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Peer reviewed: True, There is growing evidence that poor paternal diet at the time of conception increase the risk of offspring developing a range of non-communicable metabolic diseases, such as obesity, diabetes and cardiovascular disease, in adulthood. We hypothesise that a paternal low protein-high carbohydrate diet perturbs offspring tissue lipid abundance through both sperm and seminal plasma-mediated mechanisms. To test our hypothesis, we fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 8 weeks. We generated offspring through artificial insemination, in combination with vasectomised male mating. Using this approach, we derived offspring from either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Using high resolution mass-spectrometry, we found that offspring derived from either LPD sperm or seminal fluid displayed perturbed cardiac and brain lipid abundance from just three weeks of age, typically associated with the altered abundance of tissue triglycerides. We also observed the differential sex-specific patterns of lipids between the control and experimental offspring's hearts and brains. These observations indicate that poor paternal diet at the time of conception affects offspring cardiac and brain lipid profiles in an age-, sex- and generation-specific manner.

My PhD pilots a new method of vaccine safety surveillance. I do this by linking de-identified data from the Australian Immunisation Register and healthcare records to analyse people's interactions with the healthcare system after their vaccination. The data gathered through this analysis helps to guide education materials and policy to ensure that vaccines are safe for everyone. This video summary was created as part of the 2023 Visualise Your Thesis Competition. TRANSCRIPT Vaccines are one of our greatest public health achievements and save about five million lives every year around the world. Vaccines are tested before the public is allowed to get them to make sure they work and are safe. But these tests may not pick up the rarest side effects. This is why it is important for scientists to keep studying vaccines after they are given to the wider community in larger numbers. Most of the time we find out about vaccine side effects when people tell us. But we know this is just the tip of the iceberg, there are some side effects we don’t hear about. So we are making a new tool find them. We do this by anonymously linking vaccination data to data about people’s visits to their doctor or the hospital. Now we can investigate people’s vaccine experiences across the whole of Victoria! Armed with the information we can calm nerves or change policy so that vaccines are safe for everyone and continue to protect us against nasty diseases.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability world-wide, affecting approximately 69 million individuals each year. It is also recognised as one of the major, modifiable risk factors in the development of neurodegenerative disease in later life, with exposure to moderate to severe single TBI and repetitive, mild TBI both recognised as contributing factors in the development of dementia. However, the neuropathological mechanisms contributing to late neurodegeneration remain uncertain. The complex polypathology emerging from the initial biomechanical injury mirror other neurodegenerative disease and include abnormal aggregation of proteins such as tau and Aβ and neuroinflammation, which will be explored in this thesis. Methodology: Utilising material from the Glasgow TBI archive, in cohorts of patients aged ≤60 exposed to acute and long-term survival following moderate to severe, single TBI and appropriately age-matched controls, the role of the cellular adaptive immune response to injury was assessed through immunocytochemistry for T- and B-lymphocyte populations. These cohorts as well as tissue from patients exposed to repetitive mild TBI (rTBI) and appropriately matched controls were studied to characterise the differential astroglial response to injury across injury subgroups through measurement of GFAP, AQP4 and NQO1 immunoreactivity. A cohort of patients aged ≥60 years who survived acutely following moderate to severe, single TBI compared to age-matched, uninjured controls with no history of neurodegenerative disease, were examined to evaluate the effect of age and TBI using modifications of clinically recognised, standardised, semi-quantitative scoring systems of tau and Aβ immunoreactivity. Lastly, a protocol for the assessment of our archival, FFPE tissue was devised to allow comparison of proteomes of cohorts of patients exposed to mild rTBI, AD patients and appropriately matched controls, using liquid-chromatography mass-spectrometry. Results: There is no histological evidence of a significant cellular response from the adaptive immune system following exposure to moderate to severe, single TBI in patients surviving acutely or long-term after injury, with no increase in T- or B-lymphocytes. There was, unexpectedly, a decrease in T-lymphocytes in long-term survivors of TBI. Contrastingly, there was an increase in reactive astrogliosis following exposure to TBI; demonstrated by an increase in AQP4-immunoractive astrocytes in acutely surviving patients and increase in GFAP expression in long-term surviving patients and an increase in NQO1 expression in rTBI patients compared to age-matched uninjured controls. There was also an increase in both AQP4 and GFAP expression in elderly uninjured controls compared to younger uninjured controls. Examining the expression of Aβ and tau in elderly patients exposed to single, moderate to severe TBI showed an increase in neuritic Aβ plaque and in the regional distribution of all plaque compared to uninjured, elderly controls, but no increase in expression or distribution of NFTs. Finally, a protocol for processing archival FFPE resulted in identification of 267 proteins from across rTBI, AD and uninjured, non-NND controls with significantly differential expression in 84 of them. Conclusions: Together, these findings increase understanding of the neuropathological changes occurring following moderate to severe, single TBI and repetitive TBI. These data demonstrate that there is an astrogliotic but not adaptive cellular response after moderate to severe single TBI whilst also showing that age is correlated with an increase in reactive astrogliosis for several markers. Age was also examined in the examination of proteinopathic changes following acute survival after moderate to severe injury and changes suggest that TBI may occur as a result of increased amyloid pathology as neuritic plaque was observed > 2 weeks after injury. Lastly, that archival FFPE samples were successfully processed to allow identification of proteins from across a range of cohorts, revealing differences in protein expression that underpin the neuropathological changes which contribute to the long-term, post-TBI neurodegenerative process.

ASCENTS 1-2-1 Support for Science (hereafter ‘ASCENTS’) trains Science, Technology, Engineering, and Mathematics (STEM) undergraduates to provide one-to-one Science support to disadvantaged Year 11 pupils in local schools ahead of their GCSE examinations. STEM undergraduates from seven different universities will be trained to deliver mentoring sessions. The programme will run in approximately 55 schools from September 2023 to May 2024. ASCENTS has been delivered and evaluated previously. A pilot evaluation was undertaken in 2016/2017, which generated statistically significant improvements in GCSE Science results amongst Year 11 pupils eligible for Pupil Premium (Sharpe et al., 2018). Given the pilot’s promising findings, the Education Endowment Foundation (EEF) and the Wellcome Trust commissioned an efficacy trial to assess the impact of ASCENTS on a larger scale in 2019/2020 (see previous trial registered here: https://doi.org/10.1186/ISRCTN28630907). While most of the programme was delivered, the previous efficacy trial was disrupted due to the Covid-19 pandemic and associated closures of both schools and universities. Specifically, it was not possible to complete the impact assessment as planned owing to the cancellation of GCSE exams in summer 2020. However, the implementation and process evaluation (IPE) continued (though some in-person activities were cancelled) and found that the programme was delivered largely as intended and identified perceived benefits for mentees, mentors and teachers (Scandone et al., 2021). As the previous trial was unable to ascertain the impact of ASCENTS on GCSE Science outcomes, the EEF has commissioned the current ASCENTS efficacy trial to test its impact on pupil attainment. The study has three components: an impact evaluation, an implementation and process (IPE) evaluation, and a mentor follow-up study. The impact evaluation will employ a multi-site individual-level randomised control trial (RCT) design.

Attention is complex and involves multiple processes that work together to perform tasks successfully. Electroencephalography studies have provided evidence through correlation that neural oscillations in the gamma range are involved in attentional orienting processes that are important for successful behavioral performance while theta frequency range is thought to index executive control. By using gamma (60 Hz) and theta (6 Hz) transcranial alternating current stimulation at right lateral frontal sites, the present study aims to provide a causal link between the two frequencies and attention processes involved in task performance during a lateralized attention network test. Stimulation at 60 Hz stimulation was shown to impair performance during incongruent stimuli and also reduced performance generally in the ipsilateral hemifield. Conversely, theta stimulation did not significantly modulate performance. These findings provide new evidence that right frontal gamma affects attentional control processes, in a manner consistent with biased competition between the hemispheres.

IntroductionPaternal low-protein diet can alter sperm methylation status, fetal growth and program offspring ill-health, however its impact on the placenta remains poorly defined. Here we examine the influence paternal low-protein diet has on fetal and placental development and the additional impact of supplementary methyl-donors on fetoplacental physiology.MethodsMale C57BL/6J mice were fed a control normal protein diet (NPD; 18% protein), a low-protein diet (LPD; 9% protein) or LPD with methyl-donor supplementation (MD-LPD; choline chloride, betaine, methionine, folic acid, vitamin B12) for a minimum of 8 weeks. Males were mated with 8–11 week old female C57BL/6J mice and fetal and placental tissue collected on embryonic day 17.5.ResultsPaternal LPD was associated with increased fetal weights compared to NPD and MD-LPD with 22% fetuses being above the 90th centile for fetal weight. However, LPD and MD-LPD placental weights were reduced when compared to NPD. Placentas from LPD fathers demonstrated a reduced junctional zone area and reduced free-fatty acid content. MD-LPD placentas did not mirror these finding, demonstrating an increased chorion area, a reduction in junctional-specific glycogen staining and reduced placental Dnmt3b expression, none of which were apparent in either NPD or LPD placentas.DiscussionA sub-optimal paternal diet can influence fetal growth and placental development, and dietary methyl-donor supplementation alters placental morphology and gene expression differentially to that observed with LPD alone. Understanding how paternal diet and micro-nutrient supplementation influence placental development is crucial for determining connections between paternal well-being and future offspring health.

The Portable Extensible Toolkit for Scientific computation (PETSc) library delivers scalable solvers for nonlinear time-dependent differential and algebraic equations and for numerical optimization.The PETSc design for performance portability addresses fundamental GPU accelerator challenges and stresses flexibility and extensibility by separating the programming model used by the application from that used by the library, and it enables application developers to use their preferred programming model, such as Kokkos, RAJA, SYCL, HIP, CUDA, or OpenCL, on upcoming exascale systems. A blueprint for using GPUs from PETSc-based codes is provided, and case studies emphasize the flexibility and high performance achieved on current GPU-based systems., 15 pages, 10 figures, 2 tables

Assisted reproductive technologies such as artificial insemination have delivered significant benefits for farm animal reproduction. However, as with humans, assisted reproduction in livestock requires the manipulation of the gametes and preimplantation embryo. The significance of this ‘periconception’ period is that it represents the transition from parental genome regulation to that of the newly formed embryo. Environmental perturbations during these early developmental stages can result in persistent changes in embryonic gene expression, fetal organ development and ultimately the long-term health of the offspring. While associations between maternal health and offspring wellbeing are well-defined, the significance of paternal health for the quality of his semen and the post-conception development of his offspring have largely been overlooked. Human and animal model studies have identified sperm epigenetic status (DNA methylation levels, histone modifications and RNA profiles) and seminal plasma-mediated maternal uterine immunological, inflammatory and vascular responses as the two central mechanisms capable of linking paternal health and post-fertilisation development. However, there is a significant knowledge gap about the father’s contribution to the long-term health of his offspring, especially with regard to farm animals. Such insights are essential to ensure the safety of widely used assisted reproductive practices and to gain better understanding of the role of paternal health for the well-being of his offspring. In this article, we will outline the impact of male health on semen quality (both sperm and seminal plasma), reproductive fitness and post-fertilisation offspring development and explore the mechanisms underlying the paternal programming of offspring health in farm animals.

Although the impact of maternal diet on adult offspring health is well characterized, the role that a father's diet has on his offspring's health remains poorly defined. We establish the significance of a sup-optimal paternal low protein diet for offspring vascular homeostasis and define the sperm and seminal plasma specific programming effects on cardiovascular health. Male C57BL6 mice were fed either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 7 weeks. Using artificial insemination, in combination with vasectomized male mating, we generated offspring derived from either NPD or LPD sperm (devoid of seminal plasma) but in the presence of NPD or LPD seminal plasma (devoid of sperm). We observed that either LPD sperm or seminal fluid at conception impaired adult offspring vascular function in response to both vasoconstrictors and dilators. Underlying these changes in vascular function were significant changes in serum, lung and kidney angiotensin-converting enzyme (ACE) activity, established in F1 offspring from 3 weeks of age, maintained into adulthood and present also within juvenile F2 offspring. Furthermore, we observed differential expression of multiple central renin-angiotensin system regulators in adult offspring kidneys. Finally, paternal diet modified the expression profiles of central epigenetic regulators of DNA methylation, histone modifications and RNA methylation in adult F1 male testes. These novel data reveal the impact of sub-optimal paternal nutrition on offspring cardiovascular well-being, programming offspring cardiovascular function through both sperm and seminal plasma specific mechanisms over successive generations.

