Climbazole Boosts Activity of Retinoids in Skin

Abstract

Objective

To explore if climbazole enhances retinoid-associated biological activities in vitro and in vivo.

Methods

Primary human dermal fibroblasts (HDFs) were treated from six to 48 hours with either retinoids (retinol, retinyl propionate, retinyl palmitate) alone or in combination with climbazole, then assessed for cellular retinoic acid-binding protein 2 (CRABP2) mRNA expression by RT-qPCR. Next, skin equivalent (SE) cultures were topically treated with a retinol or retinyl propionate, and with or without climbazole, then measured for biological changes in retinoid biomarkers. Lastly, an IRB-approved clinical study was conducted on the outer forearm of 16 subjects to ascertain the effects of low (0.02%) or high (0.1%) levels of retinol, retinyl propionate (0.5%), climbazole (0.5%) or a combination of retinol (0.02%) /climbazole (0.5%). Indicators of retinoid activities were measured after 3 weeks.

Results

Treatment of HDFs with retinol or retinyl propionate were unaffected by climbazole but alone, resulted in a significantly (p<0.01) higher sustained CRABP2 mRNA expression than those treated with retinyl palmitate or vehicle control. In SEs, climbazole combined with either retinol or retinyl propionate, boosted retinoid related activity greater than the retinoid only, reflected by a dose-response, down-regulation of loricrin (LOR) and induction of keratin 4 (KRT4) proteins. In vivo, retinol (0.1%) and retinyl propionate (0.5%) significantly increased most evaluated biomarkers, as expected. Low dose retinol or climbazole alone did not increase these biomarkers; however, in combination, significant (p<0.05) increases in retinoid and aging biomarkers were detected.

Conclusion

Climbazole boosted retinoid activity both in the SE model, after a combined topic treatment with either retinol or retinyl propionate, and in vivo, in combination with a low level of retinol. Based upon the evidence presented here, we suggest that the topical skin application of climbazole in combination with retinoids, could deliver skin aging benefits more than a less robust retinoid alone.

This article is protected by copyright. All rights reserved.

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Investigation of heavy metal pollution in eastern Aegean Sea coastal waters by using Cystoseira barbata , Patella caerulea , and Liza aurata as biological indicators

Abstract

In order to have an extensive contamination profile of heavy metal levels (Cd, Cu, Fe, Mn, Ni, Pb, and Zn), seawater, sediment, Patella caerulea, Cystoseira barbata, and Liza aurata were investigated by using inductively coupled plasma-atomic emission spectrometry (ICP-AES). Samples were collected from five coastal stations along the eastern Aegean Sea coast (Turkey) on a monthly basis from July 2002 through May 2003. According to the results of this study, heavy metal levels were arranged in the following sequence: Fe > Pb > Zn > Mn > Ni > Cu > Cd for water, Fe > Cu > Mn > Ni > Zn > Pb > Cd for sediment, Fe > Zn > Mn > Pb > Ni > Cd > Cu for C. barbata, Fe > Zn > Mn > Ni > Pb > Cu > Cd for P. caerulea, and Fe > Zn > Mn > Cu > Ni > Pb > Cd for L. aurata. Moreover, positive relationships between Fe in water and Mn in water, Fe in sediment and Mn in sediment, Fe in C. barbata and Mn in C. barbata, Fe in P. caerulea and Mn in P. caerulea, and Fe in L. aurata and Mn in L. aurata may suggest that these metals could be originated from the same anthropogenic source. C. barbata represented with higher bioconcentration factor (BCF) values, especially for Fe, Mn, and Zn values. This observation may support that C. barbata can be used as an indicator species for the determinations of Fe, Mn, and Zn levels. Regarding Turkish Food Codex Regulation's residue limits, metal values in L. aurata were found to be lower than the maximum permissible levels issued by Turkish legislation and also the recommended limits set by FAO/WHO guidelines. The results of the investigation indicated that P. caerulea, L. aurata, and especially C. barbata are quantitative water-quality bioindicators and biomonitoring subjects for biologically available metal accumulation for Aegean Sea coastal waters.

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Sub-chronic toxicological studies of transition metal complexes of naproxen on sprague-dawley rats

Publication date: Available online 18 January 2017
Source:Alexandria Journal of Medicine
Author(s): Md. Sharif Hasan, Narhari Das, Farida Begum, S M Abdur Rahman
ObjectiveThe purpose of this research was to investigate sub-chronic toxicity in animal model.MethodsA detailed study was done on the physical, hematological, biochemical and hormonal parameters of both male and female Sprague-Dawley rats after 28days administration of naproxen and its metal complexes.ResultsThere were no significant changes found in physical parameters on observation for both male and female rats without some minor differences. However, Naproxen metal complexes showed comparatively lower side effects than naproxen. Hematological report suggested that naproxen was in process of initiating inflammation which was justified by decreasing the mean value hemoglobin and hematocrit level and increasing the white blood cells level. There were no significant changes in biochemical parameters, however, the mean value of blood glucose level and cholesterol seemed to be higher and triglyceride was lower. Thyroid hormone levels were found lower, that was another indication inflammatory process. However, this might have the ability to lower the insulin secretion resulting in increasing blood glucose level.ConclusionIn the present investigation, there were no significant alterations in histopathological studies and physical parameters though some signs of abnormalities had been found but hematological and hormonal data did not suggest any inflammatory or toxicological activity. However, we observed that naproxen showed more side effects than metal complexes which indicated that carboxylic group (COOH) of naproxen may be responsible for showing those most of the side effects.



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Systemic therapy in metastatic salivary gland carcinomas: A pathology-driven paradigm?

Publication date: March 2017
Source:Oral Oncology, Volume 66
Author(s): Salvatore Alfieri, Roberta Granata, Cristiana Bergamini, Carlo Resteghini, Paolo Bossi, Lisa F. Licitra, Laura D. Locati
Salivary gland carcinomas (SGCs) represent one of the most complex tumors from a pathological point of view. According to the World Health Organization (WHO) classification (2005), twenty-four malignant histotypes are recognized, almost all characterized by specific morphological and genetic features as well as by particular clinical behavior. Loco-regional relapse and distant metastases are quite common. Distant metastases are diagnosed in 25–55% of the patients and only 20% of them are alive after 5years. Adenoid cystic carcinoma (ACC) is the most common (60%) malignant histotype observed in patients with metastatic disease, whilst the other histotypes such as mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified (NOS), and myoepithelial carcinoma are rarer. The most common therapeutic approach in cases of metastatic disease is systemic chemotherapy, although the results with this type of approach are poor both in terms of response rate and overall outcome. No consensus has yet been reached on what the standard regimen of chemotherapy should be in this setting. New therapies are under investigation e.g. antiangiogenic agents, histone deacetylase inhibitors, and hormonal deprivation treatment. We have focused our review on systemic treatments in ACC and in non-ACC tumors, including in this latter group all SGC histotypes other than ACC.



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TCGA study identifies genomic features of cervical cancer

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified novel genomic and molecular characteristics of cervical cancer that will aid in subclassification of the disease and may help target therapies that are most appropriate for each patient.

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Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Publication date: Available online 19 January 2017
Source:Cancer Cell
Author(s): Verline Justilien, Syed A. Ali, Lee Jamieson, Ning Yin, Adrienne D. Cox, Channing J. Der, Nicole R. Murray, Alan P. Fields
The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

Graphical abstract

Teaser

Justilien et al. reveal that the guanine nucleotide exchange factor Ect2 is required for tumor initiation in a non-small-cell lung carcinoma model and uncover a nuclear role for Ect2 in promoting rDNA transcription, which is important for transformation, through a mechanism involving Rac1, NPM, and UBF1.


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Arbuscular mycorrhizal fungal community composition associated with Juniperus brevifolia in native Azorean forest

Publication date: February 2017
Source:Acta Oecologica, Volume 79
Author(s): Catarina Drumonde Melo, Sara Luna, Claudia Krüger, Christopher Walker, Duarte Mendonça, Henrique M.A.C. Fonseca, Maria Jaizme-Vega, Artur da Câmara Machado
The communities of glomeromycotan fungi (arbuscular mycorrhizal fungi, AMF) under native Juniperus brevifolia forest from two Azorean islands, Terceira and São Miguel, were compared, mainly by spore morphology, and when possible, by molecular analysis. Thirty-nine morphotypes were detected from 12 genera. Glomeromycotan fungal richness was similar in Terceira and São Miguel, but significantly different among the four fragments of native forest. Spore diversity and community composition differed significantly between the two islands. The less degraded island, Terceira, showed 10 exclusive morphotypes including more rare types, whereas the more disturbed forest on São Miguel showed 13 morphs, mostly of common types. Forests from Terceira were dominated by Acaulosporaceae and Glomeraceae. Whereas members of Acaulosporaceae, Glomeraceae and Ambisporaceae were most frequent and abundant in those from São Miguel. Spore abundance was greatest on Terceira, and correlated with soil chemical properties (pH), average monthly temperature and relative humidity.



