2,895 research outputs found
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
Stable Mode Sorting by Two-Dimensional Parity of Photonic Transverse Spatial States
We describe a mode sorter for two-dimensional parity of transverse spatial
states of light based on an out-of-plane Sagnac interferometer. Both
Hermite-Gauss (HG) and Laguerre-Gauss (LG) modes can be guided into one of two
output ports according to the two-dimensional parity of the mode in question.
Our interferometer sorts HG_nm input modes depending upon whether they have
even or odd order n+m; it equivalently sorts LG modes depending upon whether
they have an even or odd value of their orbital angular momentum. It functions
efficiently at the single-photon level, and therefore can be used to sort
single-photon states. Due to the inherent phase stability of this type of
interferometer as compared to those of the Mach-Zehnder type, it provides a
promising tool for the manipulation and filtering of higher order transverse
spatial modes for the purposes of quantum information processing. For example,
several similar Sagnacs cascaded together may allow, for the first time, a
stable measurement of the orbital angular momentum of a true single-photon
state. Furthermore, as an alternative to well-known holographic techniques, one
can use the Sagnac in conjunction with a multi-mode fiber as a spatial mode
filter, which can be used to produce spatial-mode entangled Bell states and
heralded single photons in arbitrary first-order (n+m=1) spatial states,
covering the entire Poincare sphere of first-order transverse modes.Comment: 11 pages, 12 figures, 2 appendice
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
Quantum teleportation on a photonic chip
Quantum teleportation is a fundamental concept in quantum physics which now
finds important applications at the heart of quantum technology including
quantum relays, quantum repeaters and linear optics quantum computing (LOQC).
Photonic implementations have largely focussed on achieving long distance
teleportation due to its suitability for decoherence-free communication.
Teleportation also plays a vital role in the scalability of photonic quantum
computing, for which large linear optical networks will likely require an
integrated architecture. Here we report the first demonstration of quantum
teleportation in which all key parts - entanglement preparation, Bell-state
analysis and quantum state tomography - are performed on a reconfigurable
integrated photonic chip. We also show that a novel element-wise
characterisation method is critical to mitigate component errors, a key
technique which will become increasingly important as integrated circuits reach
higher complexities necessary for quantum enhanced operation.Comment: Originally submitted version - refer to online journal for accepted
manuscript; Nature Photonics (2014
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
Age and Smoking Related Changes in Metal Ion Levels in Human Lens: Implications for Cataract Formation
Age-related cataract formation is the primary cause of blindness worldwide and although treatable by surgical removal of the lens the majority of sufferers have neither the finances nor access to the medical facilities required. Therefore, a better understanding of the pathogenesis of cataract may identify new therapeutic targets to prevent or slow its progression. Cataract incidence is strongly correlated with age and cigarette smoking, factors that are often associated with accumulation of metal ions in other tissues. Therefore this study evaluated the age-related changes in 14 metal ions in 32 post mortem human lenses without known cataract from donors of 11 to 82 years of age by inductively coupled plasma mass spectrometry; smoking-related changes in 10 smokers verses 14 non-smokers were also analysed. A significant age-related increase in selenium and decrease in copper ions was observed for the first time in the lens tissue, where cadmium ion levels were also increased as has been seen previously. Aluminium and vanadium ions were found to be increased in smokers compared to non-smokers (an analysis that has only been carried out before in lenses with cataract). These changes in metal ions, i.e. that occur as a consequence of normal ageing and of smoking, could contribute to cataract formation via induction of oxidative stress pathways, modulation of extracellular matrix structure/function and cellular toxicity. Thus, this study has identified novel changes in metal ions in human lens that could potentially drive the pathology of cataract formation
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Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimers Disease Randomized Controlled Trial.
BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM. RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout. CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies
Integrated photonic quantum gates for polarization qubits
Integrated photonic circuits have a strong potential to perform quantum
information processing. Indeed, the ability to manipulate quantum states of
light by integrated devices may open new perspectives both for fundamental
tests of quantum mechanics and for novel technological applications. However,
the technology for handling polarization encoded qubits, the most commonly
adopted approach, is still missing in quantum optical circuits. Here we
demonstrate the first integrated photonic Controlled-NOT (CNOT) gate for
polarization encoded qubits. This result has been enabled by the integration,
based on femtosecond laser waveguide writing, of partially polarizing beam
splitters on a glass chip. We characterize the logical truth table of the
quantum gate demonstrating its high fidelity to the expected one. In addition,
we show the ability of this gate to transform separable states into entangled
ones and vice versa. Finally, the full accessibility of our device is exploited
to carry out a complete characterization of the CNOT gate through a quantum
process tomography.Comment: 6 pages, 4 figure
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
A Systematic Review and Meta-Analysis of Patient Decision Aids for Socially Disadvantaged Populations:Update from the International Patient Decision Aid Standards (IDPAS)
International audienceBackground. The effectiveness of patient decision aids (PtDAs) and other shared decision-making (SDM) interventions for socially disadvantaged populations has not been well studied. Purpose. To assess whether PtDAs and other SDM interventions improve outcomes or decrease health inequalities among socially disadvantaged populations and determine the critical features of successful interventions. Data Sources. MEDLINE, CINAHL, Cochrane, Psy-cINFO, and Web of Science from inception to October 2019. Cochrane systematic reviews on PtDAs. Study Selection. Randomized controlled trials of PtDAs and SDM interventions that included socially disadvantaged populations. Data Extraction. Independent double data extraction using a standardized form and the Template for Intervention Description and Replication checklist. Data Synthesis. Twenty-five PtDA and 13 other SDM intervention trials met our inclusion criteria. Compared with usual care, PtDAs improved knowledge (mean difference = 13.91, 95% confidence interval [CI] 9.01, 18.82 [I 2 = 96%]) and patient-clinician communication (relative risk = 1.62, 95% CI 1.42, 1.84 [I 2 = 0%]). PtDAs reduced decisional conflict (mean difference = 29.59; 95% CI 218.94, 20.24 [I 2 = 84%]) and the proportion undecided (relative risk = 0.39; 95% CI 0.28, 0.53 [I 2 = 75%]). PtDAs did not affect anxiety (standardized mean difference = 0.02, 95% CI 20.22, 0.26 [I 2 = 70%]). Only 1 trial looked at clinical outcomes (hemoglobin A1C). Five of the 12 PtDA studies that compared outcomes by disadvantaged standing found that outcomes improved more for socially disadvantaged participants. No evidence indicated which intervention characteristics were most effective. Results were similar for SDM intervention trials. Limitations. Sixteen PtDA studies had an overall unclear risk of bias. Heterogeneity was high for most outcomes. Most studies only had short-term follow-up. Conclusions. PtDAs led to better outcomes among socially disadvantaged populations but did not reduce health inequalities. We could not determine which intervention features were most effective
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