This study was concerned with exploring the meaning birth relatives gave their experiences of counselling following the removal of their children from their care. An exploratory research question was formulated and addressed using a qualitative approach. The involvement of a service user as expert supervisor added an important element and certain validity to the design, analysis and findings. Interviews took place with five birth mothers who had received counselling from one birth relatives counselling service. Three master themes were constructed from the data: From feeling alone, judged and let down to feeling part of a special relationship; “The healing process”; and “My children are my world”.

Fetal growth restriction (FGR) presents with an increased risk of stillbirth and childhood and adulthood morbidity. Melatonin, a neurohormone and antioxidant, has been suggested as having therapeutic benefit in FGR. We tested the hypothesis that melatonin would increase fetal growth in two mouse models of FGR which together represent a spectrum of the placental phenotypes in this complication: namely the endothelial nitric oxide synthase knockout mouse (eNOS-/-) which presents with abnormal uteroplacental blood flow, and the placental specific Igf2 knockout mouse (P0+/-) which demonstrates aberrant placental morphology akin to human FGR. Melatonin (5 μg/ml) was administered via drinking water from embryonic day (E)12.5 in C57Bl/6J wild-type (WT), eNOS-/-, and P0+/- mice. Melatonin supplementation significantly increased fetal weight in WT, but not eNOS-/- or P0+/- mice at E18.5. Melatonin did however significantly increase abdominal circumference in P0+/- mice. Melatonin had no effect on placental weight in any group. Uterine arteries from eNOS-/- mouse demonstrated aberrant function compared with WT but melatonin treatment did not affect uterine artery vascular reactivity in either of these genotypes. Umbilical arteries from melatonin treated P0+/- mice demonstrated increased relaxation in response to the nitric oxide donor SNP compared with control. The increased fetal weight in WT mice and abdominal circumference in P0+/- , together with the lack of any effect in eNOS-/-, suggest that the presence of eNOS is required for the growth promoting effects of melatonin. This study supports further work on the possibility of melatonin as a treatment for FGR.

The 13 publications included in this thesis constitute a body of work situated within the interdisciplinary field of disability studies. As such, they are formed in the wake of the social model of disability, a radical, field-forming idea that dominates the disabled people’s movement, disability policy and practice and disability studies in the UK. The works are clustered around two interlinked areas of concern: how disability studies is practiced and influences professional and welfare practices, and how disability policy formation emerges, shapes and impacts upon the lives and wellbeing of disabled people. The unifying argument is that disability scholarship should be aligned to the communities it produces knowledge for and about. It argues that disability studies and the practices which emerge from it should remain rooted in the social model and in the disabled people’s movement.

Hypertensive disorders of pregnancy are an increasingly common disorder in modern society. The increasing prevalence of women with pre-eclampsia superimposed on a background of chronic hypertension is a significant burden in modern society and is profoundly detrimental to both mother and child; during pregnancy and beyond. Little is understood about the development of these multifactorial hypertensive disorders, however there is increasing evidence that the manifestation of hypertensive disorders during pregnancy is not solely due to placental-derived dysfunctions and has important maternally-driven components. The stroke-prone spontaneously hypertensive (SHRSP) rat is a well-established model of human essential hypertension. SHRSP dams remain hypertensive throughout pregnancy and demonstrate an abnormal uterine artery structure and function at term. This project aimed to more fully characterise pregnancy in the SHRSP rat. The objectives were to assess maternal responses and determine how maternal hypertension impacts maternal and fetal well-being as well as placental development; to investigate the underlying genetic mechanisms behind the eventual abnormal pregnancy-dependent uterine artery remodelling; and, finally, to increase the maternal cardiovascular load in SHRSP pregnancy to establish a model of superimposed pre-eclampsia. In vivo and ex vivo techniques were used to characterise cardiovascular function in the hypertensive SHRSP and normotensive WKY rats during gestation, as well as assess pregnancy outcomes. The SHRSP dams were found to have similar cardiac function compared to WKY, yet there was evidence of impaired systemic vascular structure and function in late gestation and placental abnormalities. Nevertheless, the SHRSP maintained similar litter sizes to WKY and did not demonstrate any major impact on fetal growth. Further similarities between SHRSP and WKY pregnancy were revealed with the assessment of uterine artery function in early gestation. However, using RNA sequencing to elucidate the transcriptomic profiles of the uterine arteries, SHRSP were found to have strikingly different responses to pregnancy at the transcript expression level, compared to WKY. Finally, a model of superimposed pre-eclampsia was established by increasing the cardiovascular stress in the dam using angiotensin II infusion during pregnancy in SHRSP. This model had a significantly higher systolic and diastolic blood pressure than the already hypertensive SHRSP. The pregnancy-dependent increase in cardiac output, observed in SHRSP, was negated by AngII infusion and was reduced in the highest treatment group. These major cardiovascular impairments were observed alongside increased proteinuria and reduced fetal growth; all phenotypes found in severely pre-eclamptic women. This work has provided information on systemic and uterine specific vascular responses to pregnancy in SHRSP and WKY rats alongside detail of underlying transcriptional differences. This study was the first to examine uterine artery gene expression changes during pregnancy. The different transcriptomic profiles of early pregnancy changes in the two strains make this an intriguing model to study maternal-driven vascular remodelling in hypertensive pregnancy. Furthermore, this work demonstrated that increasing the cardiovascular load during pregnancy in SHRSP successfully mimics superimposed pre-eclamptic phenotypes and could be used in the assessment of novel therapeutic strategies. To conclude, the SHRSP has the potential to aid our understanding of human pre-eclamptic conditions, especially when endeavouring to determine the impact of maternally-driven components of hypertensive disorders of pregnancy.

Pipelined Krylov methods seek to ameliorate the latency due to inner products necessary for projection by overlappingit with the computation associated with sparse matrix-vector multiplication. We clarify a folk theorem that this canonly result in a speedup of $2\times$ over the naive implementation. Examining many repeated runs, we show that stochasticnoise also contributes to the latency, and we model this using an analytical probability distribution. Our analysis showsthat speedups greater than $2\times$ are possible with these algorithms.

Pipelined Krylov methods seek to ameliorate the latency due to inner products necessary for projection by overlappingit with the computation associated with sparse matrix-vector multiplication. We clarify a folk theorem that this canonly result in a speedup of $2\times$ over the naive implementation. Examining many repeated runs, we show that stochasticnoise also contributes to the latency, and we model this using an analytical probability distribution. Our analysis showsthat speedups greater than $2\times$ are possible with these algorithms.

Women with chronic hypertension are at increased risk of maternal and fetal morbidity and mortality. We have previously characterized the stroke-prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery function and adverse pregnancy outcome compared with the control Wistar–Kyoto. The activation of the immune system plays a role in hypertension and adverse pregnancy outcome. Therefore, we investigated the role of tumor necrosis factor-[alpha] in the SHRSP phenotype in an intervention study using etanercept (0.8 mg/kg SC) at gestational days 0, 6, 12, and 18 in pregnant SHRSP compared with vehicle-treated controls (n=6). Etanercept treatment significantly lowered systolic blood pressure after gestational day 12 and increased litter size in SHRSP. At gestational day 18, etanercept improved the function of uterine arteries from pregnant SHRSP normalizing the contractile response and increasing endothelium-dependent relaxation, resulting in increased pregnancy-dependent diastolic blood flow in the uterine arteries. We identified that the source of excess tumor necrosis factor-[alpha] in the SHRSP was a pregnancy-dependent increase in peripheral and placental CD3– CD161+ natural killer cells. Etanercept treatment also had effects on placental CD161+ cells by reducing the expression of CD161 receptor, which was associated with a decrease in cytotoxic granzyme B expression. Etanercept treatment improves maternal blood pressure, pregnancy outcome, and uterine artery function in SHRSP by antagonizing signaling from excess tumor necrosis factor-[alpha] production and the reduction of granzyme B expression in CD161+ natural killer cells in SHRSP.

Proteins containing a methyl-CpG-binding domain (MBD) bind 5mC and convert the methylation pattern information into appropriate functional cellular states. The correct readout of epigenetic marks is of particular importance in the nervous system where abnormal expression or compromised MBD protein function, can lead to disease and developmental disorders. Recent evidence indicates that the genome of Drosophila melanogaster is methylated and two MBD proteins, dMBD2/3 and dMBD-R2, are present. Are Drosophila MBD proteins required for neuronal function, and as MBD-containing proteins have diverged and evolved, does the MBD domain retain the molecular properties required for conserved cellular function across species? To address these questions, we expressed the human MBD-containing protein, hMeCP2, in distinct amine neurons and quantified functional changes in sleep circuitry output using a high throughput assay in Drosophila. hMeCP2 expression resulted in phase-specific sleep loss and sleep fragmentation with the hMeCP2-mediated sleep deficits requiring an intact MBD domain. Reducing endogenous dMBD2/3 and dMBD-R2 levels also generated sleep fragmentation, with an increase in sleep occurring upon dMBD-R2 reduction. To examine if hMeCP2 and dMBD-R2 are targeting common neuronal functions, we reduced dMBD-R2 levels in combination with hMeCP2 expression and observed a complete rescue of sleep deficits. Furthermore, chromosomal binding experiments indicate MBD-R2 and MeCP2 associate on shared genomic loci. Our results provide the first demonstration that Drosophila MBD-containing family members are required for neuronal function and suggest that the MBD domain retains considerable functional conservation at the whole organism level across species.

Supplemental Digital Content is available in the text., Women with chronic hypertension are at increased risk of maternal and fetal morbidity and mortality. We have previously characterized the stroke-prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery function and adverse pregnancy outcome compared with the control Wistar–Kyoto. The activation of the immune system plays a role in hypertension and adverse pregnancy outcome. Therefore, we investigated the role of tumor necrosis factor-α in the SHRSP phenotype in an intervention study using etanercept (0.8 mg/kg SC) at gestational days 0, 6, 12, and 18 in pregnant SHRSP compared with vehicle-treated controls (n=6). Etanercept treatment significantly lowered systolic blood pressure after gestational day 12 and increased litter size in SHRSP. At gestational day 18, etanercept improved the function of uterine arteries from pregnant SHRSP normalizing the contractile response and increasing endothelium-dependent relaxation, resulting in increased pregnancy-dependent diastolic blood flow in the uterine arteries. We identified that the source of excess tumor necrosis factor-α in the SHRSP was a pregnancy-dependent increase in peripheral and placental CD3– CD161+ natural killer cells. Etanercept treatment also had effects on placental CD161+ cells by reducing the expression of CD161 receptor, which was associated with a decrease in cytotoxic granzyme B expression. Etanercept treatment improves maternal blood pressure, pregnancy outcome, and uterine artery function in SHRSP by antagonizing signaling from excess tumor necrosis factor-α production and the reduction of granzyme B expression in CD161+ natural killer cells in SHRSP.

The purpose of this note is to see to what extent ideal gas laws can be obtained from simple Newtonian mechanics, specifically elastic collisions. We present simple one-dimensional situations that seem to validate the laws. The first section describes a numerical simulation that demonstrates the second law of thermodynamics. The second section mathematically demonstrates the adiabatic law of expansion of ideal gases.

In this chapter we compare attitudes towards social inequality in Scotland with those in England, Denmark, Finland and Norway. If Scotland is more Nordic than liberal, then we would expect to see a divergence in social attitudes between Scotland and England, and a similarity between Scotland and the Nordic countries.