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Effect of transitioning to automatic milking systems on producers' perceptions of farm management and cow health in the Canadian dairy industry

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): C. Tse, H.W. Barkema, T.J. DeVries, J. Rushen, E.A. Pajor
Automatic milking systems (AMS), or milking robots, are becoming increasingly common, but there is little documentation of how AMS have affected farms as a whole and what challenges and benefits producers are experiencing during their transition to AMS. The objective of this national survey was to document the effect of transitioning to AMS on producer perceptions of change in housing, farm management, and cow health. In total, 217 AMS producers were surveyed from 8 Canadian provinces. Median time since transition for respondents was 30 mo. The mean number of lactating cows per robot was 51 cows, with a median of 2 AMS units per farm. Fifty-five percent of producers built a new barn to accommodate the AMS. Changing housing systems was necessary for 47% of producers, not necessary for 50%, and not applicable to 3% (as the AMS farm was their first farm). Cleaning and feeding practices remained the same. Overall, farms increased herd size from a median of 77 to 85 lactating cows with the transition to AMS. After the transition to AMS, 66% of producers changed their health-management practices. Producers reported either a decrease or no change in rate of clinical mastitis. Reports on change in rate of lameness and total bacterial count varied. Conception rate was reported to have increased for 63% of producers. Culling rate was perceived to have stayed the same for 59% of producers. Overall, producers perceived their transitions to AMS as successful. Findings from this project provide a benchmark of the effects of AMS on important aspects of Canadian dairy farming, as well as provide producers, AMS manufacturers, veterinarians, and dairy advisors with more detailed knowledge on what to expect when transitioning to AMS.



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Apparent ruminal synthesis of B vitamins in lactating dairy cows fed diets with different forage-to-concentrate ratios

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): M. Seck, J. A. Voelker Linton, M.S. Allen, D.S. Castagnino, P.Y. Chouinard, C.L. Girard
Effects of the forage-to-concentrate ratio on apparent ruminal synthesis of thiamine, riboflavin, niacin, vitamin B6, folates, and vitamin B12 were evaluated in an experiment using 14 ruminally and duodenally cannulated Holstein cows. The experiment was a crossover design with two 15-d treatment periods and a 14-d preliminary period in which cows were fed a diet intermediate in composition between the treatment diets. Treatments were diets containing low-forage (44.8% forage, 32.8% starch, 24.4% neutral detergent fiber) or high-forage (61.4% forage, 22.5% starch, 30.7% neutral detergent fiber) concentrations. Both diets were formulated with different proportions of the same ingredients. Concentrations of B vitamins were analyzed in feed and duodenal digesta. Apparent ruminal synthesis of each B vitamin was calculated as the duodenal flow minus the intake. The high-forage diet had the highest concentrations of riboflavin, niacin, vitamin B6, and folates, whereas the low-forage diet had the highest thiamine concentration. Vitamin B12 in the diets was under the level of detection. Consequently, despite a reduction in dry matter intake when the cows were fed the high-forage diet, increasing dietary forage concentration increased or tended to increase intakes of riboflavin, niacin, and vitamin B6 but reduced thiamine and folate intakes. Increasing dietary forage concentration reduced apparent ruminal degradation of thiamine and apparent ruminal synthesis of riboflavin, niacin, and folates and increased ruminal degradation of vitamin B6, but had no effect on ruminal synthesis of vitamin B12. As a consequence, increasing the forage-to-concentrate ratio had no effect on the amounts of thiamine, riboflavin, and vitamin B12 reaching the small intestine but decreased the amounts of niacin, vitamin B6, and folates available for absorption. Apparent ruminal syntheses of riboflavin, niacin, folates, and vitamin B12 were correlated positively with the amount of starch digested in the rumen and duodenal flow of microbial N, whereas these correlations were negative for thiamine. Apparent ruminal syntheses of thiamine and vitamin B6 were negatively correlated with their respective intakes, whereas folate intake was positively correlated with its synthesis in the rumen.



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Effects of rumen-protected Capsicum oleoresin on immune responses in dairy cows intravenously challenged with lipopolysaccharide

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): J. Oh, M. Harper, F. Giallongo, D.M. Bravo, E.H. Wall, A.N. Hristov
The objective of this experiment was to investigate the effects of rumen-protected Capsicum oleoresin (RPC) on productivity and immune responses including feed intake, milk yield and composition, white and red blood cells, lipid peroxidation, and blood concentration of cortisol, haptoglobin, glucose, and insulin in lactating dairy cows experimentally challenged with lipopolysaccharide (LPS). The experiment was a replicated 3 × 3 Latin square design with 9 multiparous Holstein cows in three 28-d periods. Treatments were 0 (control), 100, and 200 mg of RPC/cow per day, mixed with small portions of the total mixed ration and top-dressed. Bacterial LPS was intravenously administered at 1.0 μg/kg of body weight in the last week of each experimental period, and blood samples were collected at 0, 2, 4, 8, and 24 h after administration. Dry matter intake, milk yield, and white blood cells including neutrophils, lymphocytes, monocytes, and eosinophils were decreased, and rectal temperature, hemoglobin, and serum concentrations of cortisol and haptoglobin were increased by LPS. Red blood cells, platelets, and plasma concentration of thiobarbituric acid reactive substances were not affected by LPS. Dry matter intake, milk yield, and milk composition in the 5 d post-LPS challenge were not affected by RPC. Rectal temperature, white blood cells, red blood cells, hemoglobin, and platelets were also not affected by RPC. Compared with the control, RPC tended to decrease cortisol at 2 h following LPS challenge and decreased haptoglobin concentration in serum across sampling points. Concentration of thiobarbituric acid reactive substances in plasma was decreased by RPC at 24 h post-LPS challenge. Glucose and insulin were not affected by RPC, but serum insulin concentration at 8 h was lowered by RPC compared to the control. Collectively, RPC had no or subtle effects on feed intake, milk yield and composition, rectal temperature, white and red blood cells, and serum glucose and insulin concentration in dairy cows challenged by LPS. However, RPC tended to decrease cortisol and decreased concentrations of haptoglobin and thiobarbituric acid reactive substances in blood following LPS challenge. Data suggest that dietary supplementation of RPC may modulate acute phase responses induced by bacterial infection in lactating dairy cows.



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Detection of recombinant human lactoferrin and lysozyme produced in a bitransgenic cow

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): Germán G. Kaiser, Nicolás C. Mucci, Vega González, Lourdes Sánchez, José A. Parrón, María D. Pérez, Miguel Calvo, Juan F. Aller, Federico A. Hozbor, Adrián A. Mutto
Lactoferrin and lysozyme are 2 glycoproteins with great antimicrobial activity, being part of the nonspecific defensive system of human milk, though their use in commercial products is difficult because human milk is a limited source. Therefore, many investigations have been carried out to produce those proteins in biological systems, such as bacteria, yeasts, or plants. Mammals seem to be more suitable as expression systems for human proteins, however, especially for those that are glycosylated. In the present study, a bicistronic commercial vector containing a goat β-casein promoter and an internal ribosome entry site fragment between the human lactoferrin and human lysozyme genes was developed to allow the introduction of both genes into bovine adult fibroblasts in a single transfection. Embryos were obtained by somatic cell nuclear transfer, and, after 6 transferences to recipients, 3 pregnancies and 1 viable bitransgenic calf were obtained. The presence of the vector was confirmed by fluorescent in situ hybridization of skin cells. At 13 mo of life and after artificial induction of lactation, both recombinant proteins were found in the colostrum and milk of the bitransgenic calf. Human lactoferrin concentration in the colostrum was 0.0098 mg/mL and that in milk was 0.011 mg/mL, whereas human lysozyme concentration in the colostrum was 0.0022 mg/mL and that in milk was 0.0024 mg/mL. The molar concentration of both human proteins revealed no differences in protein production of the internal ribosome entry site upstream and downstream protein. The enzymatic activity of lysozyme in the transgenic milk was comparable to that of human milk, being 6 and 10 times higher than that of bovine lysozyme present in milk. This work represents an important step to obtain multiple proteins or enhance single protein production by using animal pharming and fewer regulatory and antibiotic-resistant foreign sequences, allowing the design of humanized milk with added biological value for newborn nutrition and development. Transgenic animals can offer a unique opportunity to dairy industry, providing starting materials suitable to develop specific products with high added value.



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Influence of breed, milk yield, and temperature-humidity index on dairy cow lying time, neck activity, reticulorumen temperature, and rumination behavior

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): A.E. Stone, B.W. Jones, C.A. Becker, J.M. Bewley
The objective of this study was to compare weekly mean lying time (LT), neck activity (NA), reticulorumen temperature (RT), and rumination time (RU) among 3 breed groups, milk yield (MY), and temperature-humidity index (THI). Cows (n = 36; 12 Holstein, 12 crossbred, and 12 Jersey) were blocked by parity group (primiparous or multiparous), days in milk, and MY. Lying time, NA, RT, RU, and MY were recorded and averaged by day and then by week for each cow. For study inclusion, each cow was required to have 10 wk of LT, NA, RT, and RU data. Maximum THI were recorded and averaged daily. Mean (±SE) days in milk, LT, MY, RT, RU, NA, and maximum THI were 159.0 ± 6.0 d, 11.1 ± 0.1 h/d, 28.7 ± 0.5 kg/d, 38.8 ± 0.0°C, 6.4 ± 0.1 h/d, 323.8 ± 3.8 activity units, and 56.5 ± 0.6, respectively. The MIXED Procedure of SAS (SAS Institute Inc., Cary, NC) was used to evaluate fixed effects of breed, MY, parity, THI, and their interactions on LT, NA, RT, and RU with cow nested within breed as subject. All main effects remained in each model regardless of significance level. Stepwise backward elimination was used to remove nonsignificant interactions. The interactions of breed × parity group and maximum THI × parity group were associated with RT. Increasing THI coincided with increasing RT. Least squares means LT for multiparous cows was significantly greater than LT for primiparous cows (11.4 ± 0.3 and 10.5 ± 0.5 h/d, respectively). Least squares means NA for primiparous cows was greater than for multiparous cows of all breeds (372.1 ± 10.9 and 303.4 ± 7.8, respectively). The CORR Procedure of SAS was used to evaluate relationships among RT, RU, LT, NA, and MY. Rumination time was positively correlated with MY (r = 0.30) and negatively correlated with LT (r = −0.14). Reticulorumen temperature was negatively correlated with MY (r = −0.11). Rumination time was positively correlated with NA (r = 0.18) and negatively correlated with LT (r = −0.14). Lying time and NA were negatively correlated (r = −0.43). Neck activity was positively correlated with MY (r = 0.14). Lying time was negatively correlated with MY (r = −0.25). Milk yield was associated with RU, which may be related to cows with greater MY also having a greater feed intake. Lying time increased and NA decreased with increasing parity, which may be effects of social hierarchy, where primiparous cows are more susceptible to being pushed away from the feed bunk and freestalls. Milk yield was positively associated with RU. Greater milk production requires greater feed intake, which may result in longer RU than for low-yielding cows. Lying time decreased as milk yield increased. The behavioral and physiological differences observed in this study provide new insight into the effects that breed, parity, MY, and THI have on cows.



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Elevation of blood β-hydroxybutyrate concentration affects glucose metabolism in dairy cows before and after parturition

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): M. Zarrin, L. Grossen-Rösti, R.M. Bruckmaier, J.J. Gross
Recent studies in mid- and late-lactation dairy cows showed that β-hydroxybutyrate (BHB) infusion had a considerable effect on glucose metabolism and immune response during intramammary lipopolysaccharide challenge. The objective of the present study was to infuse BHB during the dry period and after parturition to investigate the effects of elevated plasma BHB concentrations on metabolism and endocrine changes in transition dairy cows. The hypothesis tested was that regulation of glucose metabolism would change at different physiological stages and an additional elevation of BHB concentration would alter glucose concentration. Multiparous Holstein cows in wk −2 (antepartum, a.p.; n = 6) and wk +2 (postpartum, p.p.; n = 8) relative to calving were infused (4 h from 0800 to 1200 h) with a BHB solution to increase plasma BHB concentration to 1.5 to 2.0 mmol/L (HyperB). The same period the next day without any infusion was considered the control period (CON). Blood samples were taken 1 h before the start of infusion as reference samples and every 30 min during the following 6 h (4 h of infusion and 2 h after infusion) in the HyperB and CON periods, and analyzed for glucose, BHB, insulin, and glucagon concentrations. During the steady state period (the latter 2 h of the 4-h infusion), plasma BHB concentration reached 1.87 ± 0.05 mmol/L (a.p.) and 1.93 ± 0.05 mmol/L (p.p.) in HyperB compared with 0.55 ± 0.06 mmol/L (a.p.) and 0.64 ± 0.04 mmol/L (p.p.) in CON, respectively. The 4-h average BHB infusion rate was 12.4 ± 1.0 and 13.3 ± 0.9 μmol/kg of BW per minute in wk −2 and +2, respectively. Infusion of BHB caused a decrease of plasma glucose concentrations relative to preinfusion levels both before and after parturition, although basal glucose concentrations were different before and after calving. Infusion of BHB increased plasma insulin concentrations a.p. but not p.p., despite a higher basal insulin concentration before than after parturition. These findings show that effects of hyperketonemia on plasma glucose concentrations are similar before and after calving but that endocrine adaptation to hyperketonemia differs before and after parturition. We assume that BHB is a metabolic key regulator in early lactating dairy cows and may affect glucose concentration by further pathways such as gluconeogenesis and altered lipolysis.



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Short communication: Limitations of glucose tolerance tests in the assessment of peripheral tissue insulin sensitivity during pregnancy and lactation in dairy heifers

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): J. De Koster, M. Van Eetvelde, K. Hermans, W. Van den Broeck, M. Hostens, G. Opsomer
The aim of the present study was to point at the limitations of glucose tolerance tests (GTT) to assess peripheral tissue insulin sensitivity in dairy heifers in different physiological states (pregnancy and lactation). Intravenous GTT were performed in 5 nonpregnant, nonlactating heifers, 5 heifers at the end of pregnancy (12–7 d before calving), and 5 lactating primiparous cows (11–14 d after calving). Glucose and insulin concentrations were determined and area under the curve (AUC) and clearance rate of glucose and insulin were calculated. Additionally, data were analyzed using the minimal model to derive the insulin sensitivity parameter (Si). Basal glucose and insulin concentrations were greater in the nonpregnant, nonlactating heifers. Clearance rate of glucose and Si were lowest, whereas the AUC for glucose was greatest in the nonpregnant, nonlactating heifers. Insulin concentrations during the GTT were greater for the nonpregnant, nonlactating heifers. Results from the GTT in pregnant heifers and lactating primiparous cows are biased by the fact that a large part of the glucose disappearance during an intravenous GTT occurs independently of insulin by the pregnant uterus or the lactating mammary gland. As such, greater AUC of glucose, lower clearance rate of glucose, or lower Si derived from GTT performed in nonpregnant, nonlactating dairy heifers in the present study might indicate decreased peripheral tissue insulin sensitivity of the glucose metabolism or decreased insulin-independent glucose disappearance. Based on the results from a GTT, it is impossible to discriminate between both metabolic pathways. It can be concluded that parameters derived from GTT are not suited to compare peripheral tissue insulin sensitivity of the glucose metabolism between dairy heifers in different physiological states due to the large variation in insulin secretion and the substantial difference in insulin-independent glucose disposal associated with these physiological states.



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Genotype by environment (climate) interaction improves genomic prediction for production traits in US Holstein cattle

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): F. Tiezzi, G. de los Campos, K.L. Parker Gaddis, C. Maltecca
Genotype by environment interaction (G × E) in dairy cattle productive traits has been shown to exist, but current genetic evaluation methods do not take this component into account. As several environmental descriptors (e.g., climate, farming system) are known to vary within the United States, not accounting for the G × E could lead to reranking of bulls and loss in genetic gain. Using test-day records on milk yield, somatic cell score, fat, and protein percentage from all over the United States, we computed within herd-year-season daughter-yield deviations for 1,087 Holstein bulls and regressed them on genetic and environmental information to estimate variance components and to assess prediction accuracy. Genomic information was obtained from a 50k SNP marker panel. Environmental effect inputs included herd (160 levels), geographical region (7 levels), geographical location (2 variables), climate information (7 variables), and management conditions of the herds (16 total variables divided in 4 subgroups). For each set of environmental descriptors, environmental, genomic, and G × E components were sequentially fitted. Variance components estimates confirmed the presence of G × E on milk yield, with its effect being larger than main genetic effect and the environmental effect for some models. Conversely, G × E was moderate for somatic cell score and small for milk composition. Genotype by environment interaction, when included, partially eroded the genomic effect (as compared with the models where G × E was not included), suggesting that the genomic variance could at least in part be attributed to G × E not appropriately accounted for. Model predictive ability was assessed using 3 cross-validation schemes (new bulls, incomplete progeny test, and new environmental conditions), and performance was compared with a reference model including only the main genomic effect. In each scenario, at least 1 of the models including G × E was able to perform better than the reference model, although it was not possible to find the overall best-performing model that included the same set of environmental descriptors. In general, the methodology used is promising in accounting for G × E in genomic predictions, but challenges exist in identifying a unique set of covariates capable of describing the entire variety of environments.



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Use of genotype × environment interaction model to accommodate genetic heterogeneity for residual feed intake, dry matter intake, net energy in milk, and metabolic body weight in dairy cattle

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): C. Yao, G. de los Campos, M.J. VandeHaar, D.M. Spurlock, L.E. Armentano, M. Coffey, Y. de Haas, R.F. Veerkamp, C.R. Staples, E.E. Connor, Z. Wang, M.D. Hanigan, R.J. Tempelman, K.A. Weigel
Feed efficiency in dairy cattle has gained much attention recently. Due to the cost-prohibitive measurement of individual feed intakes, combining data from multiple countries is often necessary to ensure an adequate reference population. It may then be essential to model genetic heterogeneity when making inferences about feed efficiency or selecting efficient cattle using genomic information. In this study, we constructed a marker × environment interaction model that decomposed marker effects into main effects and interaction components that were specific to each environment. We compared environment-specific variance component estimates and prediction accuracies from the interaction model analyses, an across-environment analyses ignoring population stratification, and a within-environment analyses using an international feed efficiency data set. Phenotypes included residual feed intake, dry matter intake, net energy in milk, and metabolic body weight from 3,656 cows measured in 3 broadly defined environments: North America (NAM), the Netherlands (NLD), and Scotland (SAC). Genotypic data included 57,574 single nucleotide polymorphisms per animal. The interaction model gave the highest prediction accuracy for metabolic body weight, which had the largest estimated heritabilities ranging from 0.37 to 0.55. The within-environment model performed the best when predicting residual feed intake, which had the lowest estimated heritabilities ranging from 0.13 to 0.41. For traits (dry matter intake and net energy in milk) with intermediate estimated heritabilities (0.21 to 0.50 and 0.17 to 0.53, respectively), performance of the 3 models was comparable. Genomic correlations between environments also were computed using variance component estimates from the interaction model. Averaged across all traits, genomic correlations were highest between NAM and NLD, and lowest between NAM and SAC. In conclusion, the interaction model provided a novel way to evaluate traits measured in multiple environments in which genetic heterogeneity may exist. This model allowed estimation of environment-specific parameters and provided genomic predictions that approached or exceeded the accuracy of competing within- or across-environment models.



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Short communication: Glutamine modulates inflammatory responses to lipopolysaccharide in ex vivo bovine endometrium

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): Pablo G. Noleto, João Paulo E. Saut, I. Martin Sheldon
Bacteria infect the endometrium lining the uterus of cattle after parturition, and clearance of these microbes depends on a robust innate immune response to bacterial molecules, such as the endotoxin lipopolysaccharide (LPS). Endometrial inflammation is characterized by secretion of the cytokines IL-1β and IL-6 and the chemokine IL-8. However, animals often fail to clear invading bacteria and develop uterine disease if they are in negative energy balance, with reduced abundance of glucose and glutamine, which are substrates for energy in tissues. Depletion of glucose blunts inflammatory responses in the endometrium, but the role of glutamine is not clear. The present study tested the hypothesis that depletion of glutamine compromises inflammatory responses to LPS in endometrial tissue. Ex vivo organ cultures of endometrium were challenged with LPS, and culture supernatants accumulated IL-1β, IL-6, and IL-8, as expected. However, reducing the availability of glutamine in culture medium containing glucose reduced the accumulation of IL-1β, IL-6, and IL-8 by >50%. Surprisingly, in the absence of glucose, supplying increasing amounts of glutamine was not sufficient to augment inflammatory responses to LPS, whereas, in the absence of glutamine, supplying more glucose increased inflammation. Furthermore, inhibiting glycolysis reduced the accumulation of IL-1β, IL-6, and IL-8 by >50%, even when glutamine and glucose were abundant. In conclusion, depletion of glutamine reduces inflammatory responses to LPS in the endometrium, and the activity of glutamine depends on glucose and glycolysis. These data provide mechanistic insights into how negative energy balance may be linked to postpartum uterine disease.



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Strategies to gain body condition score in pasture-based dairy cows during late lactation and the far-off nonlactating period and their interaction with close-up dry matter intake

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): J.R. Roche, A. Heiser, M.D. Mitchell, M.A. Crookenden, C.G. Walker, J.K. Kay, M. Vailati Riboni, J.J. Loor, S. Meier
In pasture-based systems, cows are generally thinner at the end of lactation than cows fed total mixed rations and, as a result, over-feeding of metabolizable energy (ME) during the far-off nonlactating period is a standard management policy to achieve optimum calving body condition score (BCS). An alternative would be to manage cows to gain BCS through late lactation, such that cows ended lactation close to optimum calving BCS and maintenance of BCS through to calving. We sought to quantify the effect of moderate or excessive ME intakes during the far-off nonlactating period in cows that had been managed to gain or maintain BCS through late lactation and whether the far-off management strategy interacted with close-up level of feeding. Effects on milk production and circulating indicators of energy balance and metabolic health in early lactation were evaluated. A herd of 150 cows was randomly assigned to 1 of 2 feeding levels in late lactation to achieve a low and high BCS at the time of dry-off (approximately 4.25 and 5.0 on a 10-point scale). Following dry-off, both herds were managed to achieve a BCS of 5.0 one month before calving; this involved controlled feeding (i.e., maintenance) and over-feeding of ME during the far-off dry period. Within each far-off feeding-level treatment, cows were offered 65, 90, or 120% of their pre-calving ME requirements for 3 wk pre-calving in a 2 × 3 factorial arrangement (i.e., 25 cows/treatment). Body weight and BCS were measured weekly before and after calving, and milk production was measured weekly until wk 7 postcalving. Blood samples were collected weekly for 4 wk pre-calving and 5 wk postcalving, and on d 0, 1, 2, 3, and 4 relative to calving, and analyzed for indicators of energy balance (e.g., blood fatty acids, β-hydroxybutyrate), calcium status, and inflammatory state. No interaction was observed between far-off and close-up feeding levels. Over-feeding of ME to low BCS cows during the far-off nonlactating period reduced blood fatty acid and β-hydroxybutyrate concentrations in early lactation, and increased blood albumin to globulin ratio compared with cows that were dried off close to recommended calving BCS and control-fed during the far-off dry period. Cows consuming 65% of their ME requirements during the close-up period had lower fatty acids and β-hydroxybutyrate in early lactation, but produced less milk, particularly during the first 21 d of lactation, had more than 3-fold greater concentration of haptoglobin immediately postcalving, and had a lower blood cholesterol concentration and albumin to globulin ratio, when compared with cows offered 90 or 120% of their ME requirements. Collectively, these measurements indicate that a severe restriction (<70% of ME requirements) during the close-up nonlactating period increases the risk of disease in early lactation and reduces milk production. In summary, far-off over-feeding of ME to cows that needed to gain BCS did not influence peripartum metabolic health in grazing dairy cows, but restricting cows below 70% ME requirements during the close-up transition period resulted in a blood profile indicative of greater inflammation.



