Molecular pathology of human prion disease

Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health

Using a realist approach to evaluate smoking cessation interventions targeting pregnant women and young people

Background This paper describes a study protocol designed to evaluate a programme of smoking cessation interventions targeting pregnant women and young people living in urban and rural locations in Northeast Scotland. The study design was developed on so-called 'realist' evaluation principles, which are concerned with the implementation of interventions as well as their outcomes. Methods/design A two-phased study was designed based on the Theory of Change (TOC) using mixed methods to assess both process and outcome factors. The study was designed with input from the relevant stakeholders. The mixed-methods approach consists of semi-structured interviews with planners, service providers, service users and non-users. These qualitative interviews will be analysed using a thematic framework approach. The quantitative element of the study will include the analysis of routinely collected data and specific project monitoring data, such as data on service engagement, service use, quit rates and changes in smoking status. Discussion The process of involving key stakeholders was conducted using logic modelling and TOC tools. Engaging stakeholders, including those responsible for funding, developing and delivering, and those intended to benefit from interventions aimed at them, in their evaluation design, are considered by many to increase the validity and rigour of the subsequent evidence generated. This study is intended to determine not only the components and processes, but also the possible effectiveness of this set of health interventions, and contribute to the evidence base about smoking cessation interventions aimed at priority groups in Scotland. It is also anticipated that this study will contribute to the ongoing debate about the role and challenges of 'realist' evaluation approaches in general, and the utility of logic modelling and TOC approaches in particular, for evaluation of complex health interventions

Methods for Molecular Diagnosis of Human Prion Disease.

Human prion diseases are associated with a range of clinical presentations, and they are classified by both clinicopathological syndrome and etiology, with subclassification according to molecular criteria. Here, we describe updated procedures that are currently used within the MRC Prion Unit at UCL to determine a molecular diagnosis of human prion disease. Sequencing of the PRNP open reading frame to establish the presence of pathogenic mutations is described, together with detailed methods for immunoblot or immunohistochemical determination of the presence of abnormal prion protein in the brain or peripheral tissues

