SUMMARYThe objective of the present study was to evaluate the effects of betaine supplementation on rumen fermentation, lactation performance and plasma characteristics in dairy cows. Twenty multiparous Holstein dairy cows (597±11·8 kg body weight (BW), 88±4·5 days in milk (DIM) and average daily milk production of 26·3±0·5 kg/cow) were used in a replicated 4×4 Latin square experiment. The treatments were: control (without betaine), low-betaine (LB), medium-betaine (MB) and high-betaine (HB) with 0, 50, 100 and 150 g supplemental anhydrous betaine/cow/day, respectively. Betaine was hand-mixed into the top one-third of the daily ration at feeding. Experimental periods were 30 days with 15 days of adaptation and 15 days of sampling. Dry matter (DM) intake was not affected with increasing the betaine supplementation. There were linear increases in milk yield and fat-corrected milk yield (corrected to 40 g fat/kg) and a linear and quadratic increase in milk fat concentration with increasing the betaine supplementation, whereas the proportion and yield of milk protein and lactose, and feed efficiency, were not affected. Ruminal pH and ammonia N linearly decreased, whereas total volatile fatty acid (VFA) concentration linearly and quadratically increased with increasing the betaine supplementation. The ratio of acetate to propionate (A:P) linearly increased from 3·06 to 3·53 as betaine supplementation increased. Digestibility of DM linearly increased, whereas digestibilities of organic matter (OM), crude protein (CP), neutral detergent fibre (NDF) and acid detergent fibre (ADF) in the total tract were quadratically increased with increasing the betaine supplementation. Plasma concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA) were lower for betaine supplementation than for control, and were linearly decreased by betaine supplementation. The results indicate that supplementation of mid-lactation dairy cow diets with betaine increased milk yield through increased feed digestion. Betaine supplementation may benefit lactation performance when methionine supply is limiting.

Our recent study demonstrated that acetylcholinesterase (AChE) activity at the neuromuscular junction (NMJ) of the diaphragm decreased during sepsis. However, the mechanisms were not clearly identified. In this study, we aimed to investigate whether the decreased AChE activity was related to oxidative stress by observing AChE activity in different grades of sepsis induced by caecal ligation and puncture (CLP). At 24 h after surgery, an assay of thiobarbituric acid reactive species (TBARS) and protein carbonyls, as well as the myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activity, was conducted. AChE activity was measured by biochemical and histological detection. AChE and CAT activity in the diaphragm decreased, while the contents of TBARS and protein carbonyls, the activity of MPO and SOD, and the SOD/CAT ratios increased. The above changes were much more significant in the mid-grade septic group than in the low-grade septic group. The colour of the AChE activity staining at the NMJ gradually lightened from the sham surgery group to the mid-grade septic group. AChE activity was significantly negatively correlated with the levels of TBARS and protein carbonyls. We consider that oxidative stress might be responsible for decreased AChE activity in the diaphragms of rats induced with sepsis.

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Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.