Female Mucopolysaccharidosis IIIA Mice Exhibit Hyperactivity and a Reduced Sense of Danger in the Open Field Test

Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders

Integrated Photonic Sensing

Loss is a critical roadblock to achieving photonic quantum-enhanced technologies. We explore a modular platform for implementing integrated photonics experiments and consider the effects of loss at different stages of these experiments, including state preparation, manipulation and measurement. We frame our discussion mainly in the context of quantum sensing and focus particularly on the use of loss-tolerant Holland-Burnett states for optical phase estimation. In particular, we discuss spontaneous four-wave mixing in standard birefringent fibre as a source of pure, heralded single photons and present methods of optimising such sources. We also outline a route to programmable circuits which allow the control of photonic interactions even in the presence of fabrication imperfections and describe a ratiometric characterisation method for beam splitters which allows the characterisation of complex circuits without the need for full process tomography. Finally, we present a framework for performing state tomography on heralded states using lossy measurement devices. This is motivated by a calculation of the effects of fabrication imperfections on precision measurement using Holland-Burnett states.Comment: 19 pages, 7 figure

Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice. © The American Society of Gene & Cell Therapy

QRISK3 improves detection of cardiovascular disease risk in patients with systemic lupus erythematosus

Objective 10-year cardiovascular disease (CVD) risk scores are calculated using algorithms, including Framingham (worldwide) and QRISK2 (UK). Recently, an updated QRISK3 model was introduced, which considers new variables including SLE and steroid prescription, not included in QRISK2 and Framingham algorithms. We sought to determine the extent to which QRISK3 improves identification of high-risk patients with SLE and whether the score relates to standard and novel markers of SLE-specific endothelial dysfunction. Methods Framingham and QRISK2/3 scores were calculated in patients with SLE (n=109) and healthy controls (n=29) using clinical measures. In a smaller cohort (n=58), markers of inflammation and endothelial dysfunction, including CD144+ endothelial microvesicles (EMVs), triglycerides, vascular cell adhesion molecule (VCAM) and high-sensitivity C reactive protein (hsCRP) were quantified by flow cytometry and ELISA, respectively. Results Patients with SLE demonstrated significantly higher QRISK3 scores than controls (5.0%vs0.3%, p<0.001). 21/109 patients with SLE (19%) and 24/109(22%) were newly identified as being at high risk of a CV event when using QRISK3 versus QRISK2 (29vs8patients) and QRISK3 versus Framingham (29vs5patients; p<0.001), respectively. These ‘new QRISK3’ patients with SLE were more likely to have lupus nephritis, be anticardiolipin antibody positive, currently prescribed corticosteroids, had a higher Body Mass Index and systolic blood pressure (BP) than low-risk patients with SLE. Rates of antiplatelet (8/21) and statin use (5/21) were low in the new QRISK3 group. EMVs, hsCRP and triglyceride levels were significantly higher in new QRISK3 patientscompared with low-risk patients with SLE (p<0.05). Furthermore, pulse wave velocity and VCAM were significantly elevated in all high versus low QRISK3 patients. Conclusions QRISK3 captures significantly more patients with SLE with an elevated 10-year risk of developing CVD, which is associated with measures of endothelial dysfunction; EMVs and systolic BP. The adoption of QRISK3 will enhance management of CVD risk in patients with SLE for improved outcome

Identification of the haemodynamic environment permissive for plaque erosion

Endothelial erosion of atherosclerotic plaques is the underlying cause of approximately 30% of acute coronary syndromes (ACS). As the vascular endothelium is profoundly affected by the haemodynamic environment to which it is exposed, we employed computational fluid dynamic (CFD) analysis of the luminal geometry from 17 patients with optical coherence tomography (OCT)-defined plaque erosion, to determine the flow environment permissive for plaque erosion. Our results demonstrate that 15 of the 17 cases analysed occurred on stenotic plaques with median 31% diameter stenosis (interquartile range 28–52%), where all but one of the adherent thrombi located proximal to, or within the region of maximum stenosis. Consequently, all flow metrics related to elevated flow were significantly increased (time averaged wall shear stress, maximum wall shear stress, time averaged wall shear stress gradient) with a reduction in relative residence time, compared to a non-diseased reference segment. We also identified two cases that did not exhibit an elevation of flow, but occurred in a region exposed to elevated oscillatory flow. Our study demonstrates that the majority of OCT-defined erosions occur where the endothelium is exposed to elevated flow, a haemodynamic environment known to evoke a distinctive phenotypic response in endothelial cells

Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events

Impacts of the 2014-2015 Holuhraun eruption on the UK atmosphere

Volcanic emissions, specifically from Iceland, pose a pan-European risk and are on the UK National Risk Register due to potential impacts on aviation, public health, agriculture, the environment and the economy, both from effusive and explosive activity. During the 2014-2015 fissure eruption at Holuhraun in Iceland, the UK atmosphere was significantly perturbed. This study focuses one major incursion in September 2014, affecting the surface concentrations of both aerosols and gases across the UK, with sites in Scotland experiencing the highest sulfur dioxide (SO2) concentrations. The perturbation event observed was confirmed to originate from the fissure eruption using satellite data from GOME2B and the chemical transport model, EMEP4UK, which was used to establish the spatial distribution of the plume over the UK during the event of interest. At the two UK European Monitoring and Evaluation Program (EMEP) supersite observatories (Auchencorth Moss, SE Scotland and Harwell, SE England) significant alterations in sulfate (SO42-) content of PM10 and PM2.5 during this event, concurrently with evidence of an increase in ultrafine aerosol, most likely due to nucleation and growth of aerosol within the plume, were observed. At Auchencorth Moss, higher hydrochloric acid (HCl) concentrations during the September event (max = 1.21 µg m-3, c.f annual average 0.12 µg m-3 35 in 2013), were assessed to be due to acid displacement of chloride (Cl-) from sea salt (NaCl) to form HCl gas rather than due to primary emissions of HCl from Holuhraun. The gas and aerosol partioning at Auchencorth moss of inorganic species by thermodynamic modelling, confirmed the observed partioning of HCl. Using the data from the chemical thermodynamic model, ISORROPIA-II, there is evidence that the background aerosol, which is typically basic at this site, became acidic with an estimated pH of 3.8 during the peak of the event. Volcano plume episodes were periodically observed by the majority of the UK air quality monitoring networks during the first 4 months of the eruption (August – December 2014), at both hourly and monthly resolution. In the low resolution networks, which provide monthly SO2 averages, concentrations were found to be significantly elevated at remote “clean” sites in NE Scotland and SW England, with record high SO2 concentrations for some sites in September 2014. For sites which are regularly influenced by anthropogenic emissions, taking into account the underlying trends, the eruption led to statistically unremarkable SO2 concentrations (return probabilities >0.1, ~10 months). However for a few sites, SO2 concentrations were clearly much higher than has been previously observed (return probability 3000 months). The Holuhraun Icelandic eruption has resulted in a unique study providing direct evidence of atmospheric chemistry perturbation of both gases and aerosols in the UK background atmosphere. The measurements can be used to both challenge and verify existing atmospheric chemistry of volcano plumes, especially those originating from effusive eruptions, which have been under-explored, due to limited observations available in the literature. If all European data sets were collated this would allow improved model verification and risk assessments for future volcanic eruptions of this type

Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases

Academic Performance and Behavioral Patterns

Identifying the factors that influence academic performance is an essential part of educational research. Previous studies have documented the importance of personality traits, class attendance, and social network structure. Because most of these analyses were based on a single behavioral aspect and/or small sample sizes, there is currently no quantification of the interplay of these factors. Here, we study the academic performance among a cohort of 538 undergraduate students forming a single, densely connected social network. Our work is based on data collected using smartphones, which the students used as their primary phones for two years. The availability of multi-channel data from a single population allows us to directly compare the explanatory power of individual and social characteristics. We find that the most informative indicators of performance are based on social ties and that network indicators result in better model performance than individual characteristics (including both personality and class attendance). We confirm earlier findings that class attendance is the most important predictor among individual characteristics. Finally, our results suggest the presence of strong homophily and/or peer effects among university students