Evolution of neoplastic cell lineages in Barrett oesophagus.

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.     

The cystic fibrosis transmembrane conductance regulator (CFTR) and its stability

The cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for the disease cystic fibrosis (CF). It is a membrane protein belonging to the ABC transporter family functioning as a chloride/anion channel in epithelial cells around the body. There are over 1500 mutations that have been characterised as CF-causing; the most common of these, accounting for ~70 % of CF cases, is the deletion of a phenylalanine at position 508. This leads to instability of the nascent protein and the modified structure is recognised and then degraded by the ER quality control mechanism. However, even pharmacologically ‘rescued’ F508del CFTR displays instability at the cell’s surface, losing its channel function rapidly and it is rapidly removed from the plasma membrane for lysosomal degradation. This review will, therefore, explore the link between stability and structure/function relationships of membrane proteins and CFTR in particular and how approaches to study CFTR structure depend on its stability. We will also review the application of a fluorescence labelling method for the assessment of the thermostability and the tertiary structure of CFTR.     

Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.     

Epigenetics: a link between addiction and social environment

The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.     

The wedge and the vis viva controversy: how concepts of force influenced the practice of early eighteenth-century mechanics

This article discusses the quest for the mechanical advantage of the wedge in the eighteenth century. As a case study, the wedge enlightens our understanding of eighteenth-century mechanics in general and the controversy over “force” or vis viva in particular. In this article, I show that the two different approaches to mechanics, the one that favoured force in terms of velocities and the one that primarily used displacements—known as the ‘Newtonian’ and ‘Leibnizian’ methods, respectively—were not at all on par in their ability to solve the problem of the wedge. In general, only those who used the Leibnizian concept of force or some related notion were able to get to the conventional results. This article thus rebuts the received view that the vis viva controversy was merely a semantic one. Instead, it shows that different understandings of “force” led to real and pragmatic differences in eighteenth-century mechanics.     

Forecasting Longevity Gains Using a Seemingly Unrelated Time Series Model

In this paper a multivariate time series model using the seemingly unrelated time series equation (SUTSE) framework is proposed to forecast longevity gains. The proposed model is represented in state space form and uses Kalman filtering to estimate the unobservable components and fixed parameters. We apply the model both to male mortality rates in Portugal and the USA. Our results compare favorably, in terms of mean absolute percentage error, in‐sample and out‐of‐sample, to those obtained by the Lee–Carter method and some of its extensions. Copyright © 2015 John Wiley & Sons, Ltd.     

Ruling Engines,Diffraction Gratings and Wavelength Measurements before the Rowland Era

Diffraction gratings have contributed enormously to modern science. Although some historians have written about them, there is much more to be brought to light. This paper discusses their development and use in the period up to about 1880 before Rowland began to produce them. Rittenhouse described the action of a diffraction grating in 1786, but no explanation was possible until the wave theory of light was developed. Fraunhofer discovered the dark lines in the solar spectrum in 1814, and then investigated diffraction, producing the first ruled gratings, making detailed measurements and calculating the wavelengths of prominent spectral lines. After Bunsen and Kirchhoff showed the association between spectral lines and chemical elements there was an upsurge of interest in measuring wavelengths. The gratings used in this work almost all came from one source, a relatively unknown instrument maker called Nobert, who made them by an extremely laborious process using a machine he had built himself. The most significant wavelength measurements were made by Ångström, but Mascart, Van der Willigen, Stefan, Ditscheiner and Cornu also did important work. Nobert gratings were investigated by Quincke, copied photographically by Rayleigh, and were known and discussed in the USA. Nobert's work helped to advance spectroscopy much more than has been acknowledged.     

Vital Instability: Life and Free Will in Physics and Physiology, 1860–1880

During the period 1860–1880, a number of physicists and mathematicians, including Maxwell, Stewart, Cournot and Boussinesq, used theories formulated in terms of physics to argue that the mind, the soul or a vital principle could have an impact on the body. This paper shows that what was primarily at stake for these authors was a concern about the irreducibility of life and the mind to physics, and that their theories can be regarded primarily as reactions to the law of conservation of energy, which was used among others by Helmholtz and Du Bois-Reymond as an argument against the possibility of vital and mental causes in physiology. In light of this development, Maxwell, Stewart, Cournot and Boussinesq showed that it was still possible to argue for the irreducibility of life and the mind to physics, through an appeal to instability or indeterminism in physics: if the body is an unstable or physically indeterministic system, an immaterial principle can act through triggering or directing motions in the body, without violating the laws of physics.