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Abstract Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention.

Circular RNAs (circRNAs) are known to act as important regulators of the microRNA (miRNA) activity. Yet, computational resources to identify miRNA:circRNA interactions are mostly limited to already annotated circRNAs or affected by high rates of false positive predictions. To overcome these limitations, we developed Circr, a computational tool for the prediction of associations between circRNAs and miRNAs. Circr combines three publicly available algorithms for de novo prediction of miRNA binding sites on target sequences (miRanda, RNAhybrid, and TargetScan) and annotates each identified miRNA:target pairs with experimentally validated miRNA:RNA interactions and binding sites for Argonaute proteins derived from either ChIPseq or CLIPseq data. The combination of multiple tools for the identification of a single miRNA recognition site with experimental data allows to efficiently prioritize candidate miRNA:circRNA interactions for functional studies in different organisms. Circr can use its internal annotation database or custom annotation tables to enhance the identification of novel and not previously annotated miRNA:circRNA sites in virtually any species. Circr is written in Python 3.6 and is released under the GNU GPL3.0 License at https://github.com/bicciatolab/Circr.

Since the pioneering NCI-60 panel of the late'80's, several major screenings of genetic profiling and drug testing in cancer cell lines have been conducted to investigate how genetic backgrounds and transcriptional patterns shape cancer's response to therapy and to identify disease-specific genes associated with drug response. Historically, pharmacogenomics screenings have been largely heterogeneous in terms of investigated cell lines, assay technologies, number of compounds, type and quality of genomic data, and methods for their computational analysis. The analysis of this enormous and heterogeneous amount of data required the development of computational methods for the integration of genomic profiles with drug responses across multiple screenings. Here, we will review the computational tools that have been developed to integrate cancer cell lines' genomic profiles and sensitivity to small molecule perturbations obtained from different screenings.

Over the course of cortical neurogenesis, the transition of progenitors from proliferation to differentiation requires a precise regulation of involved gene networks under varying environmental conditions. In order to identify such regulatory mechanisms, we analyzed microRNA (miRNA) target networks in progenitors during early and late stages of neurogenesis. We found that cyclin D1 is a network hub whose expression is miRNA-dosage sensitive. Experimental validation revealed a feedback regulation between cyclin D1 and its regulating miRNAs miR-20a, miR-20b, and miR-23a. Cyclin D1 induces expression of miR-20a and miR-20b, whereas it represses miR-23a. Inhibition of any of these miRNAs increases the developmental stage-specific mean and dynamic expression range (variance) of cyclin D1 protein in progenitors, leading to reduced neuronal differentiation. Thus, miRNAs establish robustness and stage-specific adaptability to a critical dosage-sensitive gene network during cortical neurogenesis. Understanding such network regulatory mechanisms for key developmental events can provide insights into individual susceptibilities for genetically complex neuropsychiatric disorders.

This preliminary communication presents the first record of predaceous thrips Scolothrips longicornis Priesner, 1926 (Thysanoptera: Thripidae) in Slovakia. As a well known predator of numerous spider mites, e.g. Tetranychus urticae or Eutetranychus orientalis it has been considered as a suitable biological control agent recently. Tetranychids mites are harmful agriculture pests, causing damage on a variety of greenhouse and field crops (e.g. cucumber, peppers, tomatoes, potatoes, beans, corn, strawberries) and are difficult to control chemically. Scolothrips longicornis was recorded in soil and a tree photoeclector samples from Babsky les wood, a natural oak-hornbeamforest Fageto Quercetum, situated in the district of Nitra (SW Slovakia).

Heat stress during the summer season is an important factor which can impair dairy cows physiology and productivity. A survey was carried out on a sample of 30 dairy farms of the Province of Padova to assess the effectiveness of different strategies for heat stress control. All farms used a fan cooling system but in those were a sprinkler device was also operating an increased milk yield was observed (+5.0%). Cows receiving the diet in two daily distributions (morning and evening) increased DM intake (+9.0%) and milk yield (+15.0%) in comparison to animals fed once a day. No difference, instead, were observed in farms where cows were fed once a day in the morning or in the evening. A positive milk response (+8.1%) was recorded in farms equipped with wide waterers at the exit of the milking parlour.

The effects on the digestive process and the productive performances of dairy cows fed diets containing alfalfa hay from different germplasms and maturity were assessed in the present study. Three different lots of first-cut alfalfa hay were used in the study: the improved variety “Boreal”, harvested at two consecutive maturity stages (early flowering and full flowering) and the ecotype “Vogherese”, at full flowering. Cutting the plant at an earlier stage of maturity improved hay quality in comparison with the more mature forages (crude protein: 21.4 vs 16.5% DM; P DM; P er lignin content for the latter (8.6 vs 8.2% DM; P tating cows were formulated using an equal amount of corn silage and the maximum inclusion of one of the tested hays as forage base. The better quality of the early cut hay made it possible to increase its inclusion in the diet up to 44% of total dietary DM, while the two more mature hays covered only 36% of total DM of the respective diets. According to a 3 x 3 Latin square design, the diets were fed to 3 Italian Brown cows (initial average days in milk 121 ± 24 and milk yield 20 kg ± 1.3) fitted with ruminal cannula in 3 consecutive periods of 28 d each. Alfalfa stage of maturity and germplasm did not affect dietary DM intake (average 16 kg/d). Degradability parameters of dietary DM, calculated by in situ nylon bags technique, showed similar kinetics of rumen disappearance for all diets. No differences were noticed in the ruminal rate of passage of the solid phase among diets, while the liquid phase showed a slower rate of passage for the early flowering hay diet. Consistent with the degradation process, the stage of maturity or the alfalfa germplasm did not affect the rumen fluid data or the in vivo digestibility coefficients of the diets. Milk yield did not show any change due to either alfalfa maturity or cultivar, while milk protein was lowered when cows received the early cut hay diet. This result was likely due to an excess of rumen degradable dietary protein which could have been limited by replacing part of the dietary protein sources (soybean meal) with others more resistant to the ruminal degradation.

The aim of the present study was to compare the effects of soy lecithins (L), a by-product of the biodiesel production process, and choline chloride microencapsulated with hydrogenated vegetable oils (C) on dry matter intake, milk yield, milk quality traits, milk choline and haematological profile of dairy cows. A total of 12 mid-lactating Holstein Friesian cows were assigned to one of two experimental groups and fed according to cross-over design (2 diets x 2 periods). Diets were isoenergetic, isofibrous and isonitrogenous and had the same content of choline. Dry matter intake was not affected by the diet, but L led to lower milk choline (P