal

PurposeTo identify the transcriptomic changes induced by dexamethasone (DEX) in trabecular meshwork (TM) and Schlemms canal endothelial (SCE) cells with RNA-sequencing (RNA-seq). MethodsHuman TM (n=10) and SCE cell strains (n=5) were isolated from healthy donor eyes and exposed to DEX 100nM and vehicle (control). Three DEX exposure times were evaluated: 1-hour, 6-hours, and 2 days. RNA-seq was performed on Illuminas TruSeq platform and gene expression was quantified using featureCount. DESeq2 paired (treated and untreated) sample test was applied to identify genes transcriptionally responsive to DEX (DEGs) at false discovery rate <0.05. Gene-set enrichment analyses were performed on DEGs. DEGs were tested for association with glaucoma (POAG) and intraocular pressure (IOP). ResultsNine TM and 4 SCE strains passed quality control. After 2-day DEX exposure, there were 857 and 2,086 DEGs in TM and SCE, respectively. Of these, 411 genes were differentially expressed in both TM and SCE, including FKBP5 (17.3-fold-change, p=6.9x10-53) and FAM107A (25.1-fold-change, p=4.0x10-240), the most significant DEG after 2-day DEX exposure in TM and SCE, respectively. The 2-day DEX DEGs in TM and SCE were enriched in cell adhesion, extracellular matrix, and response to stimulus in Gene Ontologies (p<3.7x10-6). Early response DEGs were enriched in immune-related processes. Thirteen DEGs in TM were significant at all three time points, including PER1. LTBP2 is a TM-only DEG and FAM105A a SCE-only DEG associated with IOP and POAG risk. ConclusionsThis study identified candidate genes and pathways for glucocorticoid-induced ocular hypertension which can be further explored in human genetic analyses.

genomics↗

bioRxiv2025

Identifying Phage Host Receptors Using TraDIS

The growing antimicrobial resistance crisis has sparked renewed interest in using bacteriophage (phage) as a treatment for antibiotic-resistant infections. Phage are viruses that infect and often kill bacteria, and have served as key models for many molecular biology studies. There are many complex phage-bacterial interactions that dictate the success or failure of the phage life cycle, but many of these are not well understood or characterised. These include the specific interactions to recognize a bacterium during the infection process, bacterial phage defence mechanisms and metabolic pathways that are key to phage replication. In this study a novel Escherichia coli phage, Arnold, is characterised and the genome sequence is reported. We then use transposon-directed insertion sequencing (TraDIS) to screen a library of E. coli mutants to identify over 200 genes involved in Arnold phage infection or in phage resistance. Using this approach, we identified both an outer membrane protein (BtuB, vitamin B12 transporter) and an inner membrane protein (SdaC, serine/proton symporter) involved in phage infection. Deletions in these genes were shown to provide immunity to infection by this phage. Understanding the genetic basis of phage infection and phage resistance should allow us to select or design phage to target specific bacterial pathogens in the future.

microbiology↗

bioRxiv2025

Biological insights and methodological challenges learned from working with a diverse heterotrophic marine bacterial library

BackgroundOrganized collections of bacterial strains can help bridge the gap between studying model organisms and communities, through comparative experiments between genetically and phenotypically diverse strains. We describe the establishment and initial characterization of a library of 62 marine heterotrophic bacteria, selected to represent a significant fraction of the genome-encoded functional diversity and a wide range of known phytoplankton-bacteria interactions. We focus on important but often undiscussed aspects of collecting and maintaining such a library, verifying strain identity, and applying classical microbiological methods across diverse strains. ResultsCultured strains contain up to hundreds of mutations compared with the reference genomes, with non-synonymous mutations in rpoB and/or rpoC genes observed in [~]15% of the cultures. Most strains grow well at 25{degrees}C, but the dependence of growth rate on temperature and the width of the temperature niche vary between strains in a systematic manner. We describe steps towards designing a universal, defined, minimal media for marine bacteria, revealing that growth inhibition on amino acids and peptides by carbohydrates is widespread. Cell counts obtained from flow cytometry and colony plating differ systematically, as do different methods to assess motility. Finally, we discuss traits potentially related to microbial interactions such as hemolysis, biofilm formation, and antibiotic resistance. Gammaproteobacteria such as Alteromonas, Pseudoalteromonas, and Vibrio reveal consistently robust growth, and activity, perhaps explaining why these clades are well-explored. ConclusionExplicitly discussing the insights and challenges of working with strain libraries will pave the way to robust, reproducible, and generalizable mapping of bacterial traits across diversity.

