Gauge mediation to effective SUSY through U(1)s with a dynamical SUSY breaking, and string compactification

We investigate the possibility of U(1)' mediation, leading to an effective SUSY where the first two family sfermions are above 100 TeV but the third family sfermions and the Higgs doublets are in the TeV region(or the light stop case). The U(1)' gaugino, Zprimino, needs not to be at a TeV scale, but needs to be somewhat lighter than the messenger scale. We consider two cases, one the mediation is only through U(1)' and the other through U(1)' and the electroweak hypercharge U(1)_Y. In the SUSY field theory framework, we calculate the superpartner mass spectra for these two cases. We also point out that the particle species needed for these mechanisms are already obtained from a Z(12-I) orbifold compactification

Current reversal with type-I intermittency in deterministic inertia ratchets

The intermittency is investigated when the current reversal occurs in a deterministic inertia ratchet system. To determine which type the intermittency belongs to, we obtain the return map of velocities of particle using stroboscopic recording, and numerically calculate the distribution of average laminar length ${}$. The distribution follows the scaling law of ${} \propto {\epsilon}^{-1/2}$, the characteristic relation of type-I intermittency.Comment: 4 pages, 7 figure

String theoretic QCD axions in the light of PLANCK and BICEP2

The QCD axion solving the strong CP problem may originate from antisymmetric tensor gauge fields in compactified string theory, with a decay constant around the GUT scale. Such possibility appears to be ruled out now by the detection of tensor modes by BICEP2 and the PLANCK constraints on isocurvature density perturbations. A more interesting and still viable possibility is that the string theoretic QCD axion is charged under an anomalous U(1)_A gauge symmetry. In such case, the axion decay constant can be much lower than the GUT scale if moduli are stabilized near the point of vanishing Fayet-Illiopoulos term, and U(1)_A-charged matter fields get a vacuum value far below the GUT scale due to a tachyonic SUSY breaking scalar mass. We examine the symmetry breaking pattern of such models during the inflationary epoch with the Hubble expansion rate 10^{14} GeV, and identify the range of the QCD axion decay constant, as well as the corresponding relic axion abundance, consistent with known cosmological constraints. In addition to the case that the PQ symmetry is restored during inflation, there are other viable scenarios, including that the PQ symmetry is broken during inflation at high scales around 10^{16}-10^{17} GeV due to a large Hubble-induced tachyonic scalar mass from the U(1)_A D-term, while the present axion scale is in the range 10^{9}-5\times 10^{13} GeV, where the present value larger than 10^{12} GeV requires a fine-tuning of the axion misalignment angle. We also discuss the implications of our results for the size of SUSY breaking soft masses.Comment: 29 pages, 1 figure; v3: analysis updated including the full anharmonic effects, references added, version accepted for publication in JHE

IRAS 15099-5856: Remarkable Mid-Infrared Source with Prominent Crystalline Silicate Emission Embedded in the Supernova Remnant MSH15-52

We report new mid-infrared observations of the remarkable object IRAS 15099-5856 using the space telescopes AKARI and Spitzer, which demonstrate the presence of prominent crystalline silicate emission in this bright source. IRAS 15099-5856 has a complex morphology with a bright central compact source (IRS1) surrounded by knots, spurs, and several extended (~4') arc-like filaments. The source is seen only at >= 10 um. The Spitzer MIR spectrum of IRS1 shows prominent emission features from Mg-rich crystalline silicates, strong [Ne II] 12.81 um and several other faint ionic lines. We model the MIR spectrum as thermal emission from dust and compare with the Herbig Be star HD 100546 and the luminous blue variable R71, which show very similar MIR spectra. Molecular line observations reveal two molecular clouds around the source, but no associated dense molecular cores. We suggest that IRS1 is heated by UV radiation from the adjacent O star Muzzio 10 and that its crystalline silicates most likely originated in a mass outflow from the progenitor of the supernova remnant (SNR) MSH 15-52. IRS1, which is embedded in the SNR, could have been shielded from the SN blast wave if the progenitor was in a close binary system with Muzzio 10. If MSH15-52 is a remnant of Type Ib/c supernova (SN Ib/c), as has been previously proposed, this would confirm the binary model for SN Ib/c. IRS1 and the associated structures may be the relics of massive star death, as shaped by the supernova explosion, the pulsar wind and the intense ionizing radiation of the embedded O star.Comment: 25 pages, 7 figures, Fig. 5 revised. Accepted for publication in Ap

