On finiteness of Type IIB compactifications: Magnetized branes on elliptic Calabi-Yau threefolds

The string landscape satisfies interesting finiteness properties imposed by supersymmetry and string-theoretical consistency conditions. We study N=1 supersymmetric compactifications of Type IIB string theory on smooth elliptically fibered Calabi-Yau threefolds at large volume with magnetized D9-branes and D5-branes. We prove that supersymmetry and tadpole cancellation conditions imply that there is a finite number of such configurations. In particular, we derive an explicitly computable bound on the number of magnetic flux quanta, as well as the number of D5-branes, which is independent of the continuous moduli of the setup. The proof applies if a number of easy to check geometric conditions of the twofold base are met. We show that these geometric conditions are satisfied for the almost Fano twofold bases given by each toric variety associated to a reflexive two-dimensional polytope as well as by the generic del Pezzo surfaces dP_n with n=0,...,8. Physically, this finiteness proof shows that there exist a finite collection of four-dimensional gauge groups and chiral matter spectra in the 4D supergravity theories realized by these compactifications. As a by-product we explicitly construct all generators of the Kaehler cones of dP_n and work out their relation to representation theory.Comment: 49 pages, 1 figure, 5 tables. Minor corrections and improvements, a version to appear in JHE

A Two-Prong Approach for Targeting the mRNA Cap-Dependent Translation Initiation: Small Molecules and Hydrocarbon Stapled Peptides

Cap-dependent protein translation (CdT) is dysregulated in many types of cancer and leads to overexpression of oncogenes promoting angiogenesis, evasion of apoptosis, and cell proliferation. The protein-protein interactions (PPIs) involving eIF4E, 4E-BP1, and eIF4G1 dynamically regulate the initiation of the CdT and are therapeutic targets of interest in treatment of breast, pancreatic, ovarian, and prostate cancers; successful inhibition of the CdT could also provide selectivity towards targeting the protein translation addicted cancers over the healthy cells. In order to discover potent inhibitors of the CdT initiation, full-length eIF4E protein interactions were targeted using a two-pronged approach: small molecule discovered via high-throughput screening and rationally designed hydrocarbon stapled peptides. To conduct a high-throughput screening campaign, the assay platform catalytic enzyme-linked click chemistry assay (cat-ELCCA) was expanded to screen against full-length PPIs to create PPI cat-ELCCA and implemented for the eIF4E–4E-BP1 interaction. PPI cat-ELCCA exhibited over 10-fold improvement in limits of detection and quantification over ELISA and was successfully miniaturized using automated liquid handlers with exceptional assay parameters (Z’ > 0.6, signal-to-background > 30). Using PPI cat-ELCCA, over 50,000 natural product extracts (NPE) and custom compounds were screened, of which 18 NPE fractions and 9 compounds exhibited dose-dependent inhibition with hill slope ranging between -0.7 to -2.0. All the custom compounds were identified with micromolar inhibitory potency and 6 of the 9 compounds had demonstrated direct binding interaction to target protein eIF4E. Further re-isolation and iterative screening are pending for the active NPE fractions, and compound structure disclosures of hit molecules are awaiting approval. As an alternative drug discovery approach, the α-helical structure adopted by the 4E-BPs upon binding to eIF4E was exploited to design 4E-BP1 mimetic hydrocarbon stapled peptides (HCS). The lead HCS peptide HCS 4E-BP1 exhibited 5-fold greater inhibitory potency and eIF4E direct binding affinity (4 nM and 4 nM, respectively) than the linear 4E-BP1, accompanied by a 250% increase in peptide helicity. HCS 4E-BP1 successfully inhibited eIF4E PPIs with both 4E-BP1 and eIF4G1 in a dose-dependent manner in cellulo in presence of serum. Overall, the results from this two-pronged eIF4E inhibitor discovery campaign have pushed forward the current limits of targeting the CdT initiation and produced promising leads for further probe and drug development.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145870/1/jmsong_1.pd

Is the worst over? Economic indexes and the course of the recession in New York and New Jersey

The New York-New Jersey region entered a pronounced downturn in 2008, but the pace of decline eased considerably in spring 2009 and then leveled off in July, according to three key Federal Reserve Bank of New York economic indexes. These developments, in conjunction with a growing consensus that the national economy is headed for recovery, suggest that the worst may be over for the region's economy. However, a downsizing of the area's critical finance sector could pose a major risk to the economic outlook going forward--particularly for New York City.Federal Reserve Bank of New York ; Federal Reserve District, 2nd ; Economic conditions ; Economic indicators