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## Recent Publications

Department of Animal Sciences
The Robert H. Smith Faculty
of Agricultural, Food & Environment

The Hebrew University of Jerusalem.

P.O. Box 12, Rehovot 76100, Israel
Phone: +972-(0)8-9489119;
Fax: +972-(0)8-9465763;
Yael Lewitus, Department's Secretary
e-mail: yaellew@savion.huji.ac.il

# Publications

2017
Farberov, S. ; Meidan, R. Fibroblast growth factor-2 and transforming growth factor-beta1 oppositely regulate miR-221 that targets thrombospondin-1 in bovine luteal endothelial cells. Biology of Reproduction 2017, 98, 366 - 375. Publisher's VersionAbstract
Thrombospondin-1 (THBS1) affects corpus luteum (CL) regression. Highly induced during luteolysis, it acts as a natural anti-angiogenic, proapoptotic compound. THBS1 expression is regulated in bovine luteal endothelial cells (LECs) by fibroblast growth factor-2 (FGF2) and transforming growth factor-beta1 (TGFB1) acting in an opposite manner. Here we sought to identify specific microRNAs (miRNAs) targeting THBS1 and investigate their possible involvement in FGF2 and TGFB1-mediated THBS1 expression. Several miRNAs predicted to target THBS1 mRNA (miR-1, miR-18a, miR-144, miR-194, and miR-221) were experimentally tested. Of these, miR-221 was shown to efficiently target THBS1 expression and function in LECs. We found that this miRNA is highly expressed in luteal cells and in mid-cycle CL. Consistent with the inhibition of THBS1 function, miR-221 also reduced Serpin Family E Member 1 [SERPINE1] in LECs and promoted angiogenic characteristics of LECs. Plasminogen activator inhibitor-1 (PAI-1), the gene product of SERPINE1, inhibited cell adhesion, suggesting that PAI-1, like THBS1, has anti-angiogenic properties. Importantly, FGF2, which negatively regulates THBS1, elevates miR-221. Conversely, TGFB1 that stimulates THBS1, significantly reduces miR-221. Furthermore, FGF2 enhances the suppression of THBS1 caused by miR-221 mimic, and prevents the increase in THBS1 induced by miR-221 inhibitor. In contrast, TGFB1 reverses the inhibitory effect of miR-221 mimic on THBS1, and enhances the upregulation of THBS1 induced by miR-221 inhibitor. These data support the contention that FGF2 and TGFB1 modulate THBS1 via miR-221. These in vitro data propose that dynamic regulation of miR-221 throughout the cycle, affecting THBS1 and SERPINE1, can modulate vascular function in the CL.
Ochoa, J. C. ; Peñagaricano, F. ; Baez, G. M. ; Melo, L. F. ; Motta, J. C. L. ; Garcia-Guerra, A. ; Meidan, R. ; Pinheiro Ferreira, J. C. ; Sartori, R. ; Wiltbank, M. C. Mechanisms for rescue of corpus luteum during pregnancy: gene expression in bovine corpus luteum following intrauterine pulses of prostaglandins E1 and F2α†. Biology of Reproductionbiolreprod 2017, 98, 465 - 479. Publisher's VersionAbstract
In ruminants, uterine pulses of prostaglandin (PG) F2α characterize luteolysis, while increased PGE2/PGE1 distinguish early pregnancy. This study evaluated intrauterine (IU) infusions of PGF2α and PGE1 pulses on corpus luteum (CL) function and gene expression. Cows on day 10 of estrous cycle received 4 IU infusions (every 6 h; n = 5/treatment) of saline, PGE1 (2 mg PGE1), PGF2α (0.25 mg PGF2α), or PGE1 + PGF2α. A luteal biopsy was collected at 30 min after third infusion for determination of gene expression by RNA-Seq. As expected, IU pulses of PGF2α decreased (P < 0.01) P4 luteal volume. However, there were no differences in circulating P4 or luteal volume between saline, PGE1, and PGE1 + PGF2α, indicating inhibition of PGF2α-induced luteolysis by IU pulses of PGE1. After third pulse of PGF2α, luteal expression of 955 genes were altered (false discovery rate [FDR] < 0.01), representing both typical and novel luteolytic transcriptomic changes. Surprisingly, after third pulse of PGE1 or PGE1 + PGF2α, there were no significant changes in luteal gene expression (FDR > 0.10) compared to saline cows. Increased circulating concentrations of the metabolite of PGF2α (PGFM; after PGF2α and PGE1 + PGF2α) and the metabolite PGE (PGEM; after PGE1 and PGE1 + PGF2α) demonstrated that PGF2α and PGE1 are entering bloodstream after IU infusions. Thus, IU pulses of PGF2α and PGE1 allow determination of changes in luteal gene expression that could be relevant to understanding luteolysis and pregnancy. Unexpectedly, by third pulse of PGE1, there is complete blockade of either PGF2α transport to the CL or PGF2α action by PGE1 resulting in complete inhibition of transcriptomic changes following IU PGF2α pulses.
Levavi-Sivan, B. ; G, D. ; A, H. Vitellogenin Level in the Plasma of Russian Sturgeon (Acipenser gueldenstaedtii) Northern Israel. Journal of Marine Science: Research & Development 2017, 7 244. Publisher's VersionAbstract

In the present study, we examined the vitellogenin (Vg) level of Russian sturgeon maintained in a relatively constant aquaculture at a water temperature of 18-22°C during growth and maturation.

An increase in Vg in the blood plasma from oocytes was found in the yellow oocytes stage to the gray oocytes stage. However, no Vg was found in the pre-vitellogenic stage. Based on the present study and previous studies on hormone control reproduction and growth, we proposed a quality model that correlated between egg development and the hormones involved in controlling vitelogenesis (VTL).

Aizen, J. ; Hollander-Cohen, L. ; Shpilman, M. ; Levavi-Sivan, B. Biologically active recombinant carp LH as a spawning-inducing agent for carp. Journal of Endocrinology 2017, 232. Publisher's Version
Sanchís-Benlloch, P. J. ; Nocillado, J. ; Ladisa, C. ; Aizen, J. ; Miller, A. ; Shpilman, M. ; Levavi-Sivan, B. ; Ventura, T. ; Elizur, A. In-vitro and in-vivo biological activity of recombinant yellowtail kingfish (Seriola lalandi) follicle stimulating hormone. General and Comparative Endocrinology 2017, 241, 41 - 49. Publisher's VersionAbstract
Biologically active recombinant yellowtail kingfish follicle stimulating hormone (rytkFsh) was produced in yeast Pichia pastoris and its biological activity was demonstrated by both in-vitro and in-vivo bioassays. Incubation of ovarian and testicular fragments with the recombinant hormone stimulated E2 and 11-KT secretion, respectively. In-vivo trial in immature female YTK resulted in a significant increase of plasma E2 levels and development of oocytes. In males at the early stages of puberty, advancement of spermatogenesis was observed, however plasma 11-KT levels were reduced when administered with rytkFsh.
Spicer, O. S. ; Zmora, N. ; Wong, T. - T. ; Golan, M. ; Levavi-Sivan, B. ; Gothilf, Y. ; Zohar, Y. The gonadotropin-inhibitory hormone (Lpxrfa) system's regulation of reproduction in the brain–pituitary axis of the zebrafish (Danio rerio)†. Biology of Reproduction 2017, 96, 1031-1042. Publisher's VersionAbstract
Gonadotropin-inhibitory hormone (GNIH) was discovered in quail with the ability to reduce gonadotropin expression/secretion in the pituitary. There have been few studies on GNIH orthologs in teleosts (LPXRFamide (Lpxrfa) peptides), which have provided inconsistent results. Therefore, the goal of this study was to determine the roles and modes of action by which Lpxrfa exerts its functions in the brain–pituitary axis of zebrafish (Danio rerio). We localized Lpxrfa soma to the ventral hypothalamus, with fibers extending throughout the brain and to the pituitary. In the preoptic area, Lpxrfa fibers interact with gonadotropin-releasing hormone 3 (Gnrh3) soma. In pituitary explants, zebrafish peptide Lpxrfa-3 downregulated luteinizing hormone beta subunit and common alpha subunit expression. In addition, Lpxrfa-3 reduced gnrh3 expression in brain slices, offering another pathway for Lpxrfa to exert its effects on reproduction. Receptor activation studies, in a heterologous cell-based system, revealed that all three zebrafish Lpxrfa peptides activate Lpxrf-R2 and Lpxrf-R3 via the PKA/cAMP pathway. Receptor activation studies demonstrated that, in addition to activating Lpxrf receptors, zebrafish Lpxrfa-2 and Lpxrfa-3 antagonize Kisspeptin-2 (Kiss2) activation of Kisspeptin receptor-1a (Kiss1ra). The fact that kiss1ra-expressing neurons in the preoptic area are innervated by Lpxrfa-ir fibers suggests an additional pathway for Lpxrfa action. Therefore, our results suggest that Lpxrfa may act as a reproductive inhibitory neuropeptide in the zebrafish that interacts with Gnrh3 neurons in the brain and with gonadotropes in the pituitary, while also potentially utilizing the Kiss2/Kiss1ra pathway.
Simon, Y. ; Levavi-Sivan, B. ; Cahaner, A. ; Hulata, G. ; Antler, A. ; Rozenfeld, L. ; Halachmi, I. A behavioural sensor for fish stress. Aquacultural Engineering 2017, 77, 107 - 111. Publisher's VersionAbstract
Due to water turbidity, fish stress might be difficult to observe. Evaluation of fish stress by blood sampling requires removing a fish from the water, which is in itself a stressful event. Therefore, we designed and built a sensor to detect fish behaviour that reflects stress. The electronic sensor detected early signs of fish stress by scoring the fish's inactivity. LEDs and detectors are embedded on a steel wand that is held underwater by an operator. In this preliminary (feasibility) study, the new sensor was validated for Tilapia (Cichlidae) and Hybrid Striped Bass (Morone). We induced stressful situations in the fish tanks by manipulating oxygen and temperature levels. Results Lowering the temperature and oxygen levels both significantly increased the average number of signals identified by the sensor, which indicate stress. The effect of reducing water temperature from 24°C to 15°C was three times stronger than was the effect of lowering the oxygen saturation level from 85% to 50%. The difference in the number of signals between the good and stressful conditions was statistically significant, amounting to approximately eight sensor signals, 10.57 compared to 2.49 respectively. Lowering the temperature increased the mean number of signals by 5.85 and 6.06 at 85% and 50% oxygen saturation respectively, whereas lowering oxygen levels increased the mean number of signals by 2.02 and 2.23 at 24°C and 15°C, respectively. The results indicate that the stress status of cultured fish can be evaluated using the proposed behavioural sensor. The new sensor may provide an earlier indication of a problem in a fish tank or pond than was heretofore possible. This early warning can enable the fish farmer to take action before many fish are harmed.
Zmora, N. ; Wong, T. - T. ; Stubblefield, J. ; Levavi-Sivan, B. ; Zohar, Y. Neurokinin B regulates reproduction via inhibition of kisspeptin in a teleost, the striped bass. Journal of Endocrinology 2017, 233. Publisher's Version
Pines, M. ; Levi, O. ; Genin, O. ; Lavy, A. ; Angelini, C. ; Allamand, V. ; Halevy, O. Elevated Expression of Moesin in Muscular Dystrophies. The American Journal of Pathology 2017, 187, 654 - 664. Publisher's VersionAbstract
Fibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials.
Piestun, Y. ; Patael, T. ; Yahav, S. ; Velleman, S. G. ; Halevy, O. Early posthatch thermal stress affects breast muscle development and satellite cell growth and characteristics in broilers. Poultry Science 2017, 96, 2877 - 2888. Publisher's VersionAbstract
ABSTRACT Heat or cold stress, can disrupt well-being and physiological responses in birds. This study aimed to elucidate the effects of continuous heat exposure in the first 2 wk of age on muscle development in broilers, with an emphasis on the pectoralis muscle satellite cell population. Chicks were reared for 13 d under either commercial conditions or a temperature regime that was 5°C higher. Body and muscle weights, as well as absolute muscle growth were lower in heat-exposed chicks from d 6 onward. The number of satellite cells derived from the experimental chicks was higher in the heat-treated group on d 3 but lower on d 8 and 13 compared to controls. This was reflected in a lower number of myonuclei expressing proliferating nuclear cell antigen in cross sections of pectoralis major muscle sampled on d 8. However, a TUNEL assay revealed similar cell survival in both groups. Mean myofiber diameter and distribution were lower in muscle sections sampled on d 8 and 13 in heat-treated versus control group, suggesting that the lower muscle growth is due to changes in muscle hypertrophy. Oil-Red O staining showed a higher number of satellite cells with lipids in the heat-treated compared to the control group on these days. Moreover, lipid deposition was observed in pectoralis muscle cross sections derived from the heat-treated chicks on d 13, whereas the controls barely exhibited any lipid staining. The gene and protein expression levels of CCAAT/enhancer binding protein β in pectoralis muscle from the heat-treated group were significantly higher on d 13 than in controls, while myogenin levels were similar. The results suggest high sensitivity of muscle progenitor cells in the early posthatch period at a time when they are highly active, to chronic heat exposure, leading to impaired myogenicity of the satellite cells and increased fat deposition.
