Simulating Holographic Conformal Field Theories on Hyperbolic Lattices.

We demonstrate how tabletop settings combining hyperbolic lattices with nonlinear dynamics universally encode aspects of the bulk-boundary correspondence between gravity in anti-de-Sitter (AdS) space and conformal field theory (CFT). Our concrete and broadly applicable holographic toy model simulates gravitational self-interactions in the bulk and features an emergent CFT with nontrivial correlations on the boundary. We measure the CFT data contained in the two- and three-point functions and clarify how a thermal CFT is simulated through an effective black hole geometry. As a concrete example, we propose and simulate an experimentally feasible protocol to measure the holographic CFT using electrical circuits.

Breitenlohner-Freedman Bound on Hyperbolic Tilings.

We establish how the Breitenlohner-Freedman (BF) bound is realized on tilings of two-dimensional Euclidean Anti-de Sitter space. For the continuum, the BF bound states that on Anti-de Sitter spaces, fluctuation modes remain stable for small negative mass squared m^{2}. This follows from a real and positive total energy of the gravitational system. For finite cutoff ϵ, we solve the Klein-Gordon equation numerically on regular hyperbolic tilings. When ϵ→0, we find that the continuum BF bound is approached in a manner independent of the tiling. We confirm these results via simulations of a hyperbolic electric circuit. Moreover, we propose a novel circuit including active elements that allows us to further scan values of m^{2} above the BF bound.

Turbulent hydrodynamics in strongly correlated Kagome metals.

A current challenge in condensed matter physics is the realization of strongly correlated, viscous electron fluids. These fluids can be described by holography, that is, by mapping them onto a weakly curved gravitational theory via gauge/gravity duality. The canonical system considered for realizations has been graphene. In this work, we show that Kagome systems with electron fillings adjusted to the Dirac nodes provide a much more compelling platform for realizations of viscous electron fluids, including non-linear effects such as turbulence. In particular, we find that in Scandium Herbertsmithite, the fine-structure constant, which measures the effective Coulomb interaction, is enhanced by a factor of about 3.2 as compared to graphene. We employ holography to estimate the ratio of the shear viscosity over the entropy density in Sc-Herbertsmithite, and find it about three times smaller than in graphene. These findings put the turbulent flow regime described by holography within the reach of experiments.

Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling.

Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

Hepatocellular carcinoma: a systems biology perspective.

Hepatocellular carcinomas (HCCs) have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel-targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment.

Heterogeneous kinetics of AKT signaling in individual cells are accounted for by variable protein concentration.

In most solid cancers, cells harboring oncogenic mutations represent only a sub-fraction of the entire population. Within this sub-fraction the expression level of mutated proteins can vary significantly due to cellular variability limiting the efficiency of targeted therapy. To address the causes of the heterogeneity, we performed a systematic analysis of one of the most frequently mutated pathways in cancer cells, the phosphatidylinositol 3 kinase (PI3K) signaling pathway. Among others PI3K signaling is activated by the hepatocyte growth factor (HGF) that regulates proliferation of hepatocytes during liver regeneration but also fosters tumor cell proliferation. HGF-mediated responses of PI3K signaling were monitored both at the single cell and cell population level in primary mouse hepatocytes and in the hepatoma cell line Hepa1_6. Interestingly, we observed that the HGF-mediated AKT responses at the level of individual cells is rather heterogeneous. However, the overall average behavior of the single cells strongly resembled the dynamics of AKT activation determined at the cell population level. To gain insights into the molecular cause for the observed heterogeneous behavior of individual cells, we employed dynamic mathematical modeling in a stochastic framework. Our analysis demonstrated that intrinsic noise was not sufficient to explain the observed kinetic behavior, but rather the importance of extrinsic noise has to be considered. Thus, distinct from gene expression in the examined signaling pathway fluctuations of the reaction rates has only a minor impact whereas variability in the concentration of the various signaling components even in a clonal cell population is a key determinant for the kinetic behavior.

Towards hydrodynamics without an entropy current.

We present a generating functional which describes the equilibrium thermodynamic response of a relativistic system to external sources. A variational principle gives rise to constraints on the response parameters of relativistic hydrodynamics without making use of an entropy current. Our method reproduces and extends results available in the literature. It also provides a technique for efficiently computing n-point zero-frequency correlation functions within the hydrodynamic derivative expansion without the need to explicitly solve the equations of hydrodynamics.

Co-repressor activity of scaffold attachment factor B1 requires sumoylation.

Sumoylation is an emerging modification associated with a variety of cellular processes including the regulation of transcriptional activities of nuclear receptors and their coregulators. As SUMO modifications are often associated with transcriptional repression, we examined if sumoylation was involved in modulation of the transcriptional repressive activity of scaffold attachment factor B1. Here we show that SAFB1 is modified by both the SUMO1 and SUMO2/3 family of proteins, on lysine's K231 and K294. Further, we demonstrate that SAFB1 can interact with PIAS1, a SUMO E3 ligase which mediates SAFB1 sumoylation. Additionally, SENP1 was identified as the enzyme desumoylating SAFB1. Mutation of the SAFB1 sumoylation sites lead to a loss of transcriptional repression, at least in part due to decreased interaction with HDAC3, a known transcriptional repressor and SAFB1 binding partner. In summary, the transcriptional repressor SAFB1 is modified by both SUMO1 and SUMO2/3, and this modification is necessary for its full repressive activity.

SAFB1 mediates repression of immune regulators and apoptotic genes in breast cancer cells.

The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system. A subsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes.

Overexpression and mislocalization of the chromosomal segregation protein separase in multiple human cancers.

PURPOSE: Separase, an endopeptidase, plays a pivotal role in chromosomal segregation by separating sister chromatids during the metaphase to anaphase transition. Using a mouse mammary tumor model we have recently shown that overexpression of Separase induces aneuploidy and tumorigenesis (Zhang et al., Proc Natl Acad Sci 2008;105:13033). In the present study, we have investigated the expression level of Separase across a wide range of human tumors. EXPERIMENTAL DESIGN: To examine the expression levels and localization of Separase in human tumors, we have performed immunofluorescence microscopy using human Separase antibody and tumor tissue arrays from osteosarcoma, colorectal, breast, and prostate cancers with appropriate normal controls. RESULTS: We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens. There is a strong correlation of tumor status with the localization of Separase into the nucleus throughout all stages of the cell cycle. Unlike the normal control tissues, where Separase localization is exclusively cytoplasmic in nondividing cells, human tumor samples show significantly higher number of resting cells with a strong nuclear Separase staining. Additionally, overexpression of Separase transcript strongly correlates with high incidence of relapse, metastasis, and lower 5-year overall survival rate in breast and prostate cancer patients. CONCLUSION: These results further strengthen our hypothesis that Separase might be an oncogene, whose overexpression induces tumorigenesis, and indicates that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human cancers.

Overexpression of Separase induces aneuploidy and mammary tumorigenesis.

Separase is an endopeptidase that separates sister chromatids by cleaving cohesin Rad21 during the metaphase-to-anaphase transition. Conditional expression of Separase in tetracycline-inducible diploid FSK3 mouse mammary epithelial cells with both p53 WT and mutant (Ser-233-234) alleles of unknown physiological significance develops aneuploidy within 5 days of Separase induction in vitro. Overexpression of Separase induces premature separation of chromatids, lagging chromosomes, and anaphase bridges. In an in vivo mouse mammary transplant model, induction of Separase expression in the transplanted FSK3 cells for 3-4 weeks results in the formation of aneuploid tumors in the mammary gland. Xenograft studies combined with histological and cytogenetic analysis reveal that Separase-induced tumors are clonal in their genomic complements and have a mesenchymal phenotype suggestive of an epithelial-mesenchymal transition. Induction of Separase resulted in trisomies for chromosomes 8, 15, and 17; monosomy for chromosome 10; and amplification of the distal region of chromosomes 8 and 11. Separase protein is found to be significantly overexpressed in human breast tumors compared with matched normal tissue. These results collectively suggest that Separase is an oncogene, whose overexpression alone in mammary epithelial cells is sufficient to induce aneuploidy and tumorigenesis in a p53 mutant background.

Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma.

Osteosarcoma is a primary malignant tumor of bone arising from primitive bone-forming mesenchymal cells and accounts for approximately 60% of malignant bone tumors. Our comparative genomic hybridization (CGH) studies have identified frequent amplification at 6p12-p21, 12q13-q15, and 17p11.2 in osteosarcoma. Of these amplified regions, 6p12-p21 is particularly interesting because of its association with progression and poor prognosis in patients with osteosarcoma. In an attempt to identify aberrantly expressed gene(s) mapping to the 6p12-p21 amplicon, a region-specific array was generated using 108 overlapping BAC and P1 clones covering a 28.8-Mb region at 0.26-Mb intervals. Based on array CGH analysis, the 6p amplicon was refined to 7.9 Mb between the clones RP11-91E11 and RP1-244F2 and 10 amplified clones, with possible target genes, were identified. To study the expression pattern of the target genes from the hotspot amplicon and known candidate genes from 6p12-21, we did quantitative reverse transcription-PCR analysis of MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, BTB9, DNAH8, CCND3, PTK7, CDC5L, and RUNX2 on osteosarcoma patient samples and seven cell lines. The combined array CGH and quantitative reverse transcription-PCR analysis identified amplification and overexpression of CDC5L, CCND3, and RUNX2. We screened these three genes for protein expression by Western blotting and immunohistochemistry and detected overexpression of CDC5L. Furthermore, we used an in vivo assay to show that CDC5L possesses potential oncogenic activity. These results indicate that CDC5L, a cell cycle regulator important for the G2-M transition, is the most likely candidate oncogene for the 6p12-p21 amplicon found in osteosarcoma.

Spacetime emergence of the robertson-walker universe from a matrix model.

Using a novel, string theory-inspired formalism based on a Hamiltonian constraint, we obtain a conformal mechanical system for the spatially flat four-dimensional Robertson-Walker Universe. Depending on parameter choices, this system describes either a relativistic particle in the Robertson-Walker background or metric fluctuations of the Robertson-Walker geometry. Moreover, we derive a tree-level M theory matrix model in this time-dependent background. Imposing the Hamiltonian constraint forces the spacetime geometry to be fuzzy near the big bang, while the classical Robertson-Walker geometry emerges as the Universe expands. From our approach, we also derive the temperature of the Universe interpolating between the radiation and matter dominated eras.

PRMT2, a member of the protein arginine methyltransferase family, is a coactivator of the androgen receptor.

The basal transcriptional activity of nuclear receptors (NRs) is regulated by interactions with additional comodulator proteins (coactivator/corepressor). Here, we describe a new androgen receptor (AR)-associated coactivator, PRMT2, which belongs to the arginine methyltransferase protein family. To search for AR-interacting proteins a fragment of the AR was used in a library screen exploiting the yeast two-hybrid technique and identifying the C-terminal region of PRMT2. We demonstrated that PRMT2 acts as a strong coactivator of the AR, had modest or none influence on transcriptional activation mediated by other NRs. Interestingly, PRMT2 interaction with the estrogen receptor (ER) was strongly dependent on the cellular background, thus, suggesting the involvement of additional, differentially expressed coregulators. We also demonstrated synergistic interaction of PRMT2 with other known nuclear receptor coactivators, such as GRIP1/TIF-2. Potentiation of AR-mediated transactivation by PRMT2 alone and in synergism with GRIP1 was prevented by a competitive inhibitor of methyltransferase activity. The PRMT2 expression profile overlaps with the distribution of AR, with strongest PRMT2 abundance in androgen target tissues. Immunofluorescence experiments showed that the intracellular localization of PRMT2 depends on the presence of the cognate receptor ligand. Under androgen-free conditions, both AR and PRMT2 are confined to the cytoplasm, whereas in the presence of androgens both proteins colocalize and translocate into the nucleus. Treatment with the AR antagonist hydroxyflutamide results in nuclear translocation of the AR, but not the coactivator PRMT2. Thus, it appears that the ligand-dependent AR conformation is essential for the recruitment and nuclear translocation of PMRT2 which acts as AR-coactivator, presumably by arginine methylation.

FoxG1, a member of the forkhead family, is a corepressor of the androgen receptor.

The androgen receptor (AR) is a ligand-dependent transcriptional regulator which belongs to the nuclear receptor superfamily. The basal transcriptional activity of the androgen receptor is regulated by interaction with coactivator or corepressor proteins. The exact mechanism whereby comodulators influence target gene transcription is only partially understood, especially for corepressors. Whereas several coactivators are described for the AR, only a few corepressors are known. Here, we describe the discovery of a new androgen receptor corepressor, FoxG1, which belongs to the forkhead family. By using a fragment of the AR (aa 325-919) as bait in a yeast two hybrid screen, the C-terminal region (aa 175-489) of FoxG1 (also known as BF1), was identified as AR-interacting protein. Binding of AR to the FoxG1 fragment was verified by one- and two-hybrid assays, and pull-down experiments. In addition, we show that the full-length form of FoxG1 functions as a strong corepressor in the AR-mediated transactivation. The FoxG1 expression profile in adult individuals is restricted to brain and testis in human and decreases during aging in the rodent brain. Both AR and FoxG1 expression are developmentally regulated. Besides its reported role in neurogenesis, the strong expression of FoxG1 in AR-abundant areas of the adult brain suggests possible involvement in neuroendocrine regulation. Taken together, the data presented suggest that, in addition to repression of transcription by direct binding to DNA, FoxG1 may interact with AR in vivo, thereby targeting its repressor function specifically to sex hormone signaling.

1-D simulation of a novel nonvolatile resistive random access memory device.

The operation of a novel, nonvolatile memory device based on a conductive ferroelectric/semiconductor thin film multilayer stack is simulated numerically. The simulation involves the self-consistent steady-state solution of the transport equation for electrons assuming a drift-diffusion transport mechanism and the Poisson equation. Special emphasis is put on the screening of the spontaneous polarization by conduction electrons as a function of the applied voltage. Depending on the orientation of the polarization in the ferroelectric layer, a high and a low resistive state are found, giving rise to a hysteretic I-V characteristic. The switching ratio, ranging from > 50% to several orders of magnitude, is calculated as a function of the dopant content. The suggested model provides one possible physical explanation of the I-V hysteresis observed for single-layer ferroelectric devices, if interfacial layers are taken into consideration. The approach will allow one to develop guidelines to improve the performance of these devices.

Disruption of scaffold attachment factor B1 leads to TBX2 up-regulation, lack of p19ARF induction, lack of senescence, and cell immortalization.

Scaffold attachment factor B1 (SAFB1) is a multifunctional protein, which has previously been implicated in breast cancer. Here, we show that genetic deletion of SAFB1 in mouse embryonic fibroblasts (MEF) leads to spontaneous immortalization and altered expression of two proteins involved in immortalization and escape from senescence: low levels of p19(ARF) and high levels of TBX2. Inactivation of TBX2 using a dominant-negative TBX2 resulted in up-regulation of p19(ARF) in SAFB1 knockout MEFs. SAFB1 loss also caused lack of contact inhibition, increased foci formation, and increased oncogene-induced anchorage-independent growth. These findings suggest that SAFB1 is a novel player in cellular immortalization and transformation.

Scaffold attachment factor SAFB1 suppresses estrogen receptor alpha-mediated transcription in part via interaction with nuclear receptor corepressor.

Activity of the estrogen receptor (ER) is regulated through interaction with coactivators and corepressors. These proteins are present in large complexes, suggesting functional interactions among various cofactors. Scaffold attachment factors B1 and B2 (SAFB1/2) and nuclear receptor corepressor (N-CoR) function as ERalpha corepressors--they directly interact with ERalpha, and repress transcription via repression domains. We asked the question whether SAFB1/2 and N-CoR could directly interact with each other, and whether this interaction results in altered repressive activities. Employing coimmunoprecipitation, cofractionation, and colocalization experiments, we have shown that SAFB1/2 interact with the nuclear receptor corepressor N-CoR. This interaction was direct, and was mediated in vitro and in vivo through the C-terminal region of SAFB1 (amino acids 600-915 and the N-terminal region of N-CoR (amino acids 1-373)). Decrease of SAFB1 or N-CoR expression by small interfering RNA resulted in an increase of the estrogen response in reporter assays, confirming prior data that both proteins are attenuating estrogen-mediated induction of genes. Importantly, the effect of SAFB1 on this attenuation was significantly decreased in the presence of N-CoR small interfering RNA. Using chromatin immunoprecipitation assays, we observed that SAFB1/2 and N-CoR were recruited to the pS2 promoter in the absence of estrogen, and this recruitment was enhanced in the presence of Tamoxifen. Detailed kinetic studies showed that the addition of estrogen resulted in the concurrent release of SAFB1/2 and N-CoR from the promoter. Finally, we measured expression of SAFB1/2 and N-CoR in 289 clinical breast cancer specimens, and detected a strong and highly significant correlation between their expression levels. Taken together, our studies demonstrate that SAFB1/2 and N-CoR interact, and that this interaction is, at least in part, necessary for SAFB1's repressive activities. The coexpression of these proteins in breast cancer specimens, and the combined recruitment (and release) of SAFB1/2 and N-CoR furthermore suggests that this interaction has functional relevance.

Scaffold attachment factor B1 functions in development, growth, and reproduction.

Scaffold attachment factor B1 (SAFB1) is a multifunctional protein that can bind both DNA and RNA and is involved in RNA processing and stress response. In addition, SAFB1 contains a transcriptional repression domain and can bind certain hormone receptors and repress their activity. To assess the role of SAFB1 in vivo, we generated SAFB1 mutant mice through targeted deletion in embryonic stem cells. While viable homozygous mutant (SAFB1-/-) mice were obtained, genotypic distribution indicated that homozygous deficiency resulted in both prenatal and neonatal lethality. Mice lacking SAFB1 exhibited dwarfism, as a result of in utero growth retardation, and had low serum insulin-like growth factor 1 (IGF1) levels. In agreement with the previous characterization of SAFB1 as a corepressor for hormone receptors, we found that SAFB1-/- mice displayed dramatic defects in the development and function of the reproductive system. Male SAFB1 null mice were infertile, apparently because of low circulating levels of testosterone. SAFB1-/- testes were small and showed progressive degeneration of the germinal epithelium, increased apoptosis of germ cells, and Leydig cell hyperplasia. SAFB-/- female mice were subfertile and showed progressive infertility, in part because of defects in oviductal transport and reduced numbers of follicles. Immortalized SAFB1-/- mouse embryonic fibroblasts showed cell-intrinsic defects including increased transcriptional estrogen receptor alpha activity and enhanced responsiveness to IGF1. Together, these in vivo findings establish a critical role for SAFB1 in development, growth regulation, and reproduction.

Observation of vacancy defect migration in the cation sublattice of complex oxides by 18O tracer experiments.

We report on 18O tracer diffusion experiments and model calculations for the study of cation vacancy migration in oxide crystals. The model takes advantage of the electrostatic coupling forces between anion and cation defects that allow the evolution of the cation vacancy profile to be observed by anion tracer experiments. Applied to SrTiO3, the ambipolar diffusion of strontium vacancies with H(A)=3.5 eV was found to be the dominant reequilibration mechanism of the cation sublattice. This result is in contrast to earlier studies proposing the formation of SrO intergrowth phases.