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Microarrays have been widely implemented across the life sciences, although there is still debate on the most effective uses of such transcriptomics approaches. In genetical genomics, gene expression measurements are treated as quantitative traits, and genome regions affecting expression levels are denoted as expression QTL (eQTL). The detected eQTL can represent a locus that lies close to the gene that is being controlled (cis-acting) or one or more loci that are unlinked to the gene that is being controlled (trans-acting). One powerful outcome of genetical genomics is the reconstruction of genetic pathways underlying complex trait variation. Because of the modest size of experiments to date, genetical genomics may fall short of its promise to unravel genetic networks. We propose to combine expression studies with fine mapping of functional trait loci. This synergistic approach facilitates the implementation of genetical genomics for species without inbred resources but is equally applicable to model species. Among livestock species, poultry is well placed to embrace this technology with the availability of the chicken genome sequence, microarrays for various platforms, as well as experimental populations in which QTL have been mapped. In the buildup toward full-blown eQTL studies, we can study the effects of known candidate genes or marked QTL at the gene expression level in more focused studies. To demonstrate the potential of genetical genomics, we have identified the cis and trans effects for a functional BW QTL on chicken chromosome 4 in breast tissue samples from chickens with contrasting QTL genotypes.

Introduction/BackgroundEndometrial cancer (EC) is the most frequent of the infiltrating tumors of female genital tract. Surgical and adjuvant treatments are the cornerstone treatment for EC patients, however, the response rate to standard therapy is very limited, highlighting the need for novel and efficient treatments. ABTL0812, a small first-in-class molecule, induces cancer cell death by inhibiting the PI3K/AKT/mTOR pathway (frequently overactivated in EC) and inducing endoplasmic reticulum stress (ER-Stress).ObjectiveAssess the preclinical efficacy of ABTL0812 in EC.MethodologyWe studied ABTL0812 treatment on viability, autophagy and apoptosis in a wide panel of EC cell lines and in 3D-murine endometrial organoids. ABTL0812 efficacy was evaluated in tumor onset and progression in a tamoxifen-inducible PTEN-KO murine model and cell line- or patient-derived xenograft (PDX) models. TRIB3 mRNA levels were evaluated in blood from EC patients recruited in ongoing Phase 1b/2a clinical trial.ResultsWe demonstrated that ABTL0812 treatment in vitro reduced viability, sensitized cancer cells and induced autophagy through ER-stress induction and PI3K/AKT/mTORC1 axis inhibition. In murine PTEN-KO cells, ABTL0812 decreased proliferation and induced nuclear fragmentation/condensation and caspase activation. ABTL0812 in vivo therapeutic benefit was confirmed, leading to a marked reduction in tumor growth (p<0.05), impairing the initial progression of endometrial tumorigenesis in PTEN-KO mouse model, and inhibiting tumor progression in PDX models, potentiating carboplatin-paclitaxel treatment. Finally, ABTL0812 increased TRIB3 mRNA levels after 8h of treatment in blood of human patients.ConclusionOur results demonstrated that ABTL0812 treatment promoted autophagy followed by activation of the pro-apoptotic pathway. Collectively, we provided strong preclinical evidences of the therapeutic benefit of ABTL0812 as monotherapy or in combination with current first-line treatment in EC. Our findings present a novel and clinically applicable therapeutic strategy for EC and suggest the potential use of TRIB3 as a pharmacodynamic biomarker to monitor ABTL0812 treatment.DisclosureSonia Solé-Sánchez, Pau Muñoz-Guardiola, Elisabet Megias-Roda, Héctor Pérez-Montoyo, José Alfon, Marc Yeste-Velasco, Carles Domènech are Ability Pharmaceuticals employees. Carles Domènech CD holds shares of the Company. José Miguel Lizcano is member of its Scientific Advisory Board. Antonio Gil-Moreno, Isidre Felip, Cristian Pablo Moiola, Cristina Megino-Luque, Carlos Lopez-Gil, Silvia Cabrera, María Santacana, Xavier Dolcet, Armando Reques, Ana Oaknin, Victor Rodríguez-Freixinos Xavier Matias-Guiu, Eva Colas, Nuria Eritja, declare no conflicts of interest.

The adjuvant of the FML-vaccine against murine and canine visceral leishmaniasis, the Riedel de Haen saponin mixture, was fractionated by ion exchange chromatography on DEAE-cellulose to afford one TLC homogeneous Quillaja saponaria Molina QS21 saponin fraction (18.0%), a mixture of two deacylsaponins (19.4%), sucrose (39.9%), sucrose and glucose (19.7%), rutin (0.8%) and quercetin (2.2%), that were identified by comparison of 1H and 13C NMR spectroscopy. The QS21 shows the typical aldehyde group in C-23 (65% equatorial) and a normonoterpene moiety acylated in C-28. The deacylsaponins show the aldehyde group but do not have the normonoterpene moiety. Balb/c mice were vaccinated with 150 μg of FML antigen of Leishmania donovani and 100 μg of each obtained fraction and further challenged by infection with 10 8 amastigotes of Leishmania chagasi. The safety analysis and the effect on humoral and cellular immune responses and in clinical signs showed that the QS21 saponin and the deacylsaponins are the most active adjuvant compounds of the Riedel the Haen saponin mixture. Both induced the highest and non-significantly different increases in DTH, CD4+ T lymphocytes in spleen, IFN-γ in vitro, body weight gain and the most pronounced reduction of parasite burden in liver (95% for QS21 and 86% for deacylsaponins; p > 0.05). While the QS21 showed mild toxicity, significant adjuvant effect on the anti-FML humoral response before and after infection, and decrease in liver relative weight, the deacylsaponins showed no toxicity, less haemolysis and antibody and DTH responses increased mainly after infection, still inducing a stronger Leishmania-specific in vitro splenocyte proliferation. Our results confirm in the Riedel de Haen saponin extract the presence of deacylsaponins normonoterpene-deprivated which are non-toxic and capable of inducing a specific and strong immunoprotective response in vaccination against murine visceral leishmaniasis.

In Uruguay, reforestations with sp. is of fundamental importance to supply paper, pulp, and wood production. This study investigates genetic, productivity, stability, and adaptability parameters in the selection of full-sib hybrid clones. The study was conducted in a clonal test, repeated in two different soils types, in Rio Negro State, Uruguay. The population was characterized phenotypically for diameter at breast height (dbh) and genotyped for SNP markers (EuCHIP60K chip). Mean dbh was similar between sites and the genotype–environment interaction was simple. We found high genotype correlation in clone performance between environments (0.708), indicating the possibility of selecting the same clones for both study locations. Mean heritability between clones (0.724), coefficient of individual genetic variation (10.9 %), and relative variation (0.916), suggest the possibility of gains (estimated at 3.1 % for both sites together) by selecting clones with higher growth rates. A total of 15,196 SNPs were used to confirm parentage and test a genomic selection model for dbh. The predictive capacity was negative (-0.15) given the small population size (78 individuals). The most adaptable material among the tested study sites presented higher values for SNP heterozygosity. Thus, using molecular markers to identify clones responsive to environmental changes can act as a powerful tool in breeding programs. The hybrid population showed greater adaptability than for this region.

More accurate estimates of dairy cattle manure excretion are needed for manure management, nutrient plans, renewable bioenergy production, and environmental assessment. Consequently, it is important to quantify manure excretion by dairy herds. Current estimates use only a few animal groups and average herd characteristics to estimate fixed rates of manure excretion throughout the year. However, manure excretion varies seasonally and should be predicted based on dynamic herd group characteristics. In addition, improved prediction parameters should be incorporated. This study describes the creation of a stochastic dynamic herd model to predict seasonal manure excretion according to herd characteristics regarding milk production, pregnancy rates, and culling rates using improved prediction parameters. The Markov-chain model employed defines more than 1,400 cow states according to parity, month in milk, and pregnancy status, and includes season of the year according to pregnancy and culling rates. Although overall estimates of our model were not substantially different from commonly used approaches, strong seasonal variations of manure excretion found with our model are missed when using other approaches. Our model also gives the opportunity to tailor dairy farm specific parameters such as milk productivity, pregnancy rates, and culling rates to more accurate predictions. Predictions of the seasonal variation in dairy manure excretion aids in addressing issues related to manure use and recycling needs, bioenergy production, and assessment of environmental impacts.