Unifying CP violations of quark and lepton sectors

A preliminary determination of the Dirac phase in the PMNS matrix is \dell\approx -\frac{\pi}{2}. A rather accurately determined Jarlskog invariant $J$ in the CKM matrix is close to the maximum. Since the phases in the CKM and PMNS matrices will be accurately determined in the future, it is an interesting problem to relate these two phases. This can be achieved in a families-unified grand unification if the weak CP violation is introduced spontaneously {\it \`a la} Froggatt and Nielsen at a high energy scale, where only one meaningful Dirac CP phase appears.Comment: 10 pages with 3 figure

Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain.

Lymphocyte-specific protein-tyrosine kinase (Lck) plays an essential role in T cell receptor (TCR) signaling and T cell development, but its activation mechanism is not fully understood. To explore the possibility that plasma membrane (PM) lipids control TCR signaling activities of Lck, we measured the membrane binding properties of its regulatory Src homology 2 (SH2) and Src homology 3 domains. The Lck SH2 domain binds anionic PM lipids with high affinity but with low specificity. Electrostatic potential calculation, NMR analysis, and mutational studies identified the lipid-binding site of the Lck SH2 domain that includes surface-exposed basic, aromatic, and hydrophobic residues but not the phospho-Tyr binding pocket. Mutation of lipid binding residues greatly reduced the interaction of Lck with the chain in the activated TCR signaling complex and its overall TCR signaling activities. These results suggest that PM lipids, including phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, modulate interaction of Lck with its binding partners in the TCR signaling complex and its TCR signaling activities in a spatiotemporally specific manner via its SH2 domain.1175Ysciescopu

Probing energetic light dark matter with multi-particle tracks signatures at DUNE

The search for relativistic scattering signals of cosmogenic light dark matter at terrestrial detectors has received increasing attention as an alternative approach to probe dark-sector physics. Large-volume neutrino experiments are well motivated for searches of dark matter that interacts very weakly with Standard Model particles and/or that exhibits a small incoming flux. We perform a dedicated signal sensitivity study for a detector similar to the one proposed by the DUNE Collaboration for cosmogenic dark-matter signals resulting from a non-minimal multi-particle dark-sector scenario. The liquid argon time projection chamber technology adopted for the DUNE detectors is particularly suited for searching for complicated signatures owing to good measurement resolution and particle identification, as well as $dE/dx$ measurements to recognize merged tracks. Taking inelastic boosted dark matter as our benchmark scenario that allows for multiple visible particles in the final state, we demonstrate that the DUNE far detectors have a great potential for probing scattering signals induced by relativistic light dark matter. Detector effects and backgrounds have been estimated and taken into account. Model-dependent and model-independent expected sensitivity limits for a DUNE-like detector are presented

SH2 domains serve as lipid binding modules for pTyr-signaling proteins

The Src-homology 2 (SH2) domain is a protein interaction domain that directs myriad phosphotyrosine (pY)-signaling pathways. Genome-wide screening of human SH2 domains reveals that similar to 90% of SH2 domains bind plasma membrane lipids and many have high phosphoinositide specificity. They bind lipids using surface cationic patches separate from pY-binding pockets, thus binding lipids and the pY motif independently. The patches form grooves for specific lipid headgroup recognition or flat surfaces for non-specific membrane binding and both types of interaction are important for cellular function and regulation of SH2 domain-containing proteins. Cellular studies with ZAP70 showed that multiple lipids bind its C-terminal SH2 domain in a spatiotemporally specific manner and thereby exert exquisite spatiotemporal control over its protein binding and signaling activities in T cells. Collectively, this study reveals how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY-signaling pathways.112620Ysciescopu

Goldstone Bosons in Effective Theories with Spontaneously Broken Flavour Symmetry

The Flavour Symmetry of the Standard Model (SM) gauge sector is broken by the fermion Yukawa couplings. Promoting the Yukawa matrices to scalar spurion fields, one can break the flavour symmetry spontaneously by giving appropriate vacuum expectation values (VEVs) to the spurion fields, and one encounters Goldstone modes for every broken flavour symmetry generator. In this paper, we point out various aspects related to the possible dynamical interpretation of the Goldstone bosons: (i) In an effective-theory framework with local flavour symmetry, the Goldstone fields represent the longitudinal modes for massive gauge bosons. The spectrum of the latter follows the sequence of flavour-symmetry breaking related to the hierarchies in Yukawa couplings and flavour mixing angles. (ii) Gauge anomalies can be consistently treated by adding higher-dimensional operators. (iii) Leaving the U(1) factors of the flavour symmetry group as global symmetries, the respective Goldstone modes behave as axions which can be used to resolve the strong CP problem by a modified Peccei-Quinn mechanism. (iv) The dynamical picture of flavour symmetry breaking implies new sources of flavour-changing neutral currents, which arise from integrating out heavy scalar spurion fields and heavy gauge bosons. The coefficients of the effective operators follow the minimal-flavour violation principle.Comment: 27 pages, abstract and introduction extended, more detailed discussion of heavy gauge boson spectrum and auxiliary heavy fermions, outline restructured. Matches version to be published in JHE

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

R-parity violation in SU(5)

We show that judiciously chosen R-parity violating terms in the minimal renormalizable supersymmetric SU(5) are able to correct all the phenomenologically wrong mass relations between down quarks and charged leptons. The model can accommodate neutrino masses as well. One of the most striking consequences is a large mixing between the electron and the Higgsino. We show that this can still be in accord with data in some regions of the parameter space and possibly falsified in future experiments.Comment: 30 pages, 1 figure. Revised version. To appear in JHE

Human Neural Stem Cells Over-Expressing VEGF Provide Neuroprotection, Angiogenesis and Functional Recovery in Mouse Stroke Model

BACKGROUND: Intracerebral hemorrhage (ICH) is a lethal stroke type. As mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and induce behavioral recovery in rat ICH model, and that combined administration of NSCs and vascular endothelial growth factor (VEGF) results in improved structural and functional outcome from cerebral ischemia. METHODS AND FINDINGS: We postulated that human NSCs overexpressing VEGF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs, increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by unilateral injection of bacterial collagenase into striatum. HB1.F3.VEGF human NSC line produced an amount of VEGF four times higher than parental F3 cell line in vitro, and induced behavioral improvement and 2–3 fold increase in cell survival at two weeks and eight weeks post-transplantation. CONCLUSIONS: Brain transplantation of F3 human NSCs over-expressing VEGF near ICH lesion sites provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results suggest a possible application of the human neural stem cell line, which is genetically modified to over-express VEGF, as a therapeutic agent for ICH-stroke

Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: A complete structure–activity profile

In the last 5 years, many efforts have been conducted searching potent and selective human A3 adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group synthesized a new series of pyrazolo-triazolo-pyrimidines bearing different substitutions at the N5 and N8 positions, which have been described as highly potent and selective human A3 adenosine receptor antagonists. The present review summarizes available data and provides an overview of the structure–activity relationships found for this class of human A3 adenosine receptor antagonists