Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies

SummaryParkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies

Incidence and Clinical Significance of Inducible Atrial Tachycardia in Patients with Atrioventricular Nodal Reentrant Tachycardia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72373/1/j.1540-8167.2001.00507.x.pd

Plutonium Migration during the Leaching of Cemented Radioactive Waste Sludges

One of the most challenging components of the UK nuclear legacy is Magnox sludge, arising from the corrosion of Mg alloy-clad irradiated metallic U fuel that has been stored in high pH ponds. The sludges mainly comprise Mg hydroxide and carbonate phases, contaminated with fission products and actinides, including Pu. Cementation and deep geological disposal is one option for the long-term management of this material, but there is a need to understand how Pu may be leached from the waste, if it is exposed to groundwater. Here, we show that cemented Mg(OH)2 powder prepared with Pu(IV)aq is altered on contact with water to produce a visibly altered ‘leached zone’, which penetrates several hundred microns into the sample. In turn, this zone shows slow leaching of Pu, with long-term leaching rates between 1.8–4.4 × 10−5% of total Pu per day. Synchrotron micro-focus X-ray fluorescence mapping identified decreased Pu concentration within the ‘leached zone’. A comparison of micro-focus X-ray absorption spectroscopy (µ-XAS) spectra collected across both leached and unleached samples showed little variation, and indicated that Pu was present in a similar oxidation state and coordination environment. Fitting of the XANES spectra between single oxidation state standards and EXAFS modeling showed that Pu was present as a mixture of Pu(IV) and Pu(V). The change in Pu oxidation from the stock solution suggests that partial Pu oxidation occurred during sample ageing. Similarity in the XAS spectra from all samples, with different local chemistries, indicated that the Pu oxidation state was not perturbed by macro-scale variations in cement chemistry, surface oxidation, sample aging, or the leaching treatment. These experiments have demonstrated the potential for leaching of Pu from cementitious waste forms, and its underlying significance requires further investigation

Electrogram Polarity and Cavotricuspid Isthmus Block During Ablation of Typical Atrial Flutter

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72217/1/j.1540-8167.2001.00393.x.pd

Impact of the COVID-19 pandemic on sedentary time and behaviour in children and adults: a systematic review and meta-analysis

The aim of this meta-analysis was to quantify the change in sedentary time during the COVID-19 pandemic and its effect on health outcomes in the general population. One thousand six hundred and one articles published after 2019 were retrieved from five databases, of which 64 and 40 were included in the systematic review and meta-analysis, respectively. Studies were grouped according to population: children (65 years). Average sedentary time was calculated, with sub-analyses performed by country, behaviour type and health outcomes. Children were most affected, increasing their sedentary time by 159.5 ± 142.6 min day−1, followed by adults (+126.9 ± 42.2 min day−1) and older adults (+46.9 ± 22.0 min day−1). There were no sex differences in any age group. Screen time was the only consistently measured behaviour and accounted for 46.8% and 57.2% of total sedentary time in children and adults, respectively. Increases in sedentary time were negatively correlated with global mental health, depression, anxiety and quality of life, irrespective of age. Whilst lockdown negatively affected all age groups, children were more negatively affected than adults or older adults, highlighting this population as a key intervention target. As lockdowns ease worldwide, strategies should be employed to reduce time spent sedentary

Plutonium Migration during the Leaching of Cemented Radioactive Waste Sludges

One of the most challenging components of the UK nuclear legacy is Magnox sludge, arising from the corrosion of Mg alloy-clad irradiated metallic U fuel that has been stored in high pH ponds. The sludges mainly comprise Mg hydroxide and carbonate phases, contaminated with fission products and actinides, including Pu. Cementation and deep geological disposal is one option for the long-term management of this material, but there is a need to understand how Pu may be leached from the waste, if it is exposed to groundwater. Here, we show that cemented Mg(OH)2 powder prepared with Pu(IV)aq is altered on contact with water to produce a visibly altered ‘leached zone’, which penetrates several hundred microns into the sample. In turn, this zone shows slow leaching of Pu, with long-term leaching rates between 1.8–4.4 × 10−5% of total Pu per day. Synchrotron micro-focus X-ray fluorescence mapping identified decreased Pu concentration within the ‘leached zone’. A comparison of micro-focus X-ray absorption spectroscopy (µ-XAS) spectra collected across both leached and unleached samples showed little variation, and indicated that Pu was present in a similar oxidation state and coordination environment. Fitting of the XANES spectra between single oxidation state standards and EXAFS modeling showed that Pu was present as a mixture of Pu(IV) and Pu(V). The change in Pu oxidation from the stock solution suggests that partial Pu oxidation occurred during sample ageing. Similarity in the XAS spectra from all samples, with different local chemistries, indicated that the Pu oxidation state was not perturbed by macro-scale variations in cement chemistry, surface oxidation, sample aging, or the leaching treatment. These experiments have demonstrated the potential for leaching of Pu from cementitious waste forms, and its underlying significance requires further investigation

Competitive stochastic noises in coherently driven two-level atoms and quantum interference

A system of coherently-driven two-level atoms is analyzed in presence of two independent stochastic perturbations: one due to collisions and a second one due to phase fluctuations of the driving field. The behaviour of the quantum interference induced by the collisional noise is considered in detail. The quantum-trajectory method is utilized to reveal the phase correlations between the dressed states involved in the interfering transition channels. It is shown that the quantum interference induced by the collisional noise is remarkably robust against phase noise. This effect is due to the fact that the phase noise, similarly to collisions, stabilizes the phase-difference between the dressed states.Comment: accepted for publication in J. Opt.

Reconstruction of quantum states of spin systems via the Jaynes principle of maximum entropy

We apply the Jaynes principle of maximum entropy for the partial reconstruction of correlated spin states. We determine the minimum set of observables which are necessary for the complete reconstruction of the most correlated states of systems composed of spins-1/2 (e.g., the Bell and the Greenberger-Horne-Zeilinger states). We investigate to what extent an incomplete measurement can reveal nonclassical features of correlated spin states.Comment: 14 pages + 3 tables, LaTeX with revtex, to appear in J. Mod. Op

New horizons in geriatric medicine education and training: the need for pan-European education and training standards

The ageing population ought to be celebrated as evidence for the efficacy of modern medicine, but the challenge that this demographic shift presents for 21st century healthcare systems, with increasing numbers of people living with multi-morbidity and frailty, cannot be ignored. There is therefore a need to ensure that all healthcare professionals grasp the basic principles of care of older people. In this paper, we make a case for the development of pan-European education and training standards for the field of geriatric medicine. Firstly, the challenges which face the implementation and delivery of geriatric medicine in a systematic way across Europe are described – these include, but are not limited to; variance in geriatric medicine practice across Europe, insecurity of the specialty in some countries and significant heterogeneity in geriatric medicine training programs across Europe. The opportunities for geriatric medicine are then presented and we consider how engendering core geriatric medicine competencies amongst nongeriatricians has potential to bridge existing gaps in service provision across Europe. Finally, we consider how work can proceed to teach sufficient numbers of doctors and health professionals in the core knowledge, skills and attitudes required to do this. To safeguard the future of the specialty across Europe, we contend that there is a need to strive towards harmonisation of post-graduate geriatric medicine training across Europe, through the establishment of pan-European education and training standards in the specialty