Computational optical imaging with a photonic lantern

[EN] The thin and flexible nature of optical fibres often makes them the ideal technology to view biological processes in-vivo, but current microendoscopic approaches are limited in spatial resolution. Here, we demonstrate a route to high resolution microendoscopy using a multicore fibre (MCF) with an adiabatic multimode-to-single-mode "photonic lantern" transition formed at the distal end by tapering. We show that distinct multimode patterns of light can be projected from the output of the lantern by individually exciting the single-mode MCF cores, and that these patterns are highly stable to fibre movement. This capability is then exploited to demonstrate a form of single-pixel imaging, where a single pixel detector is used to detect the fraction of light transmitted through the object for each multimode pattern. A custom computational imaging algorithm we call SARA-COIL is used to reconstruct the object using only the pre-measured multimode patterns themselves and the detector signals.This work was funded through the "Proteus" Engineering and Physical Sciences Research Council (EPSRC) Interdisciplinary Research Collaboration (IRC) (EP/K03197X/1), by the Science and Technology Facilities Council (STFC) through STFC-CLASP grants ST/K006509/1 and ST/K006460/1, STFC Consortium grants ST/N000625/1 and ST/N000544/1. S.L. acknowledges support from the National Natural Science Foundation of China under Grant no. 61705073. DBP acknowledges support from the Royal Academy of Engineering, and the European Research Council (PhotUntangle, 804626). The authors thank Philip Emanuel for the use of his confocal image of A549 cells and Eckhardt Optics for their image of the USAF 1951 target. The authors sincerely thank the anonymous reviewers of this paper for their detailed and considered feedback which helped us to improve the quality of this paper significantly.Choudhury, D.; Mcnicholl, DK.; Repetti, A.; Gris-Sánchez, I.; Li, S.; Phillips, DB.; Whyte, G.... (2020). Computational optical imaging with a photonic lantern. Nature Communications. 11(1):1-9. https://doi.org/10.1038/s41467-020-18818-6S19111Wood, H. A. C., Harrington, K., Birks, T. A., Knight, J. C. & Stone, J. M. High-resolution air-clad imaging fibers. Opt. Lett. 43, 5311–5314 (2018).Akram, A. R. et al. In situ identification of Gram-negative bacteria in human lungs using a topical fluorescent peptide targeting lipid A. Sci. Transl. Med. 10, eaal0033 (2018).Shin, J., Bosworth, B. T. & Foster, M. A. Compressive fluorescence imaging using a multi-core fiber and spatially dependent scattering. Opt. Lett. 42, 109–112 (2017).Papadopoulos, I. N., Farahi, S., Moser, C. & Psaltis, D. Focusing and scanning light through a multimode optical fiber using digital phase conjugation. Opt. Express 20, 10583–10590 (2012).Čižmár, T. & Dholakia, K. Exploiting multimode waveguides for pure fibre-based imaging. Nat. Commun. 3, 1027 (2012).Plöschner, M., Tyc, T. & Čižmár, T. Seeing through chaos in multimode fibres. Nat. Photon. 9, 529–535 (2015).Birks, T. A., Gris-Sánchez, I., Yerolatsitis, S., Leon-Saval, S. G. & Thomson, R. R. The photonic lantern. Adv. Opt. Photon. 7, 107–167 (2015).Birks, T. A., Mangan, B. J., Díez, A., Cruz, J. L. & Murphy, D. F. Photonic lantern’ spectral filters in multi-core fiber. Opt. Express 20, 13996–14008 (2012).Edgar, M. P., Gibson, G. M. & Padgett, M. J. Principles and prospects for single-pixel imaging. Nat. Photon. 13, 13–20 (2019).Mahalati, R. N., Yu, Gu. R. & Kahn, J. M. Resolution limits for imaging through multi-mode fiber. Opt. Express 21, 1656–1668 (2013).Amitonova, L. V. & de Boer, J. F. Compressive imaging through a multimode fiber. Opt. Lett. 43, 5427–5430 (2018).Mallat, S. A Wavelet Tour of Signal Processing 2nd edn (Academic Press, Burlington, MA, 2009).Lustig, M., Donoho, D. & Pauly, J. M. Sparse MRI: the application of compressed sensing for rapid MR imaging. Magn. Reson. Med. 58, 1182–1195 (2007).Davies, M., Puy, G., Vandergheynst, P. & Wiaux, Y. A compressed sensing framework for magnetic resonance fingerprinting. SIAM J. Imaging Sci. 7, 2623–2656 (2014).Wiaux, Y., Puy, G., Scaife, A. M. M. & Vandergheynst, P. Compressed sensing imaging techniques in radio interferometry. Mon. Not. R. Astron. Soc. 395, 1733–1742 (2009).Carrillo, R. E., McEwen, J. D. & Wiaux, Y. Sparsity averaging reweighted analysis (SARA): a novel algorithm for radio-interferometric imaging. Mon. Not. R. Astron. Soc. 426, 1223–1234 (2012).Katz, O., Bromberg, Y. & Silberberg, Y. Compressive ghost imaging. Appl. Phys. Lett. 95, 131110 (2009).Sun, B., Welsh, S. S., Edgar, M. P., Shapiro, J. H. & Padgett, M. J. Normalized ghost imaging. Opt. Express 20, 16892–16901 (2012).Kim, M., Park, C., Rodriguez, C., Park, Y. & Cho, Y.-H. Superresolution imaging with optical fluctuation using speckle patterns illumination. Sci. Rep. 5, 16525 (2015).Combettes, P. L. & Pesquet, J. -C. in Fixed-Point Algorithms for Inverse Problems in Science and Engineering (Springer, New York, 2011).Komodakis, N. & Pesquet, J.-C. Playing with duality: an overview of recent primal dual approaches for solving large-scale optimization problems. IEEE Signal Proc. Mag. 32, 31–54 (2015).Chandrasekharan, H. K. et al. Multiplexed single-mode wavelength-to-time mapping of multimode light. Nat. Commun. 8, 14080 (2017).Wadsworth, W. J. et al. Very high numerical aperture fibers. Photon. Technol. Lett. 16, 843–845 (2004).Pesquet, J.-C. & Repetti, A. A class of randomized primal-dual algorithms for distributed optimization. J. Nonlinear Convex Anal. 16, 2353–2490 (2015).Chambolle, A., Ehrhardt, M. J., Richtárik, P. & Schönlieb, C.-B. Stochastic primal-dual hybrid gradient algorithm with arbitrary sampling and imaging applications. SIAM J. Optim. 28, 2783–2808 (2018).Bolte, J., Sabach, S. & Teboulle, M. Proximal alternating linearized minimization for nonconvex and nonsmooth problems. Math. Program. 146, 459–494 (2014).Chouzenoux, E., Pesquet, J.-C. & Repetti, A. A block coordinate variable metric forward-backward algorithm. J. Glob. Optim. 66, 457–485 (2016).Flusberg, B. A. et al. Fiber-optic fluorescence imaging. Nat. Methods 2, 941–950 (2005).Tsvirkun, V. et al. Bending-induced inter-core group delays in multicore fibers. Opt. Express 25, 31863–31875 (2017).Candès, E. J., Wakin, M. B. & Boyd, S. Enhancing sparsity by reweighted l1 minimization. J. Fourier Anal. Appl. 14, 877–905 (2008).Condat, L. A primal–dual splitting method for convex optimization involving lipschitzian, proximable and linear composite terms. J. Optim. Theory Appl. 158, 460–479 (2013).Vu, B. C. A splitting algorithm for dual monotone inclusions involving cocoercive operators. Adv. Comp. Math. 38, 667–681 (2013)

Risk factors for breast cancer in postmenopausal Caucasian and Chinese-Canadian women

Abstract Introduction Striking differences exist between countries in the incidence of breast cancer. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The goal of this cross-sectional study was to examine breast cancer risk factors in populations with different risks for breast cancer. Methods We compared breast cancer risk factors among three groups of postmenopausal Canadian women at substantially different risk of developing breast cancer - Caucasians (N = 413), Chinese women born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants (N = 421). Information on risk factors and dietary acculturation were collected by telephone interviews using questionnaires, and anthropometric measurements were taken at a home visit. Results Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, less often had a family history of breast cancer or a benign breast biopsy, a higher Chinese dietary score, and a lower Western dietary score. For most of these variables, Western born Chinese and early Chinese migrants had values intermediate between those of Caucasians and recent Chinese migrants. We estimated five-year absolute risks for breast cancer using the Gail Model and found that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the risk factors in the Gail Model. Conclusions Our results suggest that in addition to the risk factors in the Gail Model, there likely are other factors that also contribute to the large difference in breast cancer risk between Canada and China

The impact of nonlinear exposure-risk relationships on seasonal time-series data: modelling Danish neonatal birth anthropometric data

Background Birth weight and length have seasonal fluctuations. Previous analyses of birth weight by latitude effects identified seemingly contradictory results, showing both 6 and 12 monthly periodicities in weight. The aims of this paper are twofold: (a) to explore seasonal patterns in a large, Danish Medical Birth Register, and (b) to explore models based on seasonal exposures and a non-linear exposure-risk relationship. Methods Birth weight and birth lengths on over 1.5 million Danish singleton, live births were examined for seasonality. We modelled seasonal patterns based on linear, U- and J-shaped exposure-risk relationships. We then added an extra layer of complexity by modelling weighted population-based exposure patterns. Results The Danish data showed clear seasonal fluctuations for both birth weight and birth length. A bimodal model best fits the data, however the amplitude of the 6 and 12 month peaks changed over time. In the modelling exercises, U- and J-shaped exposure-risk relationships generate time series with both 6 and 12 month periodicities. Changing the weightings of the population exposure risks result in unexpected properties. A J-shaped exposure-risk relationship with a diminishing population exposure over time fitted the observed seasonal pattern in the Danish birth weight data. Conclusion In keeping with many other studies, Danish birth anthropometric data show complex and shifting seasonal patterns. We speculate that annual periodicities with non-linear exposure-risk models may underlie these findings. Understanding the nature of seasonal fluctuations can help generate candidate exposures

Allelic Origin of Protease-Sensitive and Protease-Resistant Prion Protein Isoforms in Gerstmann-Sträussler-Scheinker Disease with the P102L Mutation

Gerstmann-Sträussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrPSc, consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrPSc isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrPSc has been described. Here we analyze the molecular and pathological phenotype of six GSS P102L cases characterized by the presence of 21 and 8 kDa PrP fragments and two subjects with only the 8 kDa PrP fragment. Using sensitive protein separation techniques and Western blots with antibodies differentially recognizing wild-type and mutant PrP we observed a range of PrPSc allelic conformers, either resistant or sensitive to protease treatment in all investigated subjects. Additionally, tissue deposition of protease-sensitive wild-type PrPSc molecules was seen by conventional PrP immunohistochemistry and paraffin-embedded tissue blot. Our findings enlarge the spectrum of conformational allelic PrPSc quasispecies propagating in GSS P102L thus providing a molecular support to the spectrum of disease phenotypes, and, in addition, impact the diagnostic role of PrP immunohistochemistry in prion diseases

Biochemical Properties of Highly Neuroinvasive Prion Strains

Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS

Time trends in leisure time physical activity and physical fitness in elderly people: 20 year follow-up of the Spanish population national health survey (1987-2006)

<p>Abstract</p> <p>Background</p> <p>To estimate trends in leisure time physical activity and physical fitness between 1987-2006 in older Spanish people.</p> <p>Methods</p> <p>We analyzed data collected from the Spanish National Health Surveys conducted in 1987 (n = 29,647), 1993 (n = 20,707), 1995-1997 (n = 12,800), 2001 (n = 21,058), 2003 (n = 21,650), and 2006 (n = 29,478). The number of subjects aged ≥ 65 years included in the current study was 29,263 (1987: n = 4,958-16.7%; 1993: n = 3,751-17.8%; 1995-97: n = 2,229-17.4%; 2001: n = 4,356-20.7%; 2003: 6,134-28.3%; 2006: 7,835-26.5%). Main variables included leisure-time physical activity and physical fitness. We analyzed socio-demographic characteristics, self-rated health status, lifestyle habit and co-morbid conditions using multivariate logistic regression models.</p> <p>Results</p> <p>Women exhibited lower prevalence of leisure time physical activity and physical fitness compared to men (P < 0.05). The multivariate analysis for time trends found that practising leisure time physical activity increased from 1987 to 2006 (P < 0.001). Variables associated with a lower likelihood of practicing leisure time physical activity were: age ≥ 80 years old, ≥ 2 co-morbid chronic conditions, and obesity. Variables associated with lower physical fitness included: age ≥ 80 years, worse self rated health; ≥ 2 medications (only for walking), and obesity.</p> <p>Conclusions</p> <p>We found an increase in leisure time physical activity in the older Spanish population. Older age, married status, co-morbid conditions, obesity, and worse self-perceived health status were associated with lower activity. Identification of these factors can help to identify individuals at risk for physical inactivity.</p