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Comparison between direct and indirect methods for exploiting Fourier transform spectral information in estimation of breeding values for fine composition and technological properties of milk

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): V. Bonfatti, D. Vicario, L. Degano, A. Lugo, P. Carnier
The aim of this study was to compare the common method of exploiting infrared spectral data in animal breeding; that is, estimating the breeding values for the traits predicted by infrared spectroscopy, and an alternative approach based on the direct use of spectral information (direct prediction, DP) to predict the estimated breeding values (EBV). Traits were pH, milk coagulation properties, contents of the main casein and whey protein fractions, cheese yield measured by micro-cheese making, lactoferrin, Ca, and fat composition. For the DP method, the number of spectral variables was reduced by principal components analysis to 8 latent traits that explained 99% of the original spectral variation. Restricted maximum likelihood was used to estimate variance components of the latent traits. (Co)variance components of the original spectral traits were obtained by back-transformation and EBV of all derived milk traits were then predicted as traits correlated with the genetic information of the spectra. The rank correlation between the EBV obtained for the infrared-predicted traits and those obtained from the DP method was variable across traits. Rank correlations ranged from 0.07 (for the content of saturated fatty acids expressed as g/100 g of fat) to 0.96 (for dry matter cheese yield, %) and, for most traits, was <0.5. This result can be explained by the nature of the principal components analysis: it does not take into account the covariance between the spectral variables and the reference traits but produces latent traits that maximize the spectral variance explained. Thus, the direct approach is more likely to be effective for traits more related to the main sources of spectral variation (i.e., protein and fat). More research is required to study spectral genetic variation and to determine the best way to choose spectral regions and the type and number of considered latent traits for potential applications.



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Genome-wide mapping of 10 calving and fertility traits in Holstein dairy cattle with special regard to chromosome 18

Publication date: Available online 18 January 2017
Source:Journal of Dairy Science
Author(s): M.-P. Müller, S. Rothammer, D. Seichter, I. Russ, D. Hinrichs, J. Tetens, G. Thaller, I. Medugorac
Over the last decades, a dramatic decrease in reproductive performance has been observed in Holstein cattle and fertility problems have become the most common reason for a cow to leave the herd. The premature removal of animals with high breeding values results in both economic and breeding losses. For efficient future Holstein breeding, the identification of loci associated with low fertility is of major interest and thus constitutes the aim of this study. To reach this aim, a genome-wide combined linkage disequilibrium and linkage analysis (cLDLA) was conducted using data on the following 10 calving and fertility traits in the form of estimated breeding values: days from first service to conception of heifers and cows, nonreturn rate on d 56 of heifers and cows, days from calving to first insemination, days open, paternal and maternal calving ease, paternal and maternal stillbirth. The animal data set contained 2,527 daughter-proven Holstein bulls from Germany that were genotyped with Illumina's BovineSNP50 Bead Chip (Illumina Inc., San Diego, CA). For the cLDLA, 41,635 sliding windows of 40 adjacent single nucleotide polymorphisms (SNP) were used. At each window midpoint, a variance component analysis was executed using ASReml. The underlying mixed linear model included random quantitative trait locus (QTL) and polygenic effects. We identified 50 genome-wide significant QTL. The most significant peak was detected for direct calving ease at 59,179,424 bp on chromosome 18 (BTA18). Next, a mixed-linear model association (MLMA) analysis was conducted. A comparison of the cLDLA and MLMA results with special regard to BTA18 showed that the genome-wide most significant SNP from the MLMA was associated with the same trait and located on the same chromosome at 57,589,121 bp (i.e., about 1.5 Mb apart from the cLDLA peak). The results of 5 different cLDLA and 2 MLMA models, which included the fixed effects of either SNP or haplotypes, suggested that the cLDLA method outperformed the MLMA in accuracy and precision. The haplotype-based cLDLA method allowed for a more precise mapping and the definition of ancestral and derived QTL alleles, both of which are essential for the detection of underlying quantitative trait nucleotides.



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