Custodial supersymmetry in non-supersymmetric quiver theories

We consider non-supersymmetric quiver theories obtained by orbifolding the N=4 supersymmetric U(K) gauge theory by a discrete Z_\Gamma group embedded in the SU(4) R-symmetry group. We explicitly find that in such theories there are no one-loop quadratic divergences in the effective potential. Moreover, when the gauge group U(n)^\Gamma of the quiver theory is spontaneously broken down to the diagonal U(n), we identify a custodial supersymmetry which is responsible for the fermion-boson degeneracy of the mass spectrum.Comment: 10 pages, latex, references added, discussion of custodial susy in the zero-mode sector extende

TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage–induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA–mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2–miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis

The Complex Network of miRNA and mRNA Target Interactions in Pancreatic Cancer

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is one of the most lethal tumour types world-wide. The majority of patients present late with locally advanced or metastatic disease. Therefore, despite advances in operative techniques, perioperative management and oncological treatments, the overall 5-year survival remains <5%. Determining tumoural factors that contribute towards its aggressive nature may help in identifying novel molecular biomarkers and/or therapeutic targets. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target gene expression and are able to act as tumour suppressors or oncogenes. MiRNAs have been extensively profiled and implicated in the initiation and progression of PDAC. Furthermore, there is a possibility of translating miRNAs into clinically useful biomarkers. Here, I developed upon these initial observations and demonstrate that miRNAs can be used to differentiate low risk pancreatic benign cystic tumours (BCTs) from PDAC. We confirmed that these miRNAs regulate the expression of known PDAC oncogenes, and that miR-16, miR-126 and let-7d target BCL2, CRK and KRAS respectively. Next, in order to investigate the main contributors to tumourigenesis, an integrated molecular analysis (miRNA-mRNA) was performed in PDAC. By using a combination of network-based bioinformatics, miR-21, miR-23a and miR-27a were prioritised as important in PDAC progression. We demonstrated that the use of a combination of miRNA inhibitors (against miR-21, miR-23a and miR-27a) in a murine subcutaneous PDAC xenograft model was able to reduce tumour growth, better than oncomiR-21 inhibition alone. BTG2 and NEDD4L were found to be direct targets of the miRNA combination and were established as new candidate tumour suppressors in PDAC. The clinical relevance of this 3 miRNA signature was demonstrated, as high expressors of the combination have poor overall survival after surgical resection, independent of other clinicopathologic factors. Together, these studies identify specific miRNAs as important regulators of PDAC tumourigenesis and their possible use as biomarkers.Open Acces

Higgs Decays in the Low Scale Type I See-Saw Model

The couplings of the low scale type I see-saw model are severely constrained by the requirement of reproducing the correct neutrino mass and mixing parameters, by the non-observation of lepton number and charged lepton flavour violating processes and by electroweak precision data. We show that all these constraints still allow for the possibility of an exotic Higgs decay channel into a light neutrino and a heavy neutrino with a sizable branching ratio. We also estimate the prospects to observe this decay at the LHC and discuss its complementarity to the indirect probes of the low scale type I see-saw model from experiments searching for the $\mu\to e\gamma$ decay.Comment: 15 pages, 8 figures; references added and results unchanged; matched with the published version on PL

Optimisation of the Schizosaccharomyces pombe urg1 expression system

The ability to study protein function in vivo often relies on systems that regulate the presence and absence of the protein of interest. Two limitations for previously described transcriptional control systems that are used to regulate protein expression in fission yeast are: the time taken for inducing conditions to initiate transcription and the ability to achieve very low basal transcription in the "OFF-state". In previous work, we described a Cre recombination-mediated system that allows the rapid and efficient regulation of any gene of interest by the urg1 promoter, which has a dynamic range of approximately 75-fold and which is induced within 30-60 minutes of uracil addition. In this report we describe easy-to-use and versatile modules that can be exploited to significantly tune down P urg1 "OFF-levels" while maintaining an equivalent dynamic range. We also provide plasmids and tools for combining P urg1 transcriptional control with the auxin degron tag to help maintain a null-like phenotype. We demonstrate the utility of this system by improved regulation of HO-dependent site-specific DSB formation, by the regulation Rtf1-dependent replication fork arrest and by controlling Rhp18(Rad18)-dependent post replication repair

Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden

Background Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Methods Plasma was obtained from patients with benign pancreatic disease ( = 16) and PDAC ( = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, = 13; and PDAC, = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos ( = 11), compared to the source tumors ( = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; 4 cm; = 0.012). Conclusions High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients

Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR

MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA

The Influence of Moral Ideology on Religiosity, Moral Emotions, and Drinking Behaviors

Objective: The current study examined prospective relationships between religious affiliation, feelings of guilt and shame, ethical orientation (relativism and idealism), alcohol consumption and quantity of heavy episodic drinking. Participants: Three hundred and seventy-one students attending a large, public university in Texas. Method: Electronic surveys assessed predictors of college alcohol use. Comparisons were made between Christians and Non-theist participants on alcohol consumption and binge drinking, controlling for guilt, shame, relativism and idealism. Results: Christians drank more than Non-theists. Relativism was positively related to quantity of binge drinking episodes. Shame had no effect among Christians on alcohol consumption, but shame had a negative effect on alcohol consumption among Non-theists. Guilt had no effect among Christians on binge drinking, but guilt had a negative effect on binge drinking among Non-theists. There was a relativism by guilt interaction on binge drinking, with guilt having a negative effect on binge drinking only among individuals high in relativism. Conclusions: Data are supportive of continued investigation of the effects of ethical orientation and moral emotions on collegiate alcohol consumption and binge drinking

miR-515-5p controls cancer cell migration through MARK4 regulation

Here, we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seq analyses of both oestrogen receptor receptor-positive and receptor-negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3' UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation. Furthermore, miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers

Soft electroweak breaking from hard supersymmetry breaking

We present a class of four-dimensional models, with a non-supersymmetric spectrum, in which the radiative corrections to the Higgs mass are not sensitive, at least at one-loop, to the UV completion of the theory. At one loop, Yukawa interactions of the top quark contribute to a finite and negative Higgs squared mass which triggers the electroweak symmetry breaking, as in softly broken supersymmetric theories, while gauge interactions lead to a logarithmic cutoff dependent correction that can remain subdominant. Our construction relies on a hard supersymmetry breaking localized in the theory space of deconstruction models and predicts, within a renormalizable setup, analogous physics as five-dimensional scenarios of Scherk-Schwarz supersymmetry breaking. The electroweak symmetry breaking can be calculated in terms of the deconstruction scale, replication number, top-quark mass and electroweak gauge couplings. For m_top ~ 170 Gev, the Higgs mass varies from 158 GeV for N=2 to 178 GeV for N=10.Comment: LaTex, 20 pages, 6 figures. v2: typos corrected and references adde