Wein, Y. ; Geva, Z. ; Bar-Shira, E. ; Friedman, A. Transport-related stress and its resolution in turkey pullets: activation of a pro-inflammatory response in peripheral blood leukocytes. Poultry Science 2017, 96, 2601 - 2613. Publisher's VersionAbstract
The transportation process is one of the most stressful practices in poultry and livestock management. Extensive knowledge is available on the impact of transport on stress and animal welfare; however, little is known on the impact of transport on the physiology of turkey pullets, their welfare and health, and even less on the process of homeostatic recovery in the post-transport new environment. The main focus of this manuscript was to focus on trauma, stress, and recovery following transport of turkey pullets from nurseries to pullet farms. Specifically, we determined the physiological consequences of transport, the temporal restoration of homeostasis and its effects on immune system function. We hypothesized that stress signaling by stress hormones would directly activate circulating turkey blood leukocytes (TBL), thus inducing a pro-inflammatory response directed towards tissue repair and recovery. Extensive blood analyses prior to transit and during the collecting, transit, and post-transit stages revealed extensive stress (elevated heat shock protein 70) and blunt-force trauma (internal bleeding and muscle damage as well as limb fractures). TBL were shown to increase mRNA expression of cortisol and adrenergic receptors during transit, thus indicating a possible direct response to circulating stress hormones. Consequently, TBL were shown to increase mRNA expression of pro-inflammatory cytokines, as well as that of serum inflammatory proteins (lysozyme and transferrin) partaking in reducing oxygen radicals as demonstrated by consumption of these proteins. The flare-up due to transit related stress diminished with time until 10 d post-transit, a time at which most parameters returned to resting levels. Though general and vaccine-specific antibody levels were not altered by transport-related stress, the physical and physiological injury caused during transport may explain the susceptibility of turkey pullets to opportunist pathogens in the immediate post-transit period.
Tadmor-Levi, R. ; Asoulin, E. ; Hulata, G. ; David, L. Studying the Genetics of Resistance to CyHV-3 Disease Using Introgression from Feral to Cultured Common Carp Strains. Frontiers in Genetics 2017, 8 24. Publisher's VersionAbstract
Sustainability and further development of aquaculture production are constantly challenged by outbreaks of fish diseases, which are difficult to prevent or control. Developing fish strains that are genetically resistant to a disease is a cost-effective and a sustainable solution to address this challenge. To do so, heritable genetic variation in disease resistance should be identified and combined together with other desirable production traits. Aquaculture of common carp has suffered substantial losses from the infectious disease caused by the cyprinid herpes virus type 3 (CyHV-3) virus and the global spread of outbreaks indicates that many cultured strains are susceptible. In this research, CyHV-3 resistance from the feral strain “Amur Sassan” was successfully introgressed into two susceptible cultured strains up to the first backcross (BC1) generation. Variation in resistance of families from F1 and BC1 generations was significantly greater compared to that among families of any of the susceptible parental lines, a good starting point for a family selection program. Considerable additive genetic variation was found for CyHV-3 resistance. This phenotype was transferable between generations with contributions to resistance from both the resistant feral and the susceptible cultured strains. Reduced scale coverage (mirror phenotype) is desirable and common in cultured strains, but so far, cultured mirror carp strains were found to be susceptible. Here, using BC1 families ranging from susceptible to resistant, no differences in resistance levels between fully scaled and mirror full-sib groups were found, indicating that CyHV-3 resistance was successfully combined with the desirable mirror phenotype. In addition, the CyHV-3 viral load in tissues throughout the infection of susceptible and resistant fish was followed. Although resistant fish get infected, viral loads in tissues of these fish are significantly lesser than in those of susceptible fish, allowing them to survive the disease. Taken together, in this study we have laid the foundation for breeding CyHV-3-resistant strains and started to address the mechanisms underlying the phenotypic differences in resistance to this disease.
Yasur-Landau, D. ; Jaffe, C. L. ; Doron-Faigenboim, A. ; David, L. ; Baneth, G. Induction of allopurinol resistance in Leishmania infantum isolated from dogs. PLOS Neglected Tropical Diseases 2017, 11, 1-10. Publisher's VersionAbstract
Author summary Visceral leishmaniasis caused by the parasite Leishmania infantum is a neglected tropical disease transmitted from animal hosts to humans by sand fly bites. This potentially fatal disease affects thousands of people annually and threatens millions who live in disease risk areas. Domestic dogs are considered as the main reservoir of this parasite which can also cause a severe chronic canine disease. Allopurinol is the main drug used for long term treatment of this disease but it often does not eliminate infection in dogs. We have recently demonstrated that allopurinol resistant parasites can be isolated from naturally infected dogs that have developed clinical recurrence of disease during allopurinol treatment. In this study we aimed to see if resistance can be induced in susceptible parasite strains isolated from sick dogs by growing them in increasing drug concentrations under laboratory conditions. The changes in allopurinol susceptibility were measured and the impact of drug on parasite growth was monitored over 23 weeks. Induction of resistance was successful producing parasites 20-folds less susceptible to the drug. The pattern of change in drug susceptibility suggests that a genetic change is responsible for the increased resistance which is likely to mimic the formation of resistance in dogs.
Petit, J. ; David, L. ; Dirks, R. ; Wiegertjes, G. F. Genomic and transcriptomic approaches to study immunology in cyprinids: What is next?. Developmental & Comparative Immunology 2017, 75, 48 - 62. Publisher's VersionAbstract
Accelerated by the introduction of Next-Generation Sequencing (NGS), a number of genomes of cyprinid fish species have been drafted, leading to a highly valuable collective resource of comparative genome information on cyprinids (Cyprinidae). In addition, NGS-based transcriptome analyses of different developmental stages, organs, or cell types, increasingly contribute to the understanding of complex physiological processes, including immune responses. Cyprinids are a highly interesting family because they comprise one of the most-diversified families of teleosts and because of their variation in ploidy level, with diploid, triploid, tetraploid, hexaploid and sometimes even octoploid species. The wealth of data obtained from NGS technologies provides both challenges and opportunities for immunological research, which will be discussed here. Correct interpretation of ploidy effects on immune responses requires knowledge of the degree of functional divergence between duplicated genes, which can differ even between closely-related cyprinid fish species. We summarize NGS-based progress in analysing immune responses and discuss the importance of respecting the presence of (multiple) duplicated gene sequences when performing transcriptome analyses for detailed understanding of complex physiological processes. Progressively, advances in NGS technology are providing workable methods to further elucidate the implications of gene duplication events and functional divergence of duplicates genes and proteins involved in immune responses in cyprinids. We conclude with discussing how future applications of NGS technologies and analysis methods could enhance immunological research and understanding.
Argov-Argaman, N. ; Mandel, D. ; Lubetzky, R. ; Kedem, M. H. ; Cohen, B. - C. ; Berkovitz, Z. ; Reifen, R. Human milk fatty acids composition is affected by maternal age. The Journal of Maternal-Fetal & Neonatal Medicine 2017, 30, 34-37. Publisher's VersionAbstract
AbstractHuman colostrums and transition milk were collected from women under the age of 37 years and women aged 37 years and older. Transition milk of the younger group had lower fat content and 10-fold higher concentrations of omega 6 FA, eicosadecanoic, and arachdonic acids. Gestational age affected the colostrum concentration of total fat and omega 3 and omega 6 FA composition only in the older group. We concluded that age may be a factor in the FA composition of human milk. This should be taken into account when planning diets for pregnant women of different ages.
