Effect of Dietary Phosphate Deprivation on Red Blood Cell Parameters of Periparturient Dairy Cows

Postparturient hemoglobinuria is a sporadic disease characterized by intravascular hemolysis and hemoglobinuria in early lactating dairy cows. The condition has empirically been associated with phosphorus (P) deficiency or hypophosphatemia; however, the exact etiology remains obscure. This paper summarizes two controlled studies investigating the effect of P deprivation during the transition period. In Study I, 36 late pregnant dairy cows were randomly assigned to either a diet with low, or adequate, P content from four weeks before calving to four weeks after calving. In Study II, 30 late pregnant dairy cows were again assigned to either a diet with low, or adequate, P for the last four weeks before calving only. Pronounced hypophosphatemia developed during periods of restricted P supply. In early lactation, a subtle decline of the red blood cell count occurred independently of the dietary P supply. In Study I, anemia developed in 11 cows on deficient P supply, which was associated with hemoglobinuria in five cases. Neither erythrocyte total P content nor osmotic resistance of erythrocytes were altered by dietary P deprivation. Restricted dietary P supply, particularly in early lactation, may lead to postparturient hemoglobinuria, but more frequently causes clinically inapparent hemolysis and anemia in cows

Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects

YesBackgorund Prior data suggest pre-diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple-negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method NOD/SCID mice were implanted with HER2+ MDA-MB-231/LN/2-4/H2N, trastuzumab-resistant HER2+ HCC1954 or a TNBC patient-derived xenograft (PDX). A daily low-dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA-MB-231/LN/2-4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre-treatment aspirin, 3 weeks post-resection, HCC1954/TNBC animals received standard-of-care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results Aspirin delayed time to metastasis in MDA-MB-231/LN/2-4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre-treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co-culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF-C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo-preventative agent in the HER2+ or TNBC setting.Funding is acknowledged from the Irish Cancer Society Collaborative Cancer Research Centre under BREAST- PREDICT grant CCRC13GAL (www.breas tpred ict.com). I.S.M, E.M and A.T.B, are members of the EurOPDX Consortium, and receive funding from the European Union's Horizon 2020 research and innovation programme, grant agreement no. #731105 (EurOPDX Research Infrastructure, www.europ dx.eu)

The transcription factor BcLTF1 regulates virulence and light responses in the necrotrophic plant pathogen Botrytis cinerea.

Botrytis cinerea is the causal agent of gray mold diseases in a range of dicotyledonous plant species. The fungus can reproduce asexually by forming macroconidia for dispersal and sclerotia for survival; the latter also participate in sexual reproduction by bearing the apothecia after fertilization by microconidia. Light induces the differentiation of conidia and apothecia, while sclerotia are exclusively formed in the absence of light. The relevance of light for virulence of the fungus is not obvious, but infections are observed under natural illumination as well as in constant darkness. By a random mutagenesis approach, we identified a novel virulence-related gene encoding a GATA transcription factor (BcLTF1 for light-responsive TF1) with characterized homologues in Aspergillus nidulans (NsdD) and Neurospora crassa (SUB-1). By deletion and over-expression of bcltf1, we confirmed the predicted role of the transcription factor in virulence, and discovered furthermore its functions in regulation of light-dependent differentiation, the equilibrium between production and scavenging of reactive oxygen species (ROS), and secondary metabolism. Microarray analyses revealed 293 light-responsive genes, and that the expression levels of the majority of these genes (66%) are modulated by BcLTF1. In addition, the deletion of bcltf1 affects the expression of 1,539 genes irrespective of the light conditions, including the overexpression of known and so far uncharacterized secondary metabolism-related genes. Increased expression of genes encoding alternative respiration enzymes, such as the alternative oxidase (AOX), suggest a mitochondrial dysfunction in the absence of bcltf1. The hypersensitivity of Δbctlf1 mutants to exogenously applied oxidative stress--even in the absence of light--and the restoration of virulence and growth rates in continuous light by antioxidants, indicate that BcLTF1 is required to cope with oxidative stress that is caused either by exposure to light or arising during host infection

Translational medicine definition by the European Society for Translational Medicine

Progress in the field of translational medicine (TM) within the last decade attests to the importance of the TM initiative in the context of more traditional academic health science centers. In many instances, these advancements have taken place without a clear definition of TM, which signifies the urgent need for a clear, consensus definition that would serve as an integrative blueprint for the various “versions” of TM definition. The various existing definitions are reflecting the diversity of institutional translational research and deployment programs. The European Society for Translational Medicine (EUSTM) is a global non-profit and neutral society whose principal objective is to enhance world-wide healthcare through the specific development and eventual clinical implementation and exploitation of TM-based approaches, resources and expertise. In this position article, the EUSTM defines TM as an interdisciplinary branch of the biomedical field supported by three main pillars: benchside, bedside and community. The goal of TM is to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis, and therapies. Accordingly, TM is a highly interdisciplinary field, the primary goal of which is to coalesce assets of various natures within the individual pillars in order to improve the global healthcare system significantly

Varicella-Zoster Virus Gene 66 Transcription and Translation in Latently Infected Human Ganglia

Latent infection with varicella-zoster virus (VZV) is characterized by restricted virus gene expression and the absence of virus production. Of the ∼70 predicted VZV genes, only five (genes 4, 21, 29, 62, and 63) have been shown by multiple techniques to be transcribed during latency. IE62, the protein product of VZV gene 62, is the major immediate-early (IE) virus-encoded transactivator of viral gene transcription and plays a pivotal role in transactivating viral genes during lytic infection. The protein kinase (66-pk) encoded by VZV gene 66 phosphorylates IE62, resulting in cytoplasmic accumulation of IE62 that mitigates nuclear IE62-induced gene activation. Analysis of latently infected human trigeminal ganglia for 66-pk expression by reverse transcriptase-dependent nested PCR, including DNA sequence analysis, in situ hybridization, and immunohistochemistry, revealed VZV open reading frame 66 to be a previously unrecognized latently expressed virus gene and suggests that prevention of IE62 import to the nucleus by VZV 66-pk phosphorylation is one possible mechanism by which VZV latency is maintained