Flexoelectricity-Driven Mechanical Switching of Polarization in Metastable Ferroelectrics.

Flexoelectricity-based mechanical switching of ferroelectric polarization has recently emerged as a fascinating alternative to conventional polarization switching using electric fields. Here, we demonstrate hyperefficient mechanical switching of polarization exploiting metastable ferroelectricity that inherently holds a unique mechanical response. We theoretically predict that mechanical forces markedly reduce the coercivity of metastable ferroelectricity, thus greatly bolstering flexoelectricity-driven mechanical polarization switching. As predicted, we experimentally confirm the mechanical polarization switching via an unusually low mechanical force (100 nN) in metastable ferroelectric CaTiO_{3}. Furthermore, the use of low mechanical forces narrows the width of mechanically writable nanodomains to sub-10 nm, suggesting an ultrahigh data storage density of ≥1 Tbit cm^{-2}. This Letter sheds light on the mechanical switching of ferroelectric polarization as a viable key element for next-generation efficient nanoelectronics and nanoelectromechanics.

Observation of Spin-Dependent Dual Ferromagnetism in Perovskite Ruthenates.

We performed in situ angle-resolved photoemission spectroscopy (ARPES) and spin-resolved ARPES (SARPES) experiments to investigate the relationship between electronic band structures and ferromagnetism in SrRuO_{3} (SRO) thin films. Our high quality ARPES and SARPES results show clear spin-lifted band structures. The spin polarization is strongly dependent on momentum around the Fermi level, whereas it becomes less dependent at high-binding energies. This experimental observation matches our dynamical mean-field theory results very well. As temperature increases from low to the Curie temperature, spin-splitting gap decreases and band dispersions become incoherent. Based on the ARPES study and theoretical calculation results, we found that SRO possesses spin-dependent electron correlations in which majority and minority spins are localized and itinerant, respectively. Our finding explains how ferromagnetism and electronic structure are connected, which has been under debate for decades in SRO.

Polar Metal Phase Induced by Oxygen Octahedral Network Relaxation in Oxide Thin Films.

ABO3 perovskite materials and their derivatives have inherent structural flexibility due to the corner sharing network of the BO6 octahedron, and the large variety of possible structural distortions and strong coupling between lattice and charge/spin degrees of freedom have led to the emergence of intriguing properties, such as high-temperature superconductivity, colossal magnetoresistance, and improper ferroelectricity. Here, an unprecedented polar ferromagnetic metