Review: Opportunities and challenges for the genetic selection of dairy calf disease traits.

Interest in dairy cow health continues to grow as we better understand health's relationship with production potential and animal welfare. Over the past decade, efforts have been made to incorporate health traits into national genetic evaluations. However, they have focused on the mature cow, with calf health largely being neglected. Diarrhoea and respiratory disease comprise the main illnesses with regard to calf health. Conventional methods to control calf disease involve early separation of calves from the dam and housing calves individually. However, public concern regarding these methods, and growing evidence that these methods may negatively impact calf development, mean the dairy industry may move away from these practices. Genetic selection may be a promising tool to address these major disease issues. In this review, we examined current literature for enhancing calf health through genetics and discussed alternative approaches to improve calf health via the use of epidemiological modelling approaches, and the potential of indirectly selecting for improved calf health through improving colostrum quality. Heritability estimates on the observed scale for diarrhoea ranged from 0.03 to 0.20, while for respiratory disease, estimates ranged from 0.02 to 0.24. The breadth in these ranges is due, at least in part, to differences in disease prevalence, population structure, data editing and models, as well as data collection practices, which should be all considered when comparing literature values. Incorporation of epidemiological theory into quantitative genetics provides an opportunity to better determine the level of genetic variation in disease traits, as it accounts for disease transmission among contemporaries. Colostrum intake is a major determinant of whether a calf develops either respiratory disease or diarrhoea. Colostrum traits have the advantage of being measured and reported on a continuous scale, which removes the issues classically associated with binary disease traits. Overall, genetic selection for improved calf health is feasible. However, to ensure the maximum response, first steps by any industry members should focus efforts on standardising recording practices and encouragement of uploading information to genetic evaluation centres through herd management software, as high-quality phenotypes are the backbone of any successful breeding programme.

Review: When worlds collide - poultry modeling in the 'Big Data' era.

Within poultry production systems, models have provided vital decision support, opportunity analysis, and performance optimization capabilities to nutritionists and producers for decades. In recent years, due to the advancement of digital and sensor technologies, 'Big Data' streams have emerged, optimally positioned to be analyzed by machine-learning (ML) modeling approaches, with strengths in forecasting and prediction. This review explores the evolution of empirical and mechanistic models in poultry production systems, and how these models may interact with new digital tools and technologies. This review will also examine the emergence of ML and Big Data in the poultry production sector, and the emergence of precision feeding and automation of poultry production systems. There are several promising directions for the field, including: (1) application of Big Data analytics (e.g., sensor-based technologies, precision feeding systems) and ML methodologies (e.g., unsupervised and supervised learning algorithms) to feed more precisely to production targets given a 'known' individual animal, and (2) combination and hybridization of data-driven and mechanistic modeling approaches to bridge decision support with improved forecasting capabilities.

Changes in laboratory markers of thrombotic risk early in the first trimester of pregnancy may be linked to an increase in estradiol and progesterone.

BACKGROUND: Pregnant women are at increased risk of venous thrombosis compared to non-pregnant women. Epidemiological and laboratory data suggest that hypercoagulability begins in the first trimester but it is unknown exactly how early in pregnancy this develops. The mechanisms that result in a prothrombotic state may involve oestrogens and progestogens. METHODS: Plasma samples were taken prior to conception and five times in early pregnancy, up to Day 59 gestation, from 22 women undergoing natural cycle in vitro fertilization, who subsequently gave birth at term following a normal pregnancy. Thrombin generation, free Protein S, Ddimer, Fibrinogen, factor VIII, estradiol and progesterone were measured. To counter inter-individual variability, the change in laboratory measurements between the pre-pregnant and pregnant state were measured over time. RESULTS: Peak thrombin, Endogenous Thrombin Potential, Velocity Index and fibrinogen significantly increased, and free Protein S significantly decreased, from pre-pregnancy levels, by 32 days gestation. Ddimer and VIII significantly increased from pre-pregnancy levels by 59 days gestation. Estradiol significantly increased by Day 32 gestation with a non-significant increase of 67% by Day 24 gestation. Progesterone significantly increased by Day 32 gestation. Almost all laboratory markers of thrombosis correlated significantly with estradiol and progesterone. CONCLUSION: Our work is the first to demonstrate that the prothrombotic state develops very early in the first trimester. Laboratory markers of hypercoagulability correlate significantly with estradiol and progesterone suggesting these are linked to the prothrombotic state of pregnancy. Clinicians should consider commencing thromboprophylaxis early in the first trimester in women at high thrombotic risk.

Inflammation and CB2 signaling drive novel changes in the ocular lipidome and regulate immune cell activity in the eye.

