Effect of diets differing in rumen soluble nitrogen on utilization of poor-quality roughage by sheep

This study investigated the effects of replacing rapid-release nitrogen (N) from urea with a graded level of slow-release N (Optigen® II) source on intake, digestibility, rumen fermentation and microbial protein synthesis, when sheep were fed a poor-quality roughage diet. Five rumen cannulated wethers were used in a 5 x 5 Latin square experimental design. The treatments had various proportions of urea to Optigen® II (0 : 100, 25 : 75, 50 : 50, 75 : 25 and 100 : 0), with the same inclusion level of starch and a mineral premix on an iso-nitrogen basis. The 25% urea : 75% Optigen® II treatment showed significantly higher intakes of dry matter, organic matter, neutral detergent fibre and digestible organic matter than in the other treatments. No differences were recorded for apparent dry matter digestibility, organic matter digestibility and neutral detergent fibre digestibility among the treatments. However, sheep on the 100% Optigen® II treatment had a significantly lower apparent nitrogen digestibility. No differences were observed for ruminal pH and volatile fatty acid concentrations among the treatments, except for butyrate and isobutyrate concentrations. The butyrate concentration of the 100% Optigen® II treatment was significantly lower than the other treatments, whereas the isobutyrate concentration was significantly lower than in Treatments 2 (75% urea : 25% Optigen® II) and 5 (100% Optigen® II). The rumen NH3-N concentration of the 100% Optigen® II treatment was significantly lower than the 100% urea treatment at two and four hours after infusion. Based on biological responses, results suggest that up to 75% of urea could be replaced with Optigen® II in supplements.The Protein Research Foundation, Feedtek, NRF and IFS grant.http://www.sasas.co.zaam201

PARP14 is a novel target in <em>STAT6</em> mutant follicular lymphoma.

The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL

The continuous heart failure spectrum: moving beyond an ejection fraction classification.

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone

The continuous heart failure spectrum: Moving beyond an ejection fraction classification

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone. © The Author(s) 2019