Use of targeted exome sequencing as a diagnostic tool for familial hypercholesterolaemia

Familial Hypercholesterolaemia (FH) is an autosomal dominant disease, caused by mutations in LDLR, APOB or PCSK9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. An autosomal recessive form of FH is also known, due to homozygous mutations in LDLRAP1. This study assessed the utility of an exome capture method and deep sequencing in FH diagnosis

The Hong-Ou-Mandel effect with atoms

Controlling light at the level of individual photons has led to advances in fields ranging from quantum information and precision sensing to fundamental tests of quantum mechanics. A central development that followed the advent of single photon sources was the observation of the Hong-Ou- Mandel (HOM) effect, a novel two-photon path interference phenomenon experienced by indistinguishable photons. The effect is now a central technique in the field of quantum optics, harnessed for a variety of applications such as diagnosing single photon sources and creating probabilistic entanglement in linear quantum computing. Recently, several distinct experiments using atomic sources have realized the requisite control to observe and exploit Hong-Ou-Mandel interference of atoms. This article provides a summary of this phenomenon and discusses some of its implications for atomic systems. Transitioning from the domain of photons to atoms opens new perspectives on fundamental concepts, such as the classification of entanglement of identical particles. It aids in the design of novel probes of quantities such as entanglement entropy by combining well established tools of AMO physics - unity single-atom detection, tunable interactions, and scalability - with the Hong-Ou-Mandel interference. Furthermore, it is now possible for established protocols in the photon community, such as measurement-induced entanglement, to be employed in atomic experiments that possess deterministic single-particle production and detection. Hence, the realization of the HOM effect with atoms represents a productive union of central ideas in quantum control of atoms and photons.Comment: 19 pages, 7 figure

No imminent quantum supremacy by boson sampling

It is predicted that quantum computers will dramatically outperform their conventional counterparts. However, large-scale universal quantum computers are yet to be built. Boson sampling is a rudimentary quantum algorithm tailored to the platform of photons in linear optics, which has sparked interest as a rapid way to demonstrate this quantum supremacy. Photon statistics are governed by intractable matrix functions known as permanents, which suggests that sampling from the distribution obtained by injecting photons into a linear-optical network could be solved more quickly by a photonic experiment than by a classical computer. The contrast between the apparently awesome challenge faced by any classical sampling algorithm and the apparently near-term experimental resources required for a large boson sampling experiment has raised expectations that quantum supremacy by boson sampling is on the horizon. Here we present classical boson sampling algorithms and theoretical analyses of prospects for scaling boson sampling experiments, showing that near-term quantum supremacy via boson sampling is unlikely. While the largest boson sampling experiments reported so far are with 5 photons, our classical algorithm, based on Metropolised independence sampling (MIS), allowed the boson sampling problem to be solved for 30 photons with standard computing hardware. We argue that the impact of experimental photon losses means that demonstrating quantum supremacy by boson sampling would require a step change in technology.Comment: 25 pages, 9 figures. Comments welcom

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Geographical Perspectives on Transport and Ageing

In terms of ageing, we are living in unprecedented times. People across the globe are living longer than ever before and societies are ageing at increasing rates. In low to middle income countries reductions in mortality at young ages have fuelled this growth. A person born today in Brazil, for example, can expect to live 20 years longer than someone born 50 years ago (WHO, 2015). For the first time life expectancy across the globe is over 60 years of age. In high Income countries, someone born now can expect to live up to around 80 years of age on average (ONS, 2015). There are not simply a growing number of older people, but also a growing number of older people as a total percentage of the population due to people living longer and declining birth rates in many countries. Across Europe, for example, people aged over 65 years will account for 29.5% of the population in 2060 compared to around 19% now (EUROSTAT, 2017). The share of those aged 80 years or above across Europe will almost triple by 2060 (EUROSTAT, 2017)The macro level demographics and associated trends mask big differences within the ageing populations. There can be as much as 10 years difference in life expectancy within high income countries, for example in the UK someone born a baby boy born in Kensington and Chelsea has a life expectancy of 83.3 years, compared with a boy born in Glasgow who has a life expectancy of 10 years lower (73.0 years) (ONS, 2015). For newborn baby girls, life expectancy is highest in Chiltern at 86.7 years and 8 years lower Glasgow at 78.5 years (ONS, 2015; NRS, 2016). There is also considerable variation within cities, spatially and socially.This volume brings together contributions from a broad range of human geographers, with different disciplinary perspectives of transport and ageing. This chapter outlines some of the key contemporary issues for an ageing society in terms of transport and mobility, highlights the importance of considering transport and mobility for ageing populations and outlines the contribution that a geographical approach can offer to studies of transport and ageing

Elevated c-Src is linked to altered cell–matrix adhesion rather than proliferation in KM12C human colorectal cancer cells

Elevated expression and/or activity of c-Src, the prototype of the Src family of protein tyrosine kinases, is associated with the development of human colon cancer. However, despite the known pleiotropic effects of these kinases in promoting (a) cell growth downstream of growth factor receptors, and (b) the dynamic regulation of integrin adhesions in fibroblast model systems, their precise role in epithelial cancer cells is unknown. Here we addressed whether elevated expression and activity of cellular Src alters cell proliferation and/or cell–matrix adhesion in cancer cells from the Fidler model of colorectal metastasis. Although elevated Src correlates with ability to metastasise to the liver after intrasplenic injection, we found that this was not linked to enhanced growth, either in vitro or in vivo as sub-cutaneous tumours. However, elevated Src was associated with enhanced attachment to extracellular matrix. In addition, adhesion to fibronectin, was suppressed by agents that inhibited Src activity, while enforced elevation of Src in non-metastatic cells was sufficient to stimulate adhesion to fibronectin and enhanced assembly of adhesion complexes, without influencing cell growth. Thus, we conclude that one role of elevated Src in human colon cancer cells is to modulate integrin-dependent cell–matrix attachment and formation of adhesion structures, which may, in turn, influence cell motility and integrin-dependent cellular responses

Avoidable mortality attributable to anthropogenic fine particulate matter (Pm2.5) in Australia

Ambient fine particulate matter 2.5) air pollution increases premature mortalityglobally. Some PM2.5 is natural, but anthropogenic PM2.5 is comparatively avoidable. We determinedthe impact of long-term exposures to the anthropogenic PM component on mortality in Australia.PM2.5-attributable deaths were calculated for all Australian Statistical Area 2 (SA2; n = 2310) regions.All-cause death rates from Australian mortality and population databases were combined withannual anthropogenic PM2.5 exposures for the years 2006–2016. Relative risk estimates were derivedfrom the literature. Population-weighted average PM2.5 concentrations were estimated in eachSA2 using a satellite and land use regression model for Australia. PM2.5-attributable mortality wascalculated using a health-impact assessment methodology with life tables and all-cause death rates.The changes in life expectancy (LE) from birth, years of life lost (YLL), and economic cost of lostlife years were calculated using the 2019 value of a statistical life. Nationally, long-term populationweighted average total and anthropogenic PM2.5 concentrations were 6.5 µg/m3(min 1.2–max 14.2)and 3.2 µg/m3(min 0–max 9.5), respectively. Annually, anthropogenic PM2.5-pollution is associatedwith 2616 (95% confidence intervals 1712, 3455) deaths, corresponding to a 0.2-year (95% CI 0.14, 0.28)reduction in LE for children aged 0–4 years, 38,962 (95%CI 25,391, 51,669) YLL and an average annualeconomic burden of $6.2 billion (95$4.0 billion, $8.1 billion). We conclude that the anthropogenicPM2.5-related costs of mortality in Australia are higher than community standards should allow,and reductions in emissions are recommended to achieve avoidable mortality

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div

Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation.

Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions