Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Radio & Optical Interferometry: Basic Observing Techniques and Data Analysis

Astronomers usually need the highest angular resolution possible, but the blurring effect of diffraction imposes a fundamental limit on the image quality from any single telescope. Interferometry allows light collected at widely-separated telescopes to be combined in order to synthesize an aperture much larger than an individual telescope thereby improving angular resolution by orders of magnitude. Radio and millimeter wave astronomers depend on interferometry to achieve image quality on par with conventional visible and infrared telescopes. Interferometers at visible and infrared wavelengths extend angular resolution below the milli-arcsecond level to open up unique research areas in imaging stellar surfaces and circumstellar environments. In this chapter the basic principles of interferometry are reviewed with an emphasis on the common features for radio and optical observing. While many techniques are common to interferometers of all wavelengths, crucial differences are identified that will help new practitioners avoid unnecessary confusion and common pitfalls. Concepts essential for writing observing proposals and for planning observations are described, depending on the science wavelength, angular resolution, and field of view required. Atmospheric and ionospheric turbulence degrades the longest-baseline observations by significantly reducing the stability of interference fringes. Such instabilities represent a persistent challenge, and the basic techniques of phase-referencing and phase closure have been developed to deal with them. Synthesis imaging with large observing datasets has become a routine and straightforward process at radio observatories, but remains challenging for optical facilities. In this context the commonly-used image reconstruction algorithms CLEAN and MEM are presented. Lastly, a concise overview of current facilities is included as an appendix.Comment: 45 pages, 14 Figures; an abridged version of a chapter to appear in Volume 2 of Planets, Stars and Stellar Systems, to be published in 2011 by Springe

Magnetization transfer imaging in ‘premanifest’ Huntington’s disease

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in ‘premanifest’ carriers of the Huntington’s disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity

Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance

Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments

© 2015 Ye et al. Background: The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome-editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult. Methods: In this study, we developed a tumor engraftment index (TEI) to quantify the immunodeficiency response to hematologic malignant cells and solid tumor cells of six immunodeficient mouse strains and C57BL/6 wild-type mouse (WT). Results: Mice with a more severely impaired immune system attained a higher TEI score. We then validated that the NOD-scid-IL2Rg-/- (NSI) mice, which had the highest TEI score, were more suitable for xenograft and allograft experiments using multiple functional assays. Conclusions: The TEI score was effectively able to reflect the immunodeficiency of a mouse strain.Link_to_subscribed_fulltex