A Chance-Constrained Linear Model for Beef Policy Analysis

A simple linear model to evaluate different bull beef policies (BBP) by incorporating the stochastic nature of pasture yield from a database with separate chance constraints (ChC) was developed. A 100 ha farm was used, and the model was run with five different BBP and set to different levels of pasture yield risk to maximise production.ha-1.year-1. Summer was the most risky season, and the optimum mix of policies changed at different levels of risk. Chance constraint represents an interesting and simple alternative to include pasture variation into a linear model

Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy

Exon skipping is an effective strategy for the treatment of many Duchenne Muscular Dystrophy (DMD) mutations. Natural exon skipping observed in several DMD cases can help in identifying novel therapeutic tools. Here, we show a DMD study case where the lack of a splicing factor (Celf2a), which results in exon skipping and dystrophin rescue, is due to a maternally inherited trans-generational epigenetic silencing. We found that the study case and his mother express a repressive long non-coding RNA, DUXAP8, whose presence correlates with silencing of the Celf2a coding region. We also demonstrate that DUXAP8 expression is lost upon cell reprogramming and that, upon induction of iPSCs into myoblasts, Celf2a expression is recovered leading to the loss of exon skipping and loss of dystrophin synthesis. Finally, CRISPR/Cas9 inactivation of the splicing factor Celf2a was proven to ameliorate the pathological state in other DMD backgrounds establishing Celf2a ablation or inactivation as a novel therapeutic approach for the treatment of Duchenne Muscular Dystrophy

Relevant but neglected habitat types by the Directive 92/43 EEC in southern Italy

The 92/43/EEC Habitats Directive is the main European Union legal tool concerning nature conservation. The habitat types listed in Annex I to the Directive are phytosociology-based. It is widely acknowledged that phytosociological analysis is a crucial approach for habitats characterization and for monitoring their conservation status. Based on bibliographic investigations and new field survey campaigns, a list of habitat types neglected by the Habitats Directive is here presented and described for southern Italy. In this paper, 8 new habitat types and 13 subtypes are proposed. For each of these proposed new habitat types, a wide range of information, including ecology, chorology, species composition, syntaxonomy, threats, and conservation status, is here provided. To supply more detailed phytogeographical and coenological information about the proposed new habitat types, distribution maps based on 10 x 10 km reference grids and phytosociological tables including unpublished releves were carried out

Genome-wide association study provides insights into genes related with horn development in Nelore beef cattle.

Abstract The causal mutation for polledness in Nelore (Bos taurus indicus) breed seems to have appeared first in Brazil in 1957. The expression of the polled trait is known to be ruled by a few groups of alleles in taurine breeds; however, the genetic basis of this trait in indicine cattle is still unclear. The aim of this study was to identify genomic regions associated with the hornless trait in a commercial Nelore population. A total of 107,294 animals had phenotypes recorded and 2,238 were genotyped/imputed for 777k SNP. The weighted single-step approach for genome-wide association study (WssGWAS) was used to estimate the SNP effects and variances accounted for by 1 Mb sliding SNP windows. A centromeric region of chromosome 1 with 3.11 Mb size (BTA1: 878,631?3,987,104 bp) was found to be associated with hornless in the studied population. A total of 28 protein-coding genes are mapped in this region, including the taurine Polled locus and the IFNAR1, IFNAR2, IFNGR2, KRTAP11-1, MIS18A, OLIG1, OLIG2, and SOD1 genes, which expression can be related to the horn formation as described in literature. The functional enrichment analysis by DAVID tool revealed cytokine-cytokine receptor interaction, JAK-STAT signaling, natural killer cell mediated cytotoxicity, and osteoclast differentiation pathways as significant (P < 0.05). In addition, a runs of homozygosity (ROH) analysis identified a ROH island in polled animals with 2.47 Mb inside the region identified by WssGWAS. Polledness in Nelore cattle is associated with one region in the genome with 3.1 Mb size in chromosome 1. Several genes are harbored in this region, and they may act together in the determination of the polled/horned phenotype. Fine mapping the locus responsible for polled trait in Nelore breed and the identification of the molecular mechanisms regulating the horn growth deserve further investigation

Pleiotropic antitumor effects of the pan-HDAC inhibitor ITF2357 against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas,

Histone deacetylases (HDAC) extensively contribute to the c-Myc oncogenic program, pointing to their inhibition as an effective strategy against c-Myc-overexpressing cancers. We, thus, studied the therapeutic activity of the new-generation pan-HDAC inhibitor ITF2357 (Givinostat®) against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas (B-NHLs). ITF2357 anti-proliferative and pro-apoptotic effects were analyzed in B-NHL cell lines with c-Myc translocations (Namalwa, Raji and DOHH-2), stabilizing mutations (Raji) or post-transcriptional alterations (SU-DHL-4) in relationship to c-Myc modulation. ITF2357 significantly delayed the in vitro growth of all B-NHL cell lines by inducing G1 cell-cycle arrest, eventually followed by cell death. These events correlated with the extent of c-Myc protein, but not mRNA, downregulation, indicating the involvement of post-transcriptional mechanisms. Accordingly, c-Myc-targeting microRNAs let-7a and miR-26a were induced in all treated lymphomas and the cap-dependent translation machinery components 4E-BP1, eIF4E and eIF4G, as well as their upstream regulators, Akt and PIM kinases, were inhibited in function of the cell sensitivity to ITF2357, and, in turn, c-Myc downregulation. In vivo, ITF2357 significantly hampered the growth of Namalwa and Raji xenografts in immunodeficient mice. Noteworthy, its combination with suboptimal cyclophosphamide, achieved complete remissions in most animals and equaled or even exceeded the activity of optimal cyclophosphamide. Collectively, our findings provide the rationale for testing the clinical advantages of adding ITF2357 to current therapies for the still very ominous c-Myc-overexpressing lymphomas. They equally provide the proof-of-concept for its clinical evaluation in rational combination with the promising inhibitors of B-cell receptor and PI3K/Akt/mTOR axis currently in the process of development

Loss of miR-204 expression is a key event in melanoma

Cutaneous melanoma (CM) is a malignancy with increasing occurrence. Its microRNA repertoire has been defined in a number studies, leading to candidates for biological and clinical relevance: miR-200a/b/c, miR-203, miR-205, miR-204, miR-211, miR-23b and miR-26a/b. Our work was aimed to validate the role of these candidate miRNAs in melanoma, using additional patients cohorts and in vitro cultures. miR-26a, miR-204 and miR-211 were more expressed in normal melanocytes, while miR-23b, miR-200b/c, miR-203 and miR-205 in epidermis and keratinocytes. None of the keratinocyte-related miRNAs was associated with any known mutation or with clinical covariates in melanoma. On the other hand, the loss of miR-204 was enriched in melanomas with NRAS sole mutation (Fisher exact test, P = 0.001, Log Odds = 1.67), and less frequent than expected in those harbouring CDKN2A mutations (Fisher exact test, P = 0.001, Log Odds − 1.09). Additionally, miR-204 was associated with better prognosis in two independent melanoma cohorts and its exogenous expression led to growth impairment in melanoma cell lines. Thus, miR-204 represents a relevant mechanism in melanoma, with potential prognostic value and its loss seems to act in the CDKN2A pathway, in cooperation with NRAS

Genome-wide activity of unliganded estrogen receptor-\u3b1\ua0 in breast cancer cells

Estrogen receptor-\u3b1 (ER\u3b1) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ER\u3b1 has functions that are independent of ligands. In the present work, we investigated the binding of ER\u3b1 to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ER\u3b1 binds to more than 4,000 chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ER\u3b1 binding is specifically linked to genes with developmental functions, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ER\u3b1 in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Down-regulatedmRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ER\u3b1 down-regulation using shRNA, which caused cell growth arrest, was accompanied by increased H3K27me3 at ER\u3b1 binding sites. Finally, we found that FOXA1 and AP2\u3b3 binding to several sites is decreased upon ER\u3b1 silencing, suggesting that unliganded ER\u3b1 participates, together with other factors, in the maintenance of the luminal-specific cistrome in breast cancer cell

Autozygosity islands and ROH patterns in Nellore lineages: evidence of selection for functionally important traits.

Abstract Background The aim of this study was to assess genome-wide autozygosity in a Nellore cattle population and to characterize ROH patterns and autozygosity islands that may have occurred due to selection within its lineages. It attempts also to compare estimates of inbreeding calculated from ROH (FROH), genomic relationship matrix (FGRM), and pedigree-based coefficient (FPED). Results The average number of ROH per animal was 55.15&#8201;±&#8201;13.01 with an average size of 3.24 Mb. The Nellore genome is composed mostly by a high number of shorter segments accounting for 78% of all ROH, although the proportion of the genome covered by them was relatively small. The genome autozygosity proportion indicates moderate to high inbreeding levels for classical standards, with an average value of 7.15% (178.70 Mb). The average of FPED and FROH, and their correlations (&#8722;&#8201;0.05 to 0.26) were low. Estimates of correlation between FGRM-FPED was zero, while the correlation (&#8722;&#8201;0.01 to &#8722;&#8201;0.07) between FGRM-FROH decreased as a function of ROH length, except for FROH&#8201;>&#8201;8Mb (&#8722;&#8201;0.03). Overall, inbreeding coefficients were not high for the genotyped animals. Autozygosity islands were evident across the genome (n&#8201;=&#8201;62) and their genomic location did not largely differ within lineages. Enriched terms (p&#8201;<&#8201;0.01) associated with defense response to bacteria (GO:0042742), immune complex reaction (GO:0045647), pregnancy-associated glycoproteins genes (GO:0030163), and organism growth (GO:0040014) were described within the autozygotic islands. Conclusions Low FPED-FROH correlation estimates indicate that FPED is not the most suitable method for capturing ancient inbreeding when the pedigree does not extend back many generations and FROH should be used instead. Enriched terms (p <&#8201;0.01) suggest a strong selection for immune response. Non-overlapping islands within the lineages greatly explain the mechanism underlying selection for functionally important traits in Nellore cattle

Search for new phenomena with the MT2 variable in the all-hadronic final state produced in proton-proton collisions at s=13 TeV.

A search for new phenomena is performed using events with jets and significant transverse momentum imbalance, as inferred through the MT2 variable. The results are based on a sample of proton-proton collisions collected in 2016 at a center-of-mass energy of 13 TeV with the CMS detector and corresponding to an integrated luminosity of 35.9 fb-1 . No excess event yield is observed above the predicted standard model background, and the results are interpreted as exclusion limits at 95% confidence level on the masses of predicted particles in a variety of simplified models of R-parity conserving supersymmetry. Depending on the details of the model, 95% confidence level lower limits on the gluino (light-flavor squark) masses are placed up to 2025 (1550) GeV . Mass limits as high as 1070 (1175) GeV are set on the masses of top (bottom) squarks. Information is provided to enable re-interpretation of these results, including model-independent limits on the number of non-standard model events for a set of simplified, inclusive search regions