Search

Within the Standard Model, and if one assumes that soft rescattering effects are negligible, the CP asymmetry A^dir_CP (B^\pm -> \pi^\pm K) is predicted to be very small and the ratio R = BR(B_d -> \pi^\mp K^\pm)/BR(B^\pm -> \pi^\pm K) provides a bound on the angle \gamma of the unitarity triangle, sin^2 \gamma \leq R. We estimate the corrections from soft rescattering effects using an approach based on Regge phenomenology, and find effects of order 10% with large uncertainties. In particular, we conclude that A^dir_CP \sim 0.2 and sin^2 \gamma \sim 1.2 R could not be taken unambiguously to signal New Physics. Using SU(3) relations, we suggest experimental tests that could constrain the size of the soft rescattering effects thus reducing the related uncertainty. Finally, we study the effect of various models of New Physics on A^dir_CP and on R., Comment: 20 pages, RevTex, no figures; a few typos corrected, references added, brief additional discussion of uncertanties is added

We study the implications of various supersymmetric models on the rare $K^+ \to \pi^+ \nu \bar\nu$ and $K_L \to \pi^0 \nu \bar\nu$ decays. Although large effects are possible in generic supersymmetric models, most of the known supersymmetric flavor models lead to negligible effects. Thus, it is likely that one can get information about CKM matrix elements from these decays even in the presence of supersymmetry. Moreover, the possibility of large contributions to $K \to \pi \nu \bar\nu$ in generic supersymmetric models can be constrained by improved bounds on $D-\bar D$ mixing. We show that it may be possible to distinguish between different supersymmetric flavor models by combining the information from the $K \to \pi \nu \bar\nu$ decays with that from $B-\bar B$ and $D-\bar D$ mixing., Comment: 17 pgs Revtex, 1 fig. Uses epsf. Constraints in Table 1 and related text changed due to previously overlooked SU(2) relations; references updated; conclusions unchanged. Version to be published in PLB.

We analyze the decay $K_L \to \pi^0 \nu \bar \nu$ in a model independent way. If lepton flavor is conserved the final state is (to a good approximation) purely CP even. In that case this decay mode goes mainly through CP violating interference between mixing and decay. Consequently, a theoretically clean relation between the measured rate and electroweak parameters holds in any given model. Specifically, $\Gamma(K_L \to \pi^0 \nu \bar \nu)/\Gamma(K^+ \to \pi^+ \nu \bar \nu)= \sin^2\theta$ (up to known isospin corrections), where $\theta$ is the relative CP violating phase between the $K-\bar K$ mixing amplitude and the $s\to d\nu\bar\nu$ decay amplitude. The experimental bound on $BR(K^+ \to \pi^+ \nu \bar \nu)$ provides a model independent upper bound: $BR(K_L \to \pi^0 \nu \bar \nu) < 1.1 \times 10^{-8}$. In models with lepton flavor violation, the final state is not necessarily a CP eigenstate. Then CP conserving contributions can dominate the decay rate., Comment: 12 pages, revtex, no figures

We analyze the decay $K_L \to ��^0 ��\bar ��$ in a model independent way. If lepton flavor is conserved the final state is (to a good approximation) purely CP even. In that case this decay mode goes mainly through CP violating interference between mixing and decay. Consequently, a theoretically clean relation between the measured rate and electroweak parameters holds in any given model. Specifically, $��(K_L \to ��^0 ��\bar ��)/��(K^+ \to ��^+ ��\bar ��)= \sin^2��$ (up to known isospin corrections), where $��$ is the relative CP violating phase between the $K-\bar K$ mixing amplitude and the $s\to d��\bar��$ decay amplitude. The experimental bound on $BR(K^+ \to ��^+ ��\bar ��)$ provides a model independent upper bound: $BR(K_L \to ��^0 ��\bar ��) < 1.1 \times 10^{-8}$. In models with lepton flavor violation, the final state is not necessarily a CP eigenstate. Then CP conserving contributions can dominate the decay rate., 12 pages, revtex, no figures

Four topics in theory of CP violation are reviewed. (a) CP violation in $B$ decays: We describe a new clean way of constraining the angle $\gamma$ of the unitarity triangle and how new CP violation in decay amplitudes can signal new physics. (b) CP violation in $K$ decays: We explain the special features of the decay $K_L\ra\pi^0\nu\bar\nu$ both as a measurement of Standard Model CP violating parameters and as a probe of new physics. (c) CP violation in $D$ decays: We describe the consequences of CP violation from new physics in $D-\bar D$ mixing. (d) CP violation in Supersymmetry: We explain how a combination of measurements of CP violating processes will give insight into the flavor and CP structure of supersymmetry., Comment: 29 pages, LaTeX, Invited plenary talk given at the 18th International Symposium on Lepton Photon Interactions, Hamburg, Germany, July 28 -- August 1 1997. To appear in the proceedings

Following activation by antigen, costimulation, and inflammation, naïve CD8+ T cells initiate a program of clonal expansion and differentiation resulting in wide-spread changes in expression of genes involved in cell-cycle, metabolism, effector function, apoptosis, and homing. Although, several key transcription factors (TFs) have been shown to be important in effector CD8+ T cell differentiation, the precise transcriptional regulation of this differentiation program remains poorly understood. The AP-1 family member BATF plays an important role in regulating differentiation and function in CD4+ Th17 cells, CD4+ follicular helper T cells, and in Ig class switching in B cells. We now show that BATF is also required for effector CD8+ T cell differentiation and regulates a core program of genes involved in effector differentiation. We found that BATF expression is rapidly up-regulated during effector CD8+ T cell differentiation in the mouse model of lymphocytic choriomeningitis virus (LCMV) infection. To examine the role of BATF in effector differentiation, we studied congenically distinct wild type (WT) and BATF knockout (KO) naïve P14 TCR transgenic CD8+ T cells co- transferred into a WT host. Upon infection, the BATF KO cells exhibited a profound, cell-intrinsic defect in effector CD8+ T cell differentiation, with a ∼400-fold decrease in peak number of effector cells. BATF KO effectors showed sustained activation and increased cell death by the mid-expansion phase of the immune response. To address the question of how loss of BATF causes such a severely diminished antigen-specific response, we profiled the binding sites of BATF throughout the genome by chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) in primary CD8+ effector cells. We found that BATF bound to regulatory regions in many genes critical for effector differentiation, including transcription factors (e.g. Tbx21, Eomes, Prdm1), genes involved in cytokine signaling (e.g. Il12rb2, Il2ra), homing (e.g. Sell, Selp, Ccr9), effector function (e.g. Gzmb, Ifng, Il2), apoptosis (e.g. Bcl2, Bcl2l1, Mcl1), and T cell activation (e.g. Ctla4, Cd247, Tnfrsf4), suggesting a major role for BATF in effector CD8+ T cell differentiation. Indeed, we found that genes bound by BATF were highly significantly overrepresented among genes that changed as a result of naïve CD8+ T cells differentiating into effectors in vivo (P = 10-27). Comparison of gene expression in in vitro WT and BATF KO effectors confirmed that BATF bound genes were perturbed by BATF loss of function. Analysis of the kinetics of gene expression during the first 72 hours of effector differentiation showed that loss of BATF perturbed the temporal sequence of expression of critical transcription factors, such as T-bet and Eomes, and resulted in inappropriately early cytokine expression. This suggests that BATF may be required to coordinate the earliest events in CD8+ T cell effector differentiation. To test this hypothesis, we used in vivo CFSE tracking to follow the early CD8+ T cell response during LCMV infection. We found that while BATF KO CD8+ T cells initiate cell division, there was a dramatic collapse in the ability to sustain proliferation and differentiation as early as day 3 post-infection. These results indicate that BATF ensures the orderly progression of a program of genes required by effector cells, restraining the expression of some and promoting the expression of others. More broadly, our results suggest that BATF may provide a common regulatory infrastructure for the development of effector cells in all T cell lineages. Disclosures: Wherry: Genentech: Patents & Royalties.

Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens and induction of multiple autoimmune diseases. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions. IL-23 has been shown to reinforce the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R). However, the molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions is unclear. Here we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1) is critical for regulating IL-23R expression and for stabilizing the Th17 cell by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and homeostasis. We show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is critical for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation.

RORγt is a master transcription factor required for Th17 development. We identified two novel RORγt-specific inhibitors that suppress Th17 response and Th17-mediated autoimmune disease. To assess their mechanisms of action, we systemically characterize their function within the context of RORγt-directed transcriptional circuitry by integrating RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wildtype and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 differentiation and as a direct inhibitor of genes from other T-cell lineages. These inhibitors reversed both of these modes of action, but to varying extents and through distinct mechanisms. While one inhibitor displaced RORγt from its target-loci, the more potent inhibitor affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

IL-10 producing Type 1 regulatory T cells (Tr1) are crucial for maintenance of peripheral tolerance and prevention of autoimmune inflammation. Using IL-27 as the differentiation factor, we undertook a detailed whole genome transcriptional network analysis of differentiating Tr1 cells. We identified IRF-1 as a key transcriptional regulator of Tr1 differentiation. Our studies demonstrate a critical requirement for IRF1 in the generation of Tr1 cells both in vitro and in vivo. IRF1-/- mice immunized for the development of Experimental autoimmune encephalomyelitis (EAE) develop very severe clinical disease and fail to recover. Furthermore, CD4+ T cells in IRF1-deficient mice with active disease showed increased number of IL-17 secreting cells in the CNS. In fact, over-expression of IRF1 during Th17 differentiation suppresses induction of both IL17 and IL23 receptor, the role opposite to the one played by another IRF family member - IRF4. Interestingly, loss of IRF-1 enhances IRF4 binding to the key DNA-binding sites involved in Th17 differentiation and functional assays further support that IRF1 can actively repress IRF4-mediated transactivation of IL17A, pointing to a cross-competition of IRF1 and IRF4 for the same DNA-binding sites in CD4+ T cells. Collectively these data demonstrate a critical role of IRF-1 in the generation of Tr1 cells, but at the same time, the induction of IRF-1 represses Th17 differentiation by actively inhibiting IRF-4 mediated Th17 differentiation.

We discuss the discovery potential for New Physics of various measurements of CP violation. If nature is supersymmetric, then the flavor problem is even more mysterious than in the standard model. We show how we can learn about the mechanism that solves the supersymmetric flavor problem from measurements of mixing and CP violation in $K$, $D$ and $B$ decays. (Invited talk given at the Workshop on K Physics, Orsay, France, May 30 - June 4, 1996.), Comment: 16 pages, uses harvmac

The hierarchy in the Yukawa couplings may be the result of a gauged horizontal $U(1)_H$ symmetry. If the mixed anomalies of the Standard Model gauge group with $U(1)_H$ are cancelled by a Green-Schwarz mechanism, a relation between the gauge couplings, the Yukawa couplings and the $��$-term arises. Assuming that at a high energy scale $g_3^2=g_2^2={5\over3}g_1^2$ and $(m_e m_��m_��)/(m_d m_s m_b)\sim ��$ (where $��$ is of the order of the Cabibbo angle), the $U(1)_H$ symmetry solves the $��$-problem with $��\sim��m_{3/2}$., 7 pages, harvmac

We calculate the $O(��_s)$ corrections to the charged Higgs mediated inclusive semi-tauonic $B$ decay. By working in the Landau gauge, we demonstrate how to obtain the charged Higgs contributions (both direct and interference terms) from the known QCD corrections to $t \to b H^+$. Combining our results with $O(1/m_b^2)$ corrections to the spectator model and comparing the theoretical prediction with the recent experimental measurements, we find a model-independent $2��$ upper bound on the ratio of Higgs vacuum expectation values, $\tan��, 10 pages, 1 figure, revtex

To determine the signaling pathways leading from Met activation to metastasis and poor prognosis, we measured the kinetic gene alterations in breast cancer cell lines in response to HGF/SF. Using a network inference tool we analyzed the putative protein-protein interaction pathways leading from Met to these genes and studied their specificity to Met and prognostic potential. We identified a Met kinetic signature consisting of 131 genes. The signature correlates with Met activation and with response to anti-Met therapy (p1000). Moreover, we have identified novel putative Met pathways, which correlate with Met activity and patient prognosis. This signature may facilitate personalized therapy by identifying patients who will respond to anti-Met therapy. Moreover, this novel approach may be applied for other tyrosine kinases and other malignancies.

Combining the experimental data on the inclusive decays $D\to X\,e\,\nu$, $B\to X\,e\,\nu$ and $B\to X\,\tau\,\nu$, we find severe constraints on the $\bar\Lambda$ and $\lambda_1$ parameters of the Heavy Quark Effective Theory. In particular, we get $\bar\Lambda, Comment: 8pages RevTeX + 1 postscript figure included, WIS-94/2/Jan-PH

We calculate the differential decay rate for inclusive $\bar B\to\tau\,\bar\nu\,X$ transitions to order $1/m_b^2$ in the heavy quark expansion, for both polarized and unpolarized tau leptons. We show that using a systematic $1/m_b$ expansion significantly reduces the theoretical uncertainties in the calculation. We obtain for the total branching ratio ${\rm BR}(\bar B\to\tau\,\bar\nu\,X)=2.30\pm 0.25\%$, and for the tau polarization $A_{\rm pol}=-0.706\pm0.006$. {}From the experimental measurement of the branching ratio at LEP, we derive the upper bound $\lo\leq 0.8\gev^2$ for one of the parameters of the heavy quark effective theory., Comment: 16pages harvmac

We reconsider the massless up quark solution of the strong CP problem. We show that an anomaly free horizontal symmetry can naturally lead to a massless up quark and to a corresponding accidental anomalous symmetry. Reviewing the controversy about the phenomenological viability of $m_u=0$ we conclude that this possiblity is still open and can solve the strong CP problem. To appear in the Proceedings of The Yukawa Couplings and the Origins of Mass Workshop., Comment: 19 pages, WIS-94/14/Feb-PH, RU-94-24

We calculate the differential decay rate for inclusive $\bar B\to\tau\ \bar\nu\,X$ transitions to order $1/m_b^2$ in the heavy quark expansion, for both polarized and unpolarized tau leptons. We show that using a systematic $1/m_b$ expansion significantly reduces the theoretical uncertainties in the calculation. We obtain for the total branching ratio ${\rm BR}(\bar B\to\tau\,\bar\nu\,X)=2.30\pm 0.25\%$, and for the tau polarization $A_{\rm pol}=-0.706\pm0.006$. {}From the experimental measurement of the branching ratio at LEP, we derive the upper bound $\lo\leq 0.8\gev^2$ for one of the parameters of the heavy quark effective theory.

Abstract 801 We have recently found that the Wnt/b-catenin signaling pathway plays a key role in chronic lymphocytic leukemia (CLL). We were, however, intrigued by the question of whether this aberrant pathway may function differently in independent leukemias, and contribute to disease heterogeneity. To assess differential activity of the Wnt pathway across patients, we tested the effects of blocking Wnt activation on CLL cell survival. We knocked down a key downstream gene, LEF1, which is the most differentially expressed gene in CLL compared to normal B cells (based on gene expression microarrays). Addressing this question requires genetic manipulation of primary normal and malignant human B cells, and yet these cells are notoriously difficult to transfect. We therefore focused on developing a method for introducing siRNAs into normal and malignant B cells. We adapted a novel delivery system consisting of vertical silicon nanowires (SiNWs, Shalek et al PNAS 2010) that penetrate the plasma membrane in a minimally invasive fashion and deliver biomolecular cargo directly into the cytoplasm. We achieved consistent and reliable delivery of fluorescently labeled siRNAs (at 50–200 pmol) into normal and CLL B cells. siRNA was delivered to >90% of cells with >85% cell viability remaining after 48 hours. We used this platform to knockdown LEF1 in 20 CLL-B and 5 normal CD19+ B cell samples, and examined cell survival 48 hours after siRNA delivery using an ATP-based CellTiter-Glo assay. Indeed, our studies revealed a heterogeneous response among CLL-B cells to LEF1 inhibition. As a group, CLL-B cells were significantly more sensitive to LEF1 knockdown with a survival rate of 77% (12% s.e.m) compared to 97% (13% s.e.m) in normal B cells. CLL B cells from different patients showed differential sensitivity to LEF1 knockdown, with 8 non-responders, 8 intermediate responders and 4 strong responders (i.e. significant death). Sensitivity to LEF1 inhibition did not correlate with known CLL cytogenetic prognostic factors. To determine if the differential response to LEF1 knockdown was associated with specific gene signatures, we examined gene expression data generated from CLL-B cells from 12 (4 strong, 3 intermediate, and 5 non-responders) of the 20 CLLs tested (using the Affymetrix U133 Plus 2 Array). To increase statistical power, we used each CLL's expression profile (using only genes that showed variability across samples) to create clusters of ∼19 CLLs that showed similar expression profiles (using microarray data from our compendium of 177 additional CLLs). We further reduced the number of genes to ∼4000 genes by retaining only those whose expression levels were significantly different in at least one associated cluster relative to normal CD19+ B cell controls (T-test, FDR Disclosures: No relevant conflicts of interest to declare.

We present a systematic analysis of the $B^{(*)}\to\pi\,\ell\,\nu$ weak decay form factors to order $1/m_b$ in the heavy quark effective theory, including a discussion of renormalization group effects. These processes are described by a set of ten universal functions (two at leading order, and eight at order $1/m_b$), which are defined in terms of matrix elements of operators in the effective theory. In the soft pion limit, the effective theory yields normalization conditions for these functions, which generalize the well-known current algebra relations derived from the combination of heavy quark and chiral symmetries to next-to-leading order in $1/m_b$. In particular, the effects of the nearby $B^*$-pole are correctly contained in the form factors of the effective theory. We discuss the prospects for a model independent determination of $|V_{ub}|$ and the $B B^*\pi$ coupling constant from these processes., Comment: 26 pages in ReVTeX 3.0, figures appended as postscript file, SLAC-PUB-6345