Uveitis is inflammation of the uvea which consists of the iris, ciliary body and the choroid of the eye. Uveitis can lead to impaired vision and is responsible for 10% of all cases of blindness globally. Using an endotoxin-induced uveitis (EIU) rodent model, our previous data implicated the endogenous cannabinoid system (ECS) in the amelioration of many of the components of the inflammatory response. Here, we test the hypothesis that the reduction in inflammatory mediators in the EIU model by the CB2 agonist, HU308, is associated with changes in ECS endogenous ligands as well as related lipids, prostaglandins (PGs), 2-acyl glycerols, and lipoamines. Analysis of leukocytes and neutrophils, CB2 mRNA, and 26 lipids in the eye of WT mice after EIU induction and HU308 treatment were compared to the same analyses in the CB2 knock-out (CB2 KO) mouse. Endothelial leukocyte adhesion and neutrophil migration were significantly increased in both WT and CB2 KO after EIU. HU308 significantly reduced the leukocyte adhesion and neutrophil recruitment in the WT animals. HU308 also significantly reduced leukocyte adhesion in the CB2 KO mouse, yet, had no effect on neutrophil infiltration suggesting an important off-target effect of HU308. Lipidomics profiles revealed significant increases in 6 non-ECS lipids after EIU in the WT and that HU308 effectively reduced these back to control levels; in addition, HU308 increased levels of 2-acyl glycerols and decreased all N-acyl glycines. CB2 KOs with saline-injection compared to WT had significantly elevated levels of 2-acyl glycerols, whereas levels of N-oleoyl ethanolamine (OEA), N-stearoyl ethanolamine (SEA), and PGE2 were reduced. CB2 KOs with EIU had 13 lipids that were significantly lower than WT with EIU including 4 N-acyl glycines. HU308 had no effect on lipid concentrations in the CB2 KOs with EIU, however, it did cause further reductions on 3 additional lipids compared to saline controls. HU308 appears to be acting at a non-CB2 target for the reduction of leukocyte infiltration in the EIU model; however, our data suggest that HU308 is working through CB2 to reduce neutrophil migration and for the regulation of multiple lipid signaling pathways including PGs, lipoamines, and 2-acyl glycerols. These data implicate ocular CB2 as a key component of lipid signaling in the eye and part of the regulatory processes of inflammation.

Normal pregnancy is associated with an increase in thrombin generation from the very early stages of the first trimester.

BACKGROUND: Pregnancy is a hypercoagulable state associated with an increased risk of venous thrombosis, which begins during the first trimester, but the exact time of onset is unknown. Thrombin generation, a laboratory marker of thrombosis risk, increases during normal pregnancy but it is unclear exactly how early this increase occurs. METHODS: We assessed thrombin generation by Calibrated Automated Thrombography in women undergoing natural cycle in vitro fertilization, who subsequently gave birth at term following a normal pregnancy (n=22). Blood samples were taken just prior to conception and repeated five times during very early pregnancy, up to Day 59 estimated gestation. RESULTS: Mean Endogenous Thrombin Potential (ETP), peak thrombin generation and Velocity Index (VI) increased significantly from pre-pregnancy to Day 43 gestation (p=0.024-0.0004). This change persisted to Day 59 gestation. The mean of the percentage change from baseline, accounting for inter-individual variation, in ETP, peak thrombin and VI increased significantly from pre-pregnancy to Day 32 gestation (p=0.0351-<0.0001) with the mean increase from baseline persisting to Day 59 gestation. CONCLUSION: Thrombin generation increases significantly during the very early stages of normal pregnancy when compared to the pre-pregnancy state. The increased risk of venous thrombosis therefore likely begins very early in a woman's pregnancy, suggesting that women considered clinically to be at high thrombotic risk should start thromboprophylaxis as early as possible after a positive pregnancy test.

Establishing a reference range for thrombin generation using a standard plasma significantly improves assay precision.

BACKGROUND: Thrombin generation is a global coagulation assay which appears to be an effective method for assessing the potential for an individual's plasma to coagulate. However for this assay to become accepted in routine clinical practice it requires standardization. OBJECTIVES: To establish a reference range for the NIBSC reference plasma (TGT-RP) which can then become an internal quality control (IQC) for thrombin generation assays. PATIENTS/METHODS: Thrombin generation was measured in TGT-RP in 153 independent experiments using 4 assay conditions; 1 pM tissue factor (TF) or 5 pM TF +/- thrombomodulin (TM). A target value +/- 2 SD was calculated to provide an acceptance range under the 4 conditions. A plasma sample from a healthy volunteer was subsequently tested in 11 separate experiments using the TGT-RP for (i) normalisation and (ii) exclusion of experimental results when the TGT-RP results did not fall within the established acceptance range. RESULTS: An acceptance range was established for TGT-RP for the 4 assay conditions. Normalisation of all results from a healthy volunteer reduced inter-assay variability significantly (ETP: p=0.0003; Peak: p=0.001). Exclusion of results from the volunteer when concurrently run TGT-RP results fell outside the acceptance range reduced inter-assay variability significantly when reporting raw data (ETP: p=0.001; Peak: p=0.004). However normalisation of this data had no beneficial effect (ETP: p=0.126; Peak: p=0.232). CONCLUSIONS: Our work represents further progress in the standardization of thrombin generation techniques with the establishment of an IQC reference range. Using an IQC reduces inter-assay variability, whilst allowing reporting of raw data and ensures production of accurate and reproducible data.

Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH).

BACKGROUND AND AIMS: Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. METHODS: We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. RESULTS: We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). CONCLUSIONS: We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.