Signals of CP Violation Beyond the MSSM in Higgs and Flavor Physics

We study an extension of the Higgs sector of the Minimal Supersymmetric Standard Model (MSSM), considering the effects of new degrees of freedom at the TeV scale, and allowing for sources of CP violation beyond the MSSM (BMSSM). We analyze the impact of the BMSSM sources of CP violation on the Higgs collider phenomenology and on low energy flavor and CP violating observables. We identify distinct Higgs collider signatures that cannot be realized, either in the case without CP violating phases or in the CP violating MSSM, and investigate the prospects to probe them at the Tevatron and the LHC. The most striking benchmark scenario has three neutral Higgs bosons that all decay dominantly into W boson pairs and that are well within the reach of the 7 TeV LHC run. On the other hand, we also present scenarios with three Higgs bosons that have masses M_Hi > 150 GeV and decay dominantly into b bbar. Such scenarios are much more challenging to probe and can even lie completely outside the reach of the 7 TeV LHC run. We explore complementary scenarios with standard MSSM Higgs signals that allow to accommodate a sizable B_s mixing phase as indicated by D0, as well as the excess in B_s --> mu+ mu- candidates recently reported by CDF. We find that, in contrast to the MSSM, a minimal flavor violating soft sector is sufficient to generate significant corrections to CP violating observables in meson mixing, compatible with EDM constraints. In particular, a sizable B_s mixing phase, S_psiphi < 0.4, can be achieved for specific regions of parameter space. Such a large B_s mixing phase would unambiguously imply a sizable suppression of S_psiKs with respect to the SM prediction and a BR(B_s --> mu+ mu-) close to the 95% C.L. upper bound reported by CDF.Comment: 58 pages, 15 figures, 2 tables, v2 matches published versio

MED12 exon 2 mutations are common in uterine leiomyomas from South African patients

Uterine leiomyomas, or fibroids, are extremely common tumors. Regardless of their benign nature, fibroids can cause considerable morbidity. Women with African ancestry have a threefold increased risk of developing uterine leiomyomas with a greater symptom severity when compared to white women. Recently, we demonstrated that exon 2 of the MED12 gene is somatically altered in up to 70 per cent of uterine leiomyomas in a series of Finnish (Caucasian) patients. To validate these results in other populations, we sequenced a set of 28 uterine leiomyomas for MED12 exon 2 mutations from 18 different Black African or Coloured South African patients. We observed 14 mutation positive lesions (50%). When corrected by tumor size, these results are very similar to those derived in the Finnish material. This study confirms a major role of MED12 in the genesis of leiomyomas, regardless of ethnicity

Massive Spin-2 States as the Origin of the Top Quark Forward-Backward Asymmetry

We show that the anomalously large top quark forward-backward asymmetry observed by CDF and D\O\, can naturally be accommodated in models with flavor-violating couplings of a new massive spin-2 state to quarks. Regardless of its origin, the lowest-order couplings of a spin-2 boson to fermions are analogous to the coupling of the graviton to energy/momentum, leading to strong sensitivity of the effects associated with its virtual exchange to the energy scales at hand. Precisely due to this fact, the observed dependence of the asymmetry on the $t\bar t$ invariant mass fits nicely into the proposed framework. In particular, we find a vast parameter space which can lead to the central value for the observed forward-backward asymmetry in the high mass bin, while being in accord with all of the existing experimental constraints.Comment: added discussion of differential observables at the LHC, matches version accepted for publication in JHE

Long-lived stops in MSSM scenarios with a neutralino LSP

This work investigates the possibility of a long-lived stop squark in supersymmetric models with the neutralino as the lightest supersymmetric particle (LSP). We study the implications of meta-stable stops on the sparticle mass spectra and the dark matter density. We find that in order to obtain a sufficiently long stop lifetime so as to be observable as a stable R-hadron at an LHC experiment, we need to fine tune the mass degeneracy between the stop and the LSP considerably. This increases the stop-neutralino coanihilation cross section, leaving the neutralino relic density lower than what is expected from the WMAP results for stop masses ~1.5 TeV/c^2. However, if such scenarios are realised in nature we demonstrate that the long-lived stops will be produced at the LHC and that stop-based R-hadrons with masses up to 1 TeV/c^2 can be detected after one year of running at design luminosity

A new governance approach for multi-firm projects: lessons from Olkiluoto 3 and Flamanville 3 nuclear power plant projects

We analyze governance in two contemporary nuclear power plant projects: Olkiluoto 3 (Finland) and Flamanville 3 (France). We suggest that in the governance of large multi-firm projects, any of the prevalent governance approaches that rely on market, hierarchy, or hybrid forms, is not adequate as such. This paper opens up avenues towards a novel theory of governance in large projects by adopting a project network view with multiple networked firms within a single project, and by simultaneously going beyond organizational forms that cut across the traditional firm–market dichotomy. Our analysis suggests four changes in the prevailing perspective towards the governance of large projects. First, there should be a shift from viewing multi-firm projects as hierarchical contract organizations to viewing them as supply networks characterized by a complex and networked organizational structure. Second, there should be a shift in the emphasis of the predominant modes of governance, market and hierarchy towards novel governance approaches that emphasize network-level mechanisms such as self-regulation within the project. Third, there should be a shift from viewing projects as temporary endeavors to viewing projects as short-term events or episodes embedded in the long-term sphere of shared history and expected future activities among the involved actors. Fourth, there should be a shift from the prevailing narrow view of a hierarchical project management system towards an open system view of managing in complex and challenging institutional environments

Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

Background: Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.Methods: Statistical analysis was performed using multipoint parametric and nonparametric linkage.Results: Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1- q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).Conclusion: The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q

High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint

Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3' end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A(9)-G(4)-A(7) locus, in which the most common mutation was a mononucleotide deletion in the A(9) (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC

Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis - Evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers

Juvenile polyposis syndrome (JPS; OMIM 174900) is a rare disorder which is characterized by the presence of hamartomatous polyps throughout the gastrointestinal tract and an increased risk of gastrointestinal malignancy. Mutations of the SMAD4 gene on chromosome 18q21.1 have been shown to cause a subset of JPS cases, with estimates ranging from 20% to &gt;50%. Characterization of the genes that cause the remainder of JPS cases relies on the certainty that SMAD4 is not the causative gene. We have undertaken a comprehensive analysis of germline SMAD4 mutations in a cohort of JPS patients to define the spectrum of mutations that cause JPS. We have analyzed a series of polyps from these patients for SMAD4 protein expression. We have also performed a blinded assessment of polyp material to look for morphological differences between polyps from patients with and without a germline SMAD4 mutation. The results indicate that almost all germline SMAD4 mutations are readily detectable by screening genomic DNA using polymerase chain reaction-based methods; SMAD4 can be excluded as the causative gene in the majority of our JPS cohort. Loss of SMAD4 expression occurs in most polyps from SMAD4 mutation carriers, even those with missense germline mutations. SMAD4 loss in polyps is, however, not a feature of cases that are not caused by SMAD4 mutations, indicating that these polyps develop along a SMAD4-independent pathway. The morphology of polyps from SMAD4 mutation carriers is subtly different from other JPS polyps, notably including a more prominent epithelial component in the former

Chiral U(1) flavor models and flavored Higgs doublets: the top FB asymmetry and the Wjj

We present U(1) flavor models for leptophobic Z' with flavor dependent couplings to the right-handed up-type quarks in the Standard Model, which can accommodate the recent data on the top forward-backward (FB) asymmetry and the dijet resonance associated with a W boson reported by CDF Collaboration. Such flavor-dependent leptophobic charge assignments generally require extra chiral fermions for anomaly cancellation. Also the chiral nature of U(1)' flavor symmetry calls for new U(1)'-charged Higgs doublets in order for the SM fermions to have realistic renormalizable Yukawa couplings. The stringent constraints from the top FB asymmetry at the Tevatron and the same sign top pair production at the LHC can be evaded due to contributions of the extra Higgs doublets. We also show that the extension could realize cold dark matter candidates.Comment: 40 pages, 10 figures, added 1 figure and extended discussion, accepted for publication in JHE

EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis

BACKGROUND: Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors. METHODS: Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC. RESULTS: Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism. CONCLUSION: We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this