Valproic Acid Induces Hair Regeneration in Murine Model and Activates Alkaline Phosphatase Activity in Human Dermal Papilla Cells

Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2) also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth

Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population

<p>Abstract</p> <p>Background</p> <p>This study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population.</p> <p>Methods</p> <p>We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis.</p> <p>Results</p> <p>The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit.</p> <p>Conclusions</p> <p>This is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma.</p

Implication of NOD1 and NOD2 for the Differentiation of Multipotent Mesenchymal Stem Cells Derived from Human Umbilical Cord Blood

Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are known to trigger an innate immune response against microbial infection. Although studies suggest that activation of TLRs modulate the function of mesenchymal stem cells (MSCs), little is known about the role of NLRs on the MSC function. In this study, we investigated whether NOD1 and NOD2 regulate the functions of human umbilical cord blood-derived MSCs (hUCB-MSCs). The genes of TLR2, TLR4, NOD1, and NOD2 were expressed in hUCB-MSCs. Stimulation with each agonist (Pam3CSK4 for TLR2, LPS for TLR4, Tri-DAP for NOD1, and MDP for NOD2) led to IL-8 production in hUCB-MSC, suggesting the expressed receptors are functional in hUCB-MSC. CCK-8 assay revealed that none of agonist influenced proliferation of hUCB-MSCs. We next examined whether TLR and NLR agonists affect osteogenic-, adipogenic-, and chondrogenic differentiation of hUCB-MSCs. Pam3CSK4 and Tri-DAP strongly enhanced osteogenic differentiation and ERK phosphorylation in hUCB-MSCs, and LPS and MDP also slightly did. Treatment of U0126 (MEK1/2 inhibitor) restored osteogenic differentiation enhanced by Pam3CSK4. Tri-DAP and MDP inhibited adipogenic differentiation of hUCB-MSCs, but Pam3CSK4 and LPS did not. On chondrogenic differentiation, all TLR and NLR agonists could promote chondrogenesis of hUCB-MSCs with difference in the ability. Our findings suggest that NOD1 and NOD2 as well as TLRs are involved in regulating the differentiation of MSCs

Cross-Regulation between Oncogenic BRAFV600E Kinase and the MST1 Pathway in Papillary Thyroid Carcinoma

BACKGROUND:The BRAF(V600E) mutation leading to constitutive signaling of MEK-ERK pathways causes papillary thyroid cancer (PTC). Ras association domain family 1A (RASSF1A), which is an important regulator of MST1 tumor suppressor pathways, is inactivated by hypermethylation of its promoter region in 20 to 32% of PTC. However, in PTC without RASSF1A methylation, the regulatory mechanisms of RASSF1A-MST1 pathways remain to be elucidated, and the functional cooperation or cross regulation between BRAF(V600E) and MST1,which activates Foxo3,has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:The negative regulators of the cell cycle, p21 and p27, are strongly induced by transcriptional activation of FoxO3 in BRAF(V600E) positive thyroid cancer cells. The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway. Interestingly, introduction of BRAF(V600E)markedly abolished FoxO3 transactivation and resulted in the suppression of p21 and p27 expression. The suppression of FoxO3 transactivation by BRAF(V600E)is strongly increased by coexpression of MST1 but it is not observed in the cells in which MST1, but not MST2,is silenced. Mechanistically, BRAF(V600E)was able to bind to the C-terminal region of MST1 and resulted in the suppression of MST1 kinase activities. The induction of the G1-checkpoint CDK inhibitors, p21 and p27,by the RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition of BRAF(V600E) inhibits the apoptotic processes through the inactivation of MST1. Transgenic induction of BRAF(V600E)in the thyroid gland results in cancers resembling human papillary thyroid cancers. The development of BRAF(V600E)transgenic mice with the MST1 knockout background showed that these mice had abundant foci of poorly differentiated carcinomas and large areas without follicular architecture or colloid formation. CONCLUSIONS/SIGNIFICANCE:The results of this study revealed that the oncogenic effect of BRAF(V600E) is associated with the inhibition of MST1 tumor suppressor pathways, and that the activity of RASSF1A-MST1-FoxO3 pathways determines the phenotypes of BRAF(V600E) tumors

An Essential Regulatory Role of Downstream of Kinase-1 in the Ovalbumin-Induced Murine Model of Asthma

The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases

Prominent Bone Loss Mediated by RANKL and IL-17 Produced by CD4+ T Cells in TallyHo/JngJ Mice

Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis