Prion diseases: Transmission from mad cows?

AbstractPrion diseases in humans show considerable clinical and pathological heterogeneity. The identification of a new variant of Creutzfeldt–Jakob disease, and its interpretation as evidence of transmission of mad cow disease to man, rely critically on our understanding of the epidemiology of prion diseases

Neptunium Reactivity During Co-Precipitation and Oxidation of Fe(II)/Fe(III) (Oxyhydr)oxides

Fe(II) bearing iron (oxyhydr)oxides were directly co-precipitated with Np(V)O2+ under anaerobic conditions to form Np doped magnetite and green rust. These environmentally relevant mineral phases were then characterised using geochemical and spectroscopic analyses. The Np doped mineral phases were then oxidised in air over 224 days with solution chemistry and end-point oxidation solid samples collected for further characterisation. Analysis using chemical extractions and X-ray absorption spectroscopy (XAS) techniques confirmed that Np(V) was initially reduced to Np(IV) during co-precipitation of both magnetite and green rust. Extended X-Ray Absorption Fine Structure (EXAFS) modelling suggested the Np(IV) formed a bidentate binuclear sorption complex to both minerals. Furthermore, following oxidation in air over several months, the sorbed Np(IV) was partially oxidised to Np(V), but very little remobilisation to solution occurred during oxidation. Here, linear combination fitting of the X-Ray Absorption Near Edge Structure (XANES) for the end-point oxidation samples for both mineral phases suggested approximately 50% oxidation to Np(V) had occurred over 7 months of oxidation in air. Both the reduction of Np(V) to Np(IV) and inner sphere sorption in association with iron (oxyhydr)oxides, and the strong retention of Np(IV) and Np(V) species with these phases under robust oxidation conditions, have important implications in understanding the mobility of neptunium in a range of engineered and natural environments

Neptunium Reactivity During Co-Precipitation and Oxidation of Fe(II)/Fe(III) (Oxyhydr)oxides

Fe(II) bearing iron (oxyhydr)oxides were directly co-precipitated with Np(V)O2+ under anaerobic conditions to form Np doped magnetite and green rust. These environmentally relevant mineral phases were then characterised using geochemical and spectroscopic analyses. The Np doped mineral phases were then oxidised in air over 224 days with solution chemistry and end-point oxidation solid samples collected for further characterisation. Analysis using chemical extractions and X-ray absorption spectroscopy (XAS) techniques confirmed that Np(V) was initially reduced to Np(IV) during co-precipitation of both magnetite and green rust. Extended X-Ray Absorption Fine Structure (EXAFS) modelling suggested the Np(IV) formed a bidentate binuclear sorption complex to both minerals. Furthermore, following oxidation in air over several months, the sorbed Np(IV) was partially oxidised to Np(V), but very little remobilisation to solution occurred during oxidation. Here, linear combination fitting of the X-Ray Absorption Near Edge Structure (XANES) for the end-point oxidation samples for both mineral phases suggested approximately 50% oxidation to Np(V) had occurred over 7 months of oxidation in air. Both the reduction of Np(V) to Np(IV) and inner sphere sorption in association with iron (oxyhydr)oxides, and the strong retention of Np(IV) and Np(V) species with these phases under robust oxidation conditions, have important implications in understanding the mobility of neptunium in a range of engineered and natural environments

<i>Toxoplasma gondii</i> infection of BALB/c mice perturbs host neurochemistry

Toxoplasma gondii infection has been associated with psychoneurological disease in humans and behavioural changes in rodents. However, the mechanisms accounting for this have not been fully described and in some cases could be argued to reflect the severe neuropathology that some mice suffer during infection. Herein we employ a multi-omics approach to extensively examine BALB/c mice that are resistant to toxoplasmic encephalitis. Using a combination of LCMS (liquid chromatography–mass spectrometry) and RNAseq we demonstrate that infection alters the neurochemistry and the transcriptome of the brains of BALB/c mice. Notable changes to tryptophan, purine, arginine, nicotinamide and carnitine metabolism were observed in infected mice and this was accompanied with changes to the levels of a number of transcripts associated with enzymes these metabolic pathways. In addition, changes were seen in transcripts of many immunologically important genes known to contribute to immunity to T. gondii. Changes in the levels of additional transcripts during infection have previously been associated with psychoneurological diseases. The results demonstrate that the BALB/c mouse, with its relatively mild neurological disease, is a useful model for characterising the effects of T. gondii infection on murine neurochemistry. The results also implicate specific biochemical pathways in mediating these changes and should inform further mechanistic studies and suggest therapeutic targets

CLTs and asymptotic variance of time-sampled Markov chains

For a Markov transition kernel P and a probability distribution μ on nonnegative integers, a time-sampled Markov chain evolves according to the transition kernel Pμ = Σkμ(k)Pk. In this note we obtain CLT conditions for time-sampled Markov chains and derive a spectral formula for the asymptotic variance. Using these results we compare efficiency of Barker's and Metropolis algorithms in terms of asymptotic variance

Multi-omics studies demonstrate Toxoplasma gondii-induced metabolic reprogramming of murine dendritic cells

Toxoplasma gondii is capable of actively invading almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic cells are not only key to establishing parasite infection, but conversely play a pivotal role in initiating host immunity. It is now recognized that in addition to changes in canonical immune markers and mediators, alteration in metabolism occurs upon activation of phagocytic cells. These metabolic changes are important for supporting the developing immune response, but can affect the availability of nutrients for intracellular pathogens including T. gondii. However, the interaction of T. gondii with these cells and particularly how infection changes their metabolism has not been extensively investigated. Herein, we use a multi-omics approach comprising transcriptomics and metabolomics validated with functional assays to better understand early events in these cells following infection. Analysis of the transcriptome of T. gondii infected bone marrow derived dendritic cells (BMDCs) revealed significant alterations in transcripts associated with cellular metabolism, activation of T cells, inflammation mediated chemokine and cytokine signaling pathways. Multivariant analysis of metabolomic data sets acquired through non-targeted liquid chromatography mass spectroscopy (LCMS) identified metabolites associated with glycolysis, the TCA cycle, oxidative phosphorylation and arginine metabolism as major discriminants between control uninfected and T. gondii infected cells. Consistent with these observations, glucose uptake and lactate dehydrogenase activity were upregulated in T. gondii infected BMDC cultures compared with control BMDCs. Conversely, BMDC mitochondrial membrane potential was reduced in T. gondii-infected cells relative to mitochondria of control BMDCs. These changes to energy metabolism, similar to what has been described following LPS stimulation of BMDCs and macrophages are often termed the Warburg effect. This metabolic reprogramming of cells has been suggested to be an important adaption that provides energy and precursors to facilitate phagocytosis, antigen processing and cytokine production. Other changes to BMDC metabolism are evident following T. gondii infection and include upregulation of arginine degradation concomitant with increased arginase-1 activity and ornithine and proline production. As T. gondii is an arginine auxotroph the resultant reduced cellular arginine levels are likely to curtail parasite multiplication. These results highlight the complex interplay of BMDCs and parasite metabolism within the developing immune response and the consequences for adaptive immunity and pathogen clearance

Eight Weeks of Self-Resisted Neck Strength Training Improves Neck Strength in Age-Grade Rugby Union Players:A Pilot Randomized Controlled Trial

BACKGROUND: Greater neck strength is associated with fewer head and neck injuries. Neck-strengthening programs are commonly burdensome, requiring specialist equipment or significant time commitment, which are barriers to implementation. HYPOTHESIS: Completing a neck-strengthening program will increase isometric neck strength in age-group rugby players. STUDY DESIGN: A pilot randomized controlled exercise intervention study. LEVEL OF EVIDENCE: Level 2. METHODS: Twenty-eight U18 (under 18) male regional age-group rugby union players were randomized (intervention n =15/control n = 13). An 8-week exercise program was supervised during preseason at the regional training center. Control players continued their “normal practice,” which did not include neck-specific strengthening exercises. The 3-times weekly trainer-led intervention program involved a series of 15-second self-resisted contractions, where players pushed maximally against their own head, in forward, backward, left, and right directions. OUTCOME MEASURE: Peak isometric neck strength (force N) into neck flexion, extension, and left and right side flexion was measured using a handheld dynamometer. RESULTS: Postintervention between-group mean differences (MDs) in isometric neck strength change were adjusted for baseline strength and favored the intervention for total neck strength (effect size [ES] = 1.2, MD ± 95% CI = 155.9 ± 101.9 N, P = 0.004) and for neck strength into extension (ES = 1.0, MD ± 95% CI = 59.9 ± 45.4 N, P = 0.01), left side flexion (ES = 0.7, MD ± 95% CI = 27.5 ± 26.9 N, P = 0.05), and right side flexion (ES = 1.3, MD ± 95% CI = 50.5 ± 34.4 N, P = 0.006). CONCLUSION: This resource-efficient neck-strengthening program has few barriers to implementation and provides a clear benefit in U18 players’ neck strength. While the present study focused on adolescent rugby players, the program may be appropriate across all sports where head and neck injuries are of concern and resources are limited. CLINICAL RELEVANCE: Greater neck strength is associated with fewer head and neck injuries, including concussion. Performing this neck exercise program independently, or as part of a whole-body program like Activate, an interactive guide for players and coaches, could contribute to lower sports-related head and neck injuries

Riemannian tangent space mapping and elastic net regularization for cost-effective EEG markers of brain atrophy in Alzheimer's disease

The diagnosis of Alzheimer's disease (AD) in routine clinical practice is most commonly based on subjective clinical interpretations. Quantitative electroencephalography (QEEG) measures have been shown to reflect neurodegenerative processes in AD and might qualify as affordable and thereby widely available markers to facilitate the objectivization of AD assessment. Here, we present a novel framework combining Riemannian tangent space mapping and elastic net regression for the development of brain atrophy markers. While most AD QEEG studies are based on small sample sizes and psychological test scores as outcome measures, here we train and test our models using data of one of the largest prospective EEG AD trials ever conducted, including MRI biomarkers of brain atrophy.Comment: Presented at NIPS 2017 Workshop on Machine Learning for Healt