Shefer-Weinberg, D. ; Sasson, S. ; Schwartz, B. ; Argov-Argaman, N. ; Tirosh, O. Deleterious effect of n-3 polyunsaturated fatty acids in non-alcoholic steatohepatitis in the fat-1 mouse model. Clinical Nutrition Experimental 2017, 12, 37 - 49. Publisher's VersionAbstract
Summary Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies, ranging from hepatocellular steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. It has been suggested that fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFA) induce beneficial effects in NAFLD. However, n-3 PUFA are sensitive to peroxidation that generate free radicals and reactive aldehydes. We aimed at determining whether changing the tissue ratio of n-3 to n-6 PUFA may be beneficial or alternatively harmful to the etiology of NAFLD. The transgenic Fat-1 mouse model was used to determine whether n-3 PUFA positively or negatively affect the development of NAFLD. fat-1mice express the fat-1 gene of Caenorhabditis elegans, which encodes an n-3 fatty-acid desaturase that converts n-6 to n-3 fatty acids. Wild-type C57BL/6 mice served as the control group. Both groups of mice were fed methionine and choline deficient (MCD) diet, which induces NASH within 4 weeks. The study shows that NASH developed faster and was more severe in mice from the fat-1 group when compared to control C57BL/6 mice. This was due to enhanced lipid peroxidation of PUFA in the liver of the fat-1 mice as compared to the control group. Results of our mice study suggest that supplementing the diet of individuals who develop or have fatty livers with n-3 PUFA should be carefully considered and if recommended adequate antioxidants should be added to the diet in order to reduce such risk.
Chertok, I. R. A. ; Haile, Z. T. ; Eventov-Friedman, S. ; Silanikove, N. ; Argov-Argaman, N. Influence of gestational diabetes mellitus on fatty acid concentrations in human colostrum. Nutrition 2017, 36, 17 - 21. Publisher's VersionAbstract
Objective The aim of this study was to examine differences in fatty acid concentrations in colostrum of women with and without gestational diabetes mellitus (GDM). The effect of GDM on fatty acid composition of colostrum is not fully understood, although rates of GDM are increasing globally. Methods A prospective case–control study was conducted of postpartum women with and without GDM. Gas chromatographic analysis was conducted to examine differences in colostral fatty acids of the colostrum samples of 29 women with and 34 without GDM. Results Analyses of the fatty acid composition revealed significantly higher concentrations of four essential ω-6 polyunsaturated fatty acids—γ-linolenic, eicosatrienoic, arachidonic, and docosatetraenoic—in the colostrum of GDM women compared with non-GDM women. Timing of collection influenced saturated medium chain fatty acid and monounsaturated fatty acid levels. Conclusions Differences in concentrations of ω-6 fatty acids but not in dietary linoleic fatty acid or ω-3 fatty acids suggest that altered concentrations are attributed to changes in specific endogenous metabolic pathways. Implications of higher concentrations of ω-6 fatty acids in the colostrum of women with GDM have yet to be determined. Timing of colostrum collection is critical in determining colostral fatty acid and metabolite concentrations.
Hadaya, O. ; Landau, S. Y. ; Glasser, T. ; Muklada, H. ; Dvash, L. ; Mesilati-Stahy, R. ; Argov-Argaman, N. Milk composition in Damascus, Mamber and F1 Alpine crossbred goats under grazing or confinement management. Small Ruminant Research 2017, 153, 31 - 40. Publisher's VersionAbstract
The interactive effect of breed and feeding management on milk composition was established in local goats (Damascus, Mamber) and their F1 Alpine crossbreeds, half of which grazed daily for 4h in Mediterranean brushland (Pasture – P) and half were fed clover hay (Hay – H) indoors, in addition to concentrate fed individually. Milk composition and fatty acid profile were measured, and individual nutritional composition was estimated by fecal NIRS; DM intake was calculated from the proportion of dietary concentrate. Milk and feces were collected at 65 (pretreatment), 110, 135 and 170 days of lactation. DM intake was lower in the H vs. P group (P<0.0001) in Damascus and Damascus crossbreed (P<0.01), but not in the other breeds. The Alpine crossbreeds yielded 0.6kg more milk (P<0.001) than their local counterparts. P group yielded milk that was richer in protein (P<0.01) and fat (P<0.0001), especially in the Damascus breed. Urea concentration in milk was 66% higher in H-group of all breeds throughout the experiment (P<0.001). H goats produced milk richer in medium-chain fatty acids (P<0.001) and monounsaturated fatty acids (P<0.01) than P goats. Omega 6 was higher for P goats with a strong breed×diet interaction effect (P<0.01) in Mamber goats. The P group produced milk that was 20% richer in omega 3 than the H group (P<0.0001). In the P group of Damascus goats, low omega 6/3 ratio was found compared with H group. This study shows that breed and management interact to affect milk composition and fatty acid profile. Therefore both factors and their interaction should be considered when industry pursues means to enrich milk with bioactive, essential lipid components which can turn milk into health promoting commodity.
Cohen, B. - C. ; Raz, C. ; Shamay, A. ; Argov-Argaman, N. Lipid Droplet Fusion in Mammary Epithelial Cells is Regulated by Phosphatidylethanolamine Metabolism. J Mammary Gland Biol Neoplasia 2017, 22, 235-249.Abstract
Mammary epithelial cells (MEC) secrete fat in the form of milk fat globules (MFG) which are found in milk in diverse sizes. MFG originate from intracellular lipid droplets, and the mechanism underlying their size regulation is still elusive. Two main mechanisms have been suggested to control lipid droplet size. The first is a well-documented pathway, which involves regulation of cellular triglyceride content. The second is the fusion pathway, which is less-documented, especially in mammalian cells, and its importance in the regulation of droplet size is still unclear. Using biochemical and molecular inhibitors, we provide evidence that in MEC, lipid droplet size is determined by fusion, independent of cellular triglyceride content. The extent of fusion is determined by the cell membrane's phospholipid composition. In particular, increasing phosphatidylethanolamine (PE) content enhances fusion between lipid droplets and hence increases lipid droplet size. We further identified the underlying biochemical mechanism that controls this content as the mitochondrial enzyme phosphatidylserine decarboxylase; siRNA knockdown of this enzyme reduced the number of large lipid droplets threefold. Further, inhibition of phosphatidylserine transfer to the mitochondria, where its conversion to PE occurs, diminished the large lipid droplet phenotype in these cells. These results reveal, for the first time to our knowledge in mammalian cells and specifically in mammary epithelium, the missing biochemical link between the metabolism of cellular complex lipids and lipid-droplet fusion, which ultimately defines lipid droplet size.
Meidan, R. ; Girsh, E. ; Mamluk, R. ; Levy, N. ; Farberov, S. Luteolysis in Ruminants: Past Concepts, New Insights, and Persisting Challenges. In The Life Cycle of the Corpus Luteum; Meidan, R., Ed. The Life Cycle of the Corpus Luteum; Springer International Publishing: Cham, 2017; pp. 159–182. Publisher's VersionAbstract
It is well established that in ruminants, and in other species with estrous cycles, luteal regression is stimulated by the episodic release of prostaglandin F2$\alpha$ (PGF2$\alpha$) from the uterus, which reaches the corpus luteum (CL) through a countercurrent system between the uterine vein and the ovarian artery. Because of their luteolytic properties, PGF2$\alpha$ and its analogues are routinely administered to induce CL regression and synchronization of estrus, and as such, it is the basis of protocols for synchronizing ovulation. Luteal regression is defined as the loss of steroidogenic function (functional luteolysis) and the subsequent involution of the CL (structural luteolysis). During luteolysis, the CL undergoes dramatic changes in its steroidogenic capacity, vascularization, immune cell activation, ECM composition, and cell viability. Functional genomics and many other studies during the past 20 years elucidated the mechanism underlying PGF2$\alpha$ actions, substantially revising old concepts. PGF2$\alpha$ acts directly on luteal steroidogenic and endothelial cells, which express PGF2$\alpha$ receptors (PTGFR), or indirectly on immune cells lacking PTGFR, which can be activated by other cells within the CL. Accumulating evidence now indicates that the diverse processes initiated by uterine or exogenous PGF2$\alpha$, ranging from reduction of steroid production to apoptotic cell death, are mediated by locally produced factors. Data summarized here show that PGF2$\alpha$ stimulates luteal steroidogenic and endothelial cells to produce factors such as endothelin-1, angiopoietins, nitric oxide, fibroblast growth factor 2, thrombospondins, transforming growth factor-B1, and plasminogen activator inhibitor-B1, which act sequentially to inhibit progesterone production, angiogenic support, cell survival, and ECM remodeling to accomplish CL regression.