microbiology↗

bioRxiv2025

Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimers disease brain

The mechanism(s) whereby redox stress mediates aberrant immune signaling in age-related neurological disorders remains largely unknown. Normally, the innate immune system mounts a robust response to infectious stimuli. However, unintentional activation by host-derived factors, such as aggregated proteins associated with neurodegenerative disorders or by cytoplasmic genomic or mitochondrial DNA, can elicit aberrant immune responses. One such immune response is represented by the cytosolic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Using redox chemical biology and mass spectrometry approaches, we identified S-nitrosylation of STING cysteine 148 as a novel posttranslational redox modification underlying aberrant type 1 interferon signaling in Alzheimers disease (AD). Critically, we observed S-nitrosylated STING (SNO-STING) in postmortem human AD brains, in hiPSC-derived microglia (hiMG) exposed to amyloid-{beta} (A{beta})/-synuclein (Syn) aggregates, and in 5xFAD transgenic mice. Mechanistically, our findings reveal that STING S-nitrosylation is critical in initiating signaling cascades by promoting the formation of disulfide-bonded STING oligomers. This leads to neuroinflammation early in the course of disease in vivo in 5xFAD mice with consequent synaptic loss. Collectively, our research supports the role of SNO-STING in neuroinflammation associated with AD, and points to a novel druggable cysteine residue in STING to prevent this S-nitrosylation reaction with its inherent inflammatory response. One Sentence SummaryS-Nitrosylation of STING triggers activation of cGAS-STING signaling in Alzheimers disease brain and subserves a novel link between excessive nitrosative stress and dysregulated innate immunity, thus contributing to disease progression.

neuroscience↗

bioRxiv2025

APOE-ϵ4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer's disease

Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimers disease (AD), particularly in individuals carrying the APOE-{varepsilon}4 allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (A{beta}42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in APOE-{varepsilon}4 carriers. Furthermore, we found a loss-of-function variant in the fibronectin 1 (FN1) gene significantly reduces aggregated fibronectin levels and decreases AD risk among APOE-{varepsilon}4 carriers. Yet, the molecular mechanisms downstream of fibronectin at the BBB remain unclear. The extracellular matrix (ECM) plays a crucial role in maintaining BBB homeostasis and orchestrating the interactions between BBB cell types, including endothelia and astrocytes. Understanding the mechanisms affecting the ECM and BBB cell types will be critical for developing effective therapies against AD, especially among APOE-{varepsilon}4 carriers. Here, we demonstrate that APOE-{varepsilon}4, A{beta}42, and inflammation drive the induction of FN1 expression in several models including zebrafish, mice, iPSC-derived human 3D astrocyte and 3D cerebrovascular cell cultures, and in human brains. Fibronectin accumulation disrupts astroglial-endothelial interactions and the signalling cascade between vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor (HBEGF) and Insulin-like growth factor 1 (IGF1). This accumulation of fibronectin in APOE-{varepsilon}4- associated AD potentiates BBB dysfunction, which strongly implicates reducing fibronectin deposition as a potential therapeutic target for AD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/634732v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@1efff03org.highwire.dtl.DTLVardef@14f40cdorg.highwire.dtl.DTLVardef@27743aorg.highwire.dtl.DTLVardef@3fa9a9_HPS_FORMAT_FIGEXP M_FIG C_FIG Accessibility textThis image illustrates the effects of different APOE isoforms (ApoE-{varepsilon}3 and ApoE-{varepsilon}4) on blood-brain barrier (BBB) integrity, focusing on the molecular interactions between astrocytes and endothelial cells. This figure emphasizes the detrimental effects of ApoE-{varepsilon}4 on BBB integrity via fibronectin accumulation and altered signaling pathways. The top section provides a schematic overview of the blood-brain barrier, highlighting astrocytes, endothelial cells, and their interface. The left panel represents the ApoE-{varepsilon}3 condition: Normal fibronectin (FN1) levels support healthy interactions between astrocytes and endothelial cells. Growth factors, including VEGFA, HBEGF, and IGF1, maintain BBB integrity through their respective receptors (VEGFR and EGFR). Green arrows indicate activation of these signaling pathways. The right panel depicts the ApoE-{varepsilon}4 condition: Elevated fibronectin (FN1) disrupts astrocyte-endothelium interactions. FN1 binds integrins and activates focal adhesion kinase (FAK), inhibiting VEGFA, which is required for endothelial HBEGF that in turn activates IGF1 signaling. Red symbols indicate inhibition of HBEGF, VEGFA, and IGF1 pathways, leading to BBB dysfunction. HighlightsAPOE-{varepsilon}4 drives fibronectin deposition in Alzheimers, disrupting astrocyte-endothelia interactions. APOE-{varepsilon}4 and fibronectin co-localize, forming aggregates at blood-brain barrier (BBB). Fibronectin alters the signaling between VEGF, IGF1, and HBEGF impairing BBB function. Reducing fibronectin restores BBB integrity and offsets APOE-{varepsilon}4 pathology.

cell biology↗

bioRxiv2024

Rare genetic variation in Fibronectin 1 (FN1) protects against APOEe4 in Alzheimer's disease

The risk of developing Alzheimers disease (AD) significantly increases in individuals carrying the APOE{varepsilon}4 allele. Elderly cognitively healthy individuals with APOE{varepsilon}4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOE{varepsilon}4; however, these mechanisms are unknown. We hypothesized that APOE{varepsilon}4 carriers without dementia might carry genetic variations that could protect them from developing APOE{varepsilon}4-mediated AD pathology. To test this, we leveraged whole genome sequencing (WGS) data in National Institute on Aging Alzheimers Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOE{varepsilon}4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. The FN1 and COL6A2 protein levels were increased at the BBB in APOE{varepsilon}4 carriers with AD. Brain expression of cognitively unaffected homozygous APOE{varepsilon}4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOE{varepsilon}4 carriers with AD, suggesting that FN1 might be a downstream driver of APOE{varepsilon}4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b - the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests vascular deposition of FN1 is related to the pathogenicity of APOE{varepsilon}4, LOF variants in FN1 may reduce APOE{varepsilon}4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

genetics↗

bioRxiv2023

S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity

CREB-regulated transcription coactivator 1 (CRTC1) plays an important role in synaptic plasticity, learning and long-term memory formation through regulation of neuronal activity-dependent gene expression, and CRTC1 dysregulation is implicated in Alzheimers disease (AD). Here, we show that increased S-nitrosylation of CRTC1 (forming SNO-CRTC1), as seen in cell-based, animal-based, and human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neuron-based AD models, disrupts its binding with CREB and diminishes the activity-dependent gene expression mediated by the CRTC1/CREB pathway. We identified Cys216 of CRTC1 as the primary target of S-nitrosylation by nitric oxide (NO)-related species. Using CRISPR/Cas9 techniques, we mutated Cys216 to Ala in hiPSC-derived cerebrocortical neurons bearing one allele of the APPSwe mutation (AD-hiPSC neurons). Introduction of this non-nitrosylatable CRTC1 construct rescued defects in AD-hiPSC neurons, including decreased neurite length and increased neuronal cell death. Additionally, expression of non-nitrosylatable CRTC1 in vivo in the hippocampus rescued synaptic plasticity in the form of long-term potentiation (LTP) in 5XFAD mice. Taken together, these results demonstrate that formation of SNO-CRTC1 contributes to the pathogenesis of AD by attenuating the neuronal activity-dependent CREB transcriptional pathway, and suggests a novel therapeutic target for AD.

neuroscience↗

bioRxiv2022

Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila

Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/486211v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@15b8de3org.highwire.dtl.DTLVardef@1c037e8org.highwire.dtl.DTLVardef@9674bborg.highwire.dtl.DTLVardef@1c9c010_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Task Demands Change Motion Information Coding in Area MT of the Macaque

Neurons in the primate Middle Temporal (MT) area signal information about visual motion and work together with the lateral prefrontal cortex (LPFC) to support memory-guided comparisons of visual motion direction. These areas are reciprocally connected, and both contain neurons that signal visual motion direction in the strength of their responses. Previously, LPFC was shown to display marked changes in stimulus coding with altered task demands, including changes in selectivity for motion direction, trial-to-trial variability in responses, and comparison effects. Since MT and LPFC are directly interconnected, we sought to determine if MT neurons display similar dependence on task demands. We found that active participation in a motion direction comparison task affected both sensory and non-sensory activity in MT neurons. In fact, neurons that became less-selective for motion direction during the active task showed increased signalling for cognitive aspects of the task. This heterogeneity in neural modification with heightened task demands suggests a division of labor in MT, whereby sensory and cognitive signals are both heightened in different subpopulations of neurons.

neuroscience↗

bioRxiv2020

Evolution of the Analytical Scattering Model of Live Escherichia Coli

We have revised a previously reported multi-scale model for (ultra) small angle X-ray (USAXS/SAXS) and (very) small angle neutron scattering (VSANS/SANS) of live Escherichia coli based on compositional/metabolomic and ultrastructural constraints. The cellular body is modelled, as previously described, by an ellipsoid with multiple shells. However, scattering originating from flagella was substituted by a term accounting for the oligosaccharide cores of the lipopolysaccharide leaflet of the outer membrane including its cross-term with the cellular body. This was mainly motivated by (U)SAXS experiments showing indistinguishable scattering for bacteria in the presence and absence of flagella or fimbrae. The revised model succeeded in fitting USAXS/SAXS and differently contrasted VSANS/SANS data of E. coli ATCC 25922 over four orders of magnitude in length scale, providing specifically detailed insight into structural features of the cellular envelope, including the distance of the inner and outer membranes, as well as the scattering length densities of all bacterial compartments. Consecutively, the model was also successfully applied to E. coli K12, used for our original modelling, as well as for two other E. coli strains, detecting significant differences between the different strains in terms of bacterial size, intermembrane distance and its positional fluctuations. These findings corroborate the general applicability of our approach to quantitatively study the effect of bactericidal compounds on ultrastructural features of Gram-negative bacteria without the need to resort to any invasive staining or labelling agents.

biophysics↗

bioRxiv2020

Structure of a dominant negative mutant reveals a stalled intermediate in anthrax protective antigen pore maturation

Anthrax is a severe bacterial infection caused by Bacillus anthracis, which produces a tripartite toxin that includes protective antigen (PA), lethal factor (LF) and edema factor (EF). A series of dominant-negative mutations have been previously identified that prevent the heptameric PA prepore from forming the pH-induced, membrane spanning beta-barrel pore that is required for translocation of EF and LF to the cytoplasm of the infected cell. Here we show that the dominant negative D425A mutation stalls the formation of the pore at a reversible intermediate maturation state, which exhibits many of the structural aspects of the pore but fails to form the phi({phi})-clamp and beta-barrel structure needed for full pore maturation. Overall, this structure reveals that {phi}-clamp and beta-barrel pore formation are later steps in the pathway to pore formation, thereby providing a regulatory mechanism to prevent premature translocation of EF and LF.

biophysics↗

bioRxiv2019

Independence of HIF1a and androgen signaling pathways in prostate cancer

Androgen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

cancer biology↗

bioRxiv2019

Productive lifespan and resilience rank can be predicted from on-farm first parity sensor data but not using a common equation across farms

A dairy cows lifetime resilience and her ability to re-calve gain importance on dairy farms as they affect all aspects of the sustainability of the dairy industry. Many modern farms today have milk meters and activity sensors that accurately measure yield and activity at a high frequency for monitoring purposes. We hypothesized that these same sensors can be used for precision phenotyping of complex traits such as lifetime resilience or productive lifespan. The objective of this study was to investigate if lifetime resilience and productive lifespan of dairy cows can be predicted using sensor-derived proxies of first parity sensor data. We used a data set from 27 Belgian and British dairy farms with an automated milking system containing at least 5 years of successive measurements. All of these farms had milk meter data available, and 13 of these farms were also equipped with activity sensors. This subset was used to investigate the added value of activity meters to improve the models prediction accuracy. To rank cows for lifetime resilience, a score was attributed to each cow based on her number of calvings, her 305-day milk yield, her age at first calving, her calving intervals and the days in milk at the moment of culling, taking her entire lifetime into account. Next, this lifetime resilience score was used to rank the cows within their herd resulting in a lifetime resilience ranking. Based on this ranking, the cows were classified in a low (last third), moderate (middle third) or high (first third) resilience category. In total 45 biologically-sound sensor features were defined from the time-series data, including measures of variability, lactation curve shape, milk yield perturbations, activity spikes indicating estrous events and activity dynamics representing health events. These features, calculated on first lactation data, were used to predict the lifetime resilience rank and thus, the classification within the herd (low/moderate/high). Using a specific linear regression model progressively including features stepwise selected at farm level (cut-off P-value of 0.2), classification performances were between 35.9% and 70.0% (46.7 {+/-} 8.0, mean {+/-} standard deviation) for milk yield features only and between 46.7% and 84.0% (55.5 {+/-} 12.1, mean {+/-} standard deviation) for lactation and activity features together. This is respectively 13.7 and 22.2% higher than what random classification would give. Moreover, using these individual farm models, only 3.5% and 2.3% of the cows were classified high while being low and vice versa, while respectively 91.8% and 94.1% of the wrongly classified animals were predicted in an adjacent category. A common equation across farms to predict this rank could not be found, which demonstrates the variability in culling and management strategies across farms and within farms over time. The lack of a common model structure across farms suggests the need to consider local (and evidence based) culling management rules when developing decision support tools for dairy farms. With this study we showed the potential of precision phenotyping of complex traits based on biologically meaningful features derived from readily available sensor data. We conclude that first lactation milk and activity sensor data have the potential to predict cows lifetime resilience rankings within farms but that consistency over farms is currently lacking.

bioengineering↗

bioRxiv2019

Maternal antioxidant treatment prevents behavioural and neural changes in offspring exposed to prenatal social stress

Maternal exposure to social stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. However, the mechanism through which the effects of maternal stress are transmitted to the foetus is unclear. Using a rat model, we explored the mechanisms by which maternal social stress is conveyed to the foetus and the potential for targeted treatment to prevent disease in the offspring. Maternal stress increased circulating corticosterone in the mother, but not the foetuses. Maternal stress also induced oxidative stress in the placenta, but not in the foetal brain, and this was prevented by administration of a nanoparticle-bound antioxidant. Moreover, antioxidant treatment prevented prenatal stress-induced anxiety-like behaviour in the adult male offspring, along with several stress-induced neuroanatomical, neurochemical and gene expression changes in the offspring brain. Importantly, many of these neural effects were mimicked in neuronal cultures by application of placental-conditioned medium or foetal plasma from stressed pregnancies. Both placental-conditioned medium and foetal plasma contained differentially abundant extracellular microRNAs following prenatal stress. The present study highlights the crucial role of the placenta, and the molecules it secretes, in foetal brain development and provides evidence of the potential for treatment that can prevent maternal stress-induced foetal programming of neurological disease.

neuroscience↗