Biomarker Discovery in Animal Health and Disease: The Application of Post-Genomic Technologies

The causes of many important diseases in animals are complex and multifactorial, which present unique challenges. Biomarkers indicate the presence or extent of a biological process, which is directly linked to the clinical manifestations and outcome of a particular disease. Identifying biomarkers or biomarker profiles will be an important step towards disease characterization and management of disease in animals. The emergence of post-genomic technologies has led to the development of strategies aimed at identifying specific and sensitive biomarkers from the thousands of molecules present in a tissue or biological fluid. This review will summarize the current developments in biomarker discovery and will focus on the role of transcriptomics, proteomics and metabolomics in biomarker discovery for animal health and disease

Biomarkers for ragwort poisoning in horses: identification of protein targets

BACKGROUND: Ingestion of the poisonous weed ragwort (Senecio jacobea) by horses leads to irreversible liver damage. The principal toxins of ragwort are the pyrrolizidine alkaloids that are rapidly metabolised to highly reactive and cytotoxic pyrroles, which can escape into the circulation and bind to proteins. In this study a non-invasive in vitro model system has been developed to investigate whether pyrrole toxins induce specific modifications of equine blood proteins that are detectable by proteomic methods. RESULTS: One dimensional gel electrophoresis revealed a significant alteration in the equine plasma protein profile following pyrrole exposure and the formation of a high molecular weight protein aggregate. Using mass spectrometry and confirmation by western blotting the major components of this aggregate were identified as fibrinogen, serum albumin and transferrin. CONCLUSION: These findings demonstrate that pyrrolic metabolites can modify equine plasma proteins. The high molecular weight aggregate may result from extensive inter- and intra-molecular cross-linking of fibrinogen with the pyrrole. This model has the potential to form the basis of a novel proteomic strategy aimed at identifying surrogate protein biomarkers of ragwort exposure in horses and other livestock

Post-diagnosis body mass index and mortality among women diagnosed with endometrial cancer: Results from the Women\u27s Health Initiative.

Higher body mass index (BMI) measured before endometrial cancer diagnosis has been associated with greater risk of developing endometrial cancer and higher mortality, but the association between BMI measured after diagnosis and mortality risk is unclear. We identified 467 women (91 deaths) in the Women\u27s Health Initiative (WHI) with information on BMI measured after diagnosis and used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Comparing BMI 35+ with/m2, we observed no association with all-cause mortality (HR = 1.02, 95% CI 0.55-1.91). Our study does not support the hypothesis that higher BMI after endometrial cancer diagnosis is associated with poorer survival

Motivation as a mechanism underpinning exercise-based falls prevention programmes for older adults with cognitive impairment: a realist review

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. Objectives This review aimed to identify mechanisms underlying participation in falls prevention interventions, in older adults with cognitive impairment. In particular we studied the role of motivation. Design A realist review of the literature. Data sources EMBASE, MEDLINE, CINAHL, the Cochrane Library, PsycINFO and PEDRO. Eligibility criteria Publications reporting exercise-based interventions for people with cognitive impairment, including dementia, living in the community. Data extraction and synthesis A â €" rough programme theory' (a preliminary model of how an intervention works) was developed, tested against findings from the published literature and refined. Data were collected according to elements of the programme theory and not isolated to outcomes. Motivation emerged as a key element, and was prioritised for further study. Results An individual will access mechanisms to support participation when they think that exercise will be beneficial to them. Supportive mechanisms include having a â €" gate-keeper', such as a carer or therapist, who shares responsibility for the perception of exercise as beneficial. Lack of access to support decreases adherence and participation in exercise. Motivational mechanisms were particularly relevant for older adults with mild-To-moderate dementia, where the exercise intervention was multicomponent, in a preferred setting, at the correct intensity and level of progression, correctly supported and considered, and flexibly delivered. Conclusion Motivation is a key element enabling participation in exercise-based interventions for people with cognitive impairment. Many of the mechanisms identified in this review have parallels in motivational theory. Clinically relevant recommendations were derived and will be used to further develop and test a motivationally considered exercise-based falls intervention for people with mild dementia. PROSPERO registration number CRD42015030169

Promoting activity, independence and stability in early dementia and mild cognitive impairment (PrAISED): development of an intervention for people with mild cognitive impairment and dementia

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless, they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is an understanding of how to develop an intervention for people with mild cognitive impairment and dementia to promote their independence, stability, and physical activit

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1 -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.</p

Connecting stellar mass and star-formation rate to dark matter halo mass out to z ~ 2

We have constructed an extended halo model (EHM) which relates the total stellar mass and star-formation rate (SFR) to halo mass (M_h). An empirical relation between the distribution functions of total stellar mass of galaxies and host halo mass, tuned to match the spatial density of galaxies over 0<z<2 and the clustering properties at z~0, is extended to include two different scenarios describing the variation of SFR on M_h. We also present new measurements of the redshift evolution of the average SFR for star-forming galaxies of different stellar mass up to z=2, using data from the Herschel Multi-tiered Extragalactic Survey (HerMES) for infrared-bright galaxies. Combining the EHM with the halo accretion histories from numerical simulations, we trace the stellar mass growth and star-formation history in halos spanning a range of masses. We find that: (1) The intensity of the star-forming activity in halos in the probed mass range has steadily decreased from z~2 to 0; (2) At a given epoch, halos in the mass range between a few times 10^{11} M_Sun and a few times 10^{12} M_Sun are the most efficient at hosting star formation; (3) The peak of SFR density shifts to lower mass halos over time; (4) Galaxies that are forming stars most actively at z~2 evolve into quiescent galaxies in today's group environments, strongly supporting previous claims that the most powerful starbursts at z~2 are progenitors of today's elliptical galaxies.Comment: 15 pages, 12 figures, accepted for publication in MNRA

Galaxy Collisions - Dawn of a New Era

The study of colliding galaxies has progressed rapidly in the last few years, driven by observations with powerful new ground and space-based instruments. These instruments have used for detailed studies of specific nearby systems, statistical studies of large samples of relatively nearby systems, and increasingly large samples of high redshift systems. Following a brief summary of the historical context, this review attempts to integrate these studies to address the following key issues. What role do collisions play in galaxy evolution, and how can recently discovered processes like downsizing resolve some apparently contradictory results of high redshift studies? What is the role of environment in galaxy collisions? How is star formation and nuclear activity orchestrated by the large scale dynamics, before and during merger? Are novel modes of star formation involved? What are we to make of the association of ultraluminous X-ray sources with colliding galaxies? To what do degree do mergers and feedback trigger long-term secular effects? How far can we push the archaeology of individual systems to determine the nature of precursor systems and the precise effect of the interaction? Tentative answers to many of these questions have been suggested, and the prospects for answering most of them in the next few decades are good.Comment: 44 pages, 9 figures, review article in press for Astrophysics Update Vol.

Improved Resolution of Reef-Coral Endosymbiont (Symbiodinium) Species Diversity, Ecology, and Evolution through psbA Non-Coding Region Genotyping

Ribosomal DNA sequence data abounds from numerous studies on the dinoflagellate endosymbionts of corals, and yet the multi-copy nature and intragenomic variability of rRNA genes and spacers confound interpretations of symbiont diversity and ecology. Making consistent sense of extensive sequence variation in a meaningful ecological and evolutionary context would benefit from the application of additional genetic markers. Sequences of the non-coding region of the plastid psbA minicircle (psbAncr) were used to independently examine symbiont genotypic and species diversity found within and between colonies of Hawaiian reef corals in the genus Montipora. A single psbAncr haplotype was recovered in most samples through direct sequencing (∼80–90%) and members of the same internal transcribed spacer region 2 (ITS2) type were phylogenetically differentiated from other ITS2 types by substantial psbAncr sequence divergence. The repeated sequencing of bacterially-cloned fragments of psbAncr from samples and clonal cultures often recovered a single numerically common haplotype accompanied by rare, highly-similar, sequence variants. When sequence artifacts of cloning and intragenomic variation are factored out, these data indicate that most colonies harbored one dominant Symbiodinium genotype. The cloning and sequencing of ITS2 DNA amplified from these same samples recovered numerically abundant variants (that are diagnostic of distinct Symbiodinium lineages), but also generated a large amount of sequences comprising PCR/cloning artifacts combined with ancestral and/or rare variants that, if incorporated into phylogenetic reconstructions, confound how small sequence differences are interpreted. Finally, psbAncr sequence data from a broad sampling of Symbiodinium diversity obtained from various corals throughout the Indo-Pacific were concordant with ITS lineage membership (defined by denaturing gradient gel electrophoresis screening), yet exhibited substantially greater sequence divergence and revealed strong phylogeographic structure corresponding to major biogeographic provinces. The detailed genetic resolution provided by psbAncr data brings further clarity to the ecology, evolution, and systematics of symbiotic dinoflagellates

Fitting the integrated Spectral Energy Distributions of Galaxies

Fitting the spectral energy distributions (SEDs) of galaxies is an almost universally used technique that has matured significantly in the last decade. Model predictions and fitting procedures have improved significantly over this time, attempting to keep up with the vastly increased volume and quality of available data. We review here the field of SED fitting, describing the modelling of ultraviolet to infrared galaxy SEDs, the creation of multiwavelength data sets, and the methods used to fit model SEDs to observed galaxy data sets. We touch upon the achievements and challenges in the major ingredients of SED fitting, with a special emphasis on describing the interplay between the quality of the available data, the quality of the available models, and the best fitting technique to use in order to obtain a realistic measurement as well as realistic uncertainties. We conclude that SED fitting can be used effectively to derive a range of physical properties of galaxies, such as redshift, stellar masses, star formation rates, dust masses, and metallicities, with care taken not to over-interpret the available data. Yet there still exist many issues such as estimating the age of the oldest stars in a galaxy, finer details ofdust properties and dust-star geometry, and the influences of poorly understood, luminous stellar types and phases. The challenge for the coming years will be to improve both the models and the observational data sets to resolve these uncertainties. The present review will be made available on an interactive, moderated web page (sedfitting.org), where the community can access and change the text. The intention is to expand the text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics & Space Scienc