Gene expression identifies metabolic and functional differences between intramuscular and subcutaneous adipocytes in cattle

Background This study used a genome-wide screen of gene expression to better understand the metabolic and functional differences between commercially valuable intramuscular fat (IMF) and commercially wasteful subcutaneous (SC) fat depots in Bos taurus beef cattle. Results We confirmed many findings previously made at the biochemical level and made new discoveries. The fundamental lipogenic machinery, such as ACACA and FASN encoding the rate limiting Acetyl CoA carboxylase and Fatty Acid synthase were expressed at 1.6–1.8 fold lower levels in IMF, consistent with previous findings. The FA elongation pathway including the rate limiting ELOVL6 was also coordinately downregulated in IMF compared to SC as expected. A 2-fold lower expression in IMF of ACSS2 encoding Acetyl Coenzyme A synthetase is consistent with utilisation of less acetate for lipogenesis in IMF compared to SC as previously determined using radioisotope incorporation. Reduced saturation of fat in the SC depot is reflected by 2.4 fold higher expression of the SCD gene encoding the Δ9 desaturase enzyme. Surprisingly, CH25H encoding the cholesterol 25 hydroxylase enzyme was ~ 36 fold upregulated in IMF compared to SC. Moreover, its expression in whole muscle tissue appears representative of the proportional representation of bovine marbling adipocytes. This suite of observations prompted quantification of a set of oxysterols (oxidised forms of cholesterol) in the plasma of 8 cattle exhibiting varying IMF. Using Liquid Chromatography-Mass Spectrometry (LC-MS) we found the levels of several oxysterols were significantly associated with multiple marbling measurements across the musculature, but (with just one exception) no other carcass phenotypes. Conclusions These data build on our molecular understanding of ruminant fat depot biology and suggest oxysterols represent a promising circulating biomarker for cattle marbling

Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer

Quantum optics in the phase space - A tutorial on Gaussian states

In this tutorial, we introduce the basic concepts and mathematical tools needed for phase-space description of a very common class of states, whose phase properties are described by Gaussian Wigner functions: the Gaussian states. In particular, we address their manipulation, evolution and characterization in view of their application to quantum information.Comment: Tutorial. 23 pages, 1 figure. Updated version accepted for publication in EPJ - ST devoted to the memory of Federico Casagrand

Middle to late Pleistocene palaeoecological reconstructions and palaeotemperature estimates for cold/cool stage deposits at Whittlesey, eastern England

Fossiliferous beds in a complex sequence of late Middle to Late Pleistocene deposits at Whittlesey, eastern England, provided a rare opportunity for a multidisciplinary study of the palaeoecology of cool/cold stage deposits from different glacial stages. The fossiliferous sediments investigated form part of the River Nene 1st Terrace. Three of the four fossil assemblages investigated pre-date the last interglacial stage (Ipswichian/Eemian/marine oxygen isotope stage (MIS) 5e), whereas the other dates to part of the MIS 3 interstadial complex (Middle Devensian/Weichselian). Pollen, plant macrofossil, molluscan, coleopteran, ostracod, foraminifera and vertebrate data are available to a greater or lesser extent for each cool/cold stage assemblage, and they broadly present the same ecological picture for each one: a continuum from low-energy permanent to non-permanent aquatic habitats through marshland with associated waterside taxa, together with flood influxes of fluvial, riparian and ruderal taxa. Although each fossil assemblage records cool/cold climatic conditions, to a greater or lesser extent, these conditions are more apparent in the insect and ostracod faunas. In comparison with results published for the Last Glacial Maximum (LGM) stadial in The Netherlands, palaeotemperature estimates based on ranges of mutual agreement between independent coleopteran and ostracod methods for the three pre-Ipswichian/Eemian assemblages indicate minimum mean July air temperatures that are from +1° to +3 °C warmer, but January values that embrace the −8 °C estimate for the LGM. There is, however, a disparity between the coleopteran and ostracod palaeotemperature estimates for the Middle Devensian/Weichselian fossil assemblage, which are based on two different sample stratigraphic levels; the lower, coleopteran assemblage is indicative of very cool, continental climates, whereas the stratigraphically slightly higher ostracod assemblage suggests a climatic amelioration. Lack of numerical age-estimates prevents a robust stratigraphical interpretation, but the youngest pre-Ipswichian/Eemian fossil assemblage could date to the MIS 7–6 transition, at a time when cooling possibly preceded glacially driven sea-level fall. It is apparent from the rich coleopteran data that some continental cold-indicator taxa also appeared in pre-Ipswichian/Eemian cold stages and therefore assignment of continental cold-indicator taxa to particular Devensian/Weichselian intervals should be undertaken with care

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6,809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes