Liver lipid content and inflammometabolic indices in peripartal dairy cows are altered in response to prepartal energy intake and postpartal intramammary inflammatory challenge.

This study evaluated the effect of feeding a control diet (CON) or a moderate energy diet (overfed, OVE) during the dry period (∼45d) and a postpartum intramammary lipopolysaccharide (LPS) challenge on blood metabolic and inflammatory indices, milk production, and hepatic gene expression. A subset of cows (n=9/diet) in CON (1.34 Mcal/kg of dry matter) and OVE (1.62 Mcal/kg of dry matter) received an intramammary LPS challenge (200 μg; CON-LPS, OVE-LPS, respectively). Liver biopsies were harvested at -14 d from calving, and postpartum at 2.5h post-LPS on d 7, 14, and 30. Prepartum, the OVE group was in more positive energy balance (EB) and had greater body condition score compared with CON. In contrast, during wk 1 postpartum and before the LPS challenge, the OVE group was in greater negative EB than CON. Prepartal diet did not affect postpartal milk production or dry matter intake. At 2h postchallenge on d 7, we observed an increase in serum nonesterified fatty acids (NEFA) and bilirubin and a decrease in hydroxybutyrate, regardless of diet. That was coupled with greater haptoglobin in OVE-LPS compared with CON-LPS. In addition, OVE-LPS cows versus CON nonchallenged, OVE nonchallenged, and CON-LPS had greater liver triacylglycerol (TAG) concentration 2.5h postchallenge on d 7. The concentration of TAG in liver of OVE-LPS remained elevated by 30d postpartum. The liver TAG concentration in OVE-LPS compared with CON-LPS cows was associated with greater serum concentration of NEFA and reactive oxygen metabolites on d 10 and 14 postpartum. Cows in OVE-LPS also had greater concentrations of ceruloplasmin, cholesterol, and vitamin E from d 10 through 21. Among 28 genes associated with fatty acid oxidation, inflammation, oxidative stress, and gluconeogenesis, only SAA3 (which encodes an acute phase protein) was greater in CON-LPS compared with OVE-LPS at 2.5h postchallenge. Expression of HP, which encodes another acute phase protein, was greater in OVE-LPS than in CON-LPS at 14 and 30 d postpartum. Several inflammation-related genes (TNF, IRAK1, NFKB1, ANGPTL4) showed markedly decreased expression between 7 and 14 d, after which expression remained unchanged. No differences were observed in several genes of the growth-hormone/insulin-like growth factor-1 axis, except for SOCS2, expression of which decreased markedly between 7 and 14 d in OVE-LPS but not in CON-LPS. These data suggest that overfeeding a moderate-energy diet prepartum alters the response of the cow to an intramammary challenge after calving and may predispose it to sustained liver lipidosis

Consumption of endophyte-infected fescue seed during the dry period does not decrease milk production in the following lactation.

Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and may reduce milk production of cows consuming these grasses. We investigated the effects of consuming endophyte-infected fescue seed during late lactation and the dry period on mammary growth, differentiation, and milk production. Twenty-four multiparous Holstein cows were randomly assigned to 3 treatment groups. Starting at 90±4 d prepartum, cows were fed endophyte-free fescue seed (control; CON), endophyte-free fescue seed plus 3×/wk subcutaneous injections of bromocriptine (0.1mg/kg of body weight, positive control; BROMO), or endophyte-infected fescue seed (INF) as 10% of the diet on an as fed basis. Although milk yield of groups did not differ before treatment, at dry off (-60 d prepartum) INF and BROMO cows produced less milk than CON. Throughout the treatment period, basal concentrations of PRL and the prepartum increase in plasma PRL were reduced in INF and BROMO cows compared with CON cows. Three weeks after the end of treatment, circulating concentrations of PRL were equivalent across groups. In the subsequent lactation milk yield was not decreased; in fact, BROMO cows exhibited a 9% increase in milk yield relative to CON. Evaluation of mammary tissue during the dry period and the subsequent lactation, by quantitative histology and immunohistochemical analysis of proliferation markers and putative mammary stem or progenitor cell markers, indicated that feeding endophyte-infected fescue seed did not significantly affect mammary growth and development. Feeding endophyte-infected grasses during the dry period may permit effective utilization of feed resources without compromising milk production in the next lactation

An epigenetic clock for gestational age at birth based on blood methylation data

Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances

A heritable subset of the core rumen microbiome dictates dairy cow productivity and emissions

A 1000-cow study across four European countries was undertaken to understand to what extent ruminant microbiomes can be controlled by the host animal and to identify characteristics of the host rumen microbiome axis that determine productivity and methane emissions. A core rumen microbiome, phylogenetically linked and with a preserved hierarchical structure, was identified. A 39-member subset of the core formed hubs in co-occurrence networks linking microbiome structure to host genetics and phenotype (methane emissions, rumen and blood metabolites, and milk production efficiency). These phenotypes can be predicted from the core microbiome using machine learning algorithms. The heritable core microbes, therefore, present primary targets for rumen manipulation toward sustainable and environmentally friendly agriculture

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Medical Research Council (Grant IDs: MC_UU_12015/1, MC_UU_12015/2), Wellcome Trust. Detailed acknowledgements are included in the Supplementary Information that accompanies the paper on the Molecular Psychiatry website

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P-Bonferroni <1.06 x 10(-7)). In additional analyses in 7,278 participants,Peer reviewe

«La relation de limitation et d’exception dans le français d’aujourd’hui : excepté, sauf et hormis comme pivots d’une relation algébrique »

L’analyse des emplois prépositionnels et des emplois conjonctifs d’ “excepté”, de “sauf” et d’ “hormis” permet d’envisager les trois prépositions/conjonctions comme le pivot d’un binôme, comme la plaque tournante d’une structure bipolaire. Placées au milieu du binôme, ces prépositions sont forcées par leur sémantisme originaire dûment métaphorisé de jouer le rôle de marqueurs d’inconséquence systématique entre l’élément se trouvant à leur gauche et celui qui se trouve à leur droite. L’opposition qui surgit entre les deux éléments n’est donc pas une incompatibilité naturelle, intrinsèque, mais extrinsèque, induite. Dans la plupart des cas (emplois limitatifs), cette opposition prend la forme d’un rapport entre une « classe » et le « membre (soustrait) de la classe », ou bien entre un « tout » et une « partie » ; dans d’autres (emplois exceptifs), cette opposition se manifeste au contraire comme une attaque de front portée par un « tout » à un autre « tout ». De plus, l’inconséquence induite mise en place par la préposition/conjonction paraît, en principe, tout à fait insurmontable. Dans l’assertion « les écureuils vivent partout, sauf en Australie » (que l’on peut expliciter par « Les écureuils vivent partout, sauf [qu’ils ne vivent pas] en Australie »), la préposition semble en effet capable d’impliquer le prédicat principal avec signe inverti, et de bâtir sur une telle implication une sorte de sous énoncé qui, à la rigueur, est totalement inconséquent avec celui qui le précède (si « les écureuils ne vivent pas en Australie », le fait qu’ils « vivent partout » est faux). Néanmoins, l’analyse montre qu’alors que certaines de ces oppositions peuvent enfin être dépassées, d’autres ne le peuvent pas. C’est, respectivement, le cas des relations limitatives et des relations exceptives. La relation limitative, impliquant le rapport « tout » - « partie », permet de résoudre le conflit dans les termes d’une somme algébrique entre deux sous énoncés pourvus de différent poids informatif et de signe contraire. Les valeurs numériques des termes de la somme étant déséquilibrées, le résultat est toujours autre que zéro. La relation exceptive, au contraire, qui n’implique pas le rapport « tout » - « partie », n’est pas capable de résoudre le conflit entre deux sous énoncés pourvus du même poids informatif et en même temps de signe contraire : les valeurs numériques des termes de la somme étant symétriques et égales, le résultat sera toujours équivalent à zéro