ASU Scholarship Showcase

Although insulin resistance in skeletal muscle is well-characterized, the role of circulating whole blood in the metabolic syndrome phenotype is not well understood. We set out to test the hypothesis that genes involved in inflammation, insulin signaling and mitochondrial function would be altered in expression in the whole blood of individuals with metabolic syndrome. We further wanted to examine whether similar relationships that we have found previously in skeletal muscle exist in peripheral whole blood cells. All subjects (n=184) were Latino descent from the Arizona Insulin Resistance registry. Subjects were classified based on the metabolic syndrome phenotype according to the National Cholesterol Education Program’s Adult Treatment Panel III. Of the 184 Latino subjects in the study, 74 were classified with the metabolic syndrome and 110 were without. Whole blood gene expression profiling was performed using the Agilent 4x44K Whole Human Genome Microarray. Whole blood microarray analysis identified 1,432 probes that were altered in expression ≥1.2 fold and P<0.05 after Benjamini-Hochberg in the metabolic syndrome subjects. KEGG pathway analysis revealed significant enrichment for pathways including ribosome, oxidative phosphorylation and MAPK signaling (all Benjamini-Hochberg P<0.05). Whole blood mRNA expression changes observed in the microarray data were confirmed by quantitative RT-PCR. Transcription factor binding motif enrichment analysis revealed E2F1, ELK1, NF-kappaB, STAT1 and STAT3 significantly enriched after Bonferroni correction (all P<0.05). The results of the present study demonstrate that whole blood is a useful tissue for studying the metabolic syndrome and its underlying insulin resistance although the relationship between blood and skeletal muscle differs.

We present a new approach to computing event shape distributions or, more precisely, charge flow correlations in a generic conformal field theory (CFT). These infrared finite observables are familiar from collider physics studies and describe the angular distribution of global charges in outgoing radiation created from the vacuum by some source. The charge flow correlations can be expressed in terms of Wightman correlation functions in a certain limit. We explain how to compute these quantities starting from their Euclidean analogues by means of a nontrivial analytic continuation which, in the framework of CFT, can be performed elegantly in Mellin space. The relation between the charge flow correlations and Euclidean correlation functions can be reformulated directly in configuration space, bypassing the Mellin representation, as a certain Lorentzian double discontinuity of the correlation function integrated along the cuts. We illustrate the general formalism in N = 4 SYM, making use of the well-known results on the four-point correlation function of half-BPS scalar operators. We compute the double scalar flow correlation in N = 4 SYM, at weak and strong coupling and show that it agrees with known results obtained by different techniques. One of the remarkable features of the N = 4 theory is that the scalar and energy flow correlations are proportional to each other. Imposing natural physical conditions on the energy flow correlations (finiteness, positivity and regularity), we formulate additional constraints on the four-point correlation functions in N = 4SYM that should be valid at any coupling and away from the planar limit.

The Operator Product Expansion for null polygonal Wilson loop in planar maximally supersymmetric Yang–Mills theory runs systematically in terms of multi-particle pentagon transitions which encode the physics of excitations propagating on the color flux tube ending on the sides of the four-dimensional contour. Their dynamics was unraveled in the past several years and culminated in a complete description of pentagons as an exact function of the 't Hooft coupling. In this paper we provide a solution for the last building block in this program, the SU(4) matrix structure arising from internal symmetry indices of scalars and fermions. This is achieved by a recursive solution of the Mirror and Watson equations obeyed by the so-called singlet pentagons and fixing the form of the twisted component in their tensor decomposition. The non-singlet, or charged, pentagons are deduced from these by a limiting procedure.

We address the near-collinear expansion of NMHV six-particle scattering amplitudes at strong value of the 't Hooft coupling in planar maximally supersymmetric Yang–Mills theory. We complement recent studies of this observable within the context of the Pentagon Operator Product Expansion, via the dual superWilson loop description, by studying effects of multiple scalar exchanges that accompany (or not) massive flux-tube excitations. Due to the fact that holes have a very small, nonperturbatively generated mass m_h which is exponentially suppressed in the 't Hooft coupling, their exchanges must be resummed in the ultraviolet limit, T <<1/m_h. This procedure yields a contribution to the expectation value of the superloop which enters on equal footing with the classical area — a phenomenon which was earlier observed for MHV amplitudes. In all components, the near-massless scalar exchanges factorize from the ones of massive particles, at leading order in strong coupling.

Scattering amplitudes in maximally supersymmetric gauge theory receive a dual description in terms of the expectation value of the super Wilson loop stretched on a null polygonal contour. This makes the analysis amenable to nonperturbative techniques. Presently, we elaborate on a refined form of the operator product expansion in terms of pentagon transitions to compute twist-two contributions to NMHV amplitudes. To start with, we provide a novel derivation of scattering matrices starting from Baxter equations for flux-tube excitations propagating on magnon background. We propose bootstrap equations obeyed by pentagon form factors with nonsinglet quantum numbers with respect to the R-symmetry group and provide solutions to them to all orders in 't Hooft coupling. These are then successfully confronted against available perturbative calculations for NMHV amplitudes to four-loop order.

We address the near-collinear expansion of multiparticle NMHV amplitudes, namely, the heptagon and octagons in the dual language of null polygonal super Wilson loops. In particular, we verify multiparticle factorization of charged pentagon transitions in terms of pentagons for single flux-tube excitations within the framework of refined operator product expansion. We find a perfect agreement with available tree and one-loop data.

Scattering amplitudes in maximally supersymmetric gauge theory are dual to super-Wilson loops on null polygonal contours. The operator product expansion for the latter revealed that their dynamics is governed by the evolution of multiparticle GKP excitations. They were shown to emerge from the spectral problem of an underlying open spin chain. In this work we solve this model with the help of the Baxter Q-operator and Sklyanin's Separation of Variables methods. We provide an explicit construction for eigenfunctions and eigenvalues of GKP excitations. We demonstrate how the former define the so-called multiparticle hexagon transitions in super-Wilson loops and prove their factorized form at leading order of 't Hooft coupling for particle number-preserving transitions that were suggested earlier in a generic case.

We compute one-loop renormalization group equations for non-singlet twist-four operators in QCD. The calculation heavily relies on the light-cone gauge formalism in the momentum fraction space that essentially rephrases the analysis of all two-to-two and two-to-three transition kernels to purely algebraic manipulations both for non- and quasipartonic operators. This is the first brute force calculation of this sector available in the literature. Fourier transforming our findings to the coordinate space, we checked them against available results obtained within a conformal symmetry-based formalism that bypasses explicit diagrammatic calculations and confirmed agreement with the latter.

Background: Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity.

Methods: Cereblon binding partners were identified from a MM cell line expressing histidine-tagged cereblon by pulling down cereblon and its binding partners and verified by co-immunoprecipitation. IMiD effects were determined by western blot analysis, cell viability assay, microRNA array and apoptosis analysis.

Results: We identified argonaute 2 (AGO2) as a cereblon binding partner and found that the steady-state levels of AGO2 were regulated by cereblon. Upon treatment of IMiD-sensitive MM cells with lenalidomide, the steady-state levels of cereblon were significantly increased, whereas levels of AGO2 were significantly decreased. It has been reported that AGO2 plays a pivotal role in microRNA maturation and function. Interestingly, upon treatment of MM cells with lenalidomide, the steady-state levels of microRNAs were significantly altered. In addition, silencing of AGO2 in MM cells, regardless of sensitivity to IMiDs, significantly decreased the levels of AGO2 and microRNAs and massively induced cell death.

Conclusion: These results support the notion that the cereblon binding partner AGO2 plays an important role in regulating MM cell growth and survival and AGO2 could be considered as a novel drug target for overcoming IMiD resistance in MM cells.

Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m²) and lean (BMI, 22±1 kg/m²) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h^-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = – 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish impaired β-F1-ATPase translation as an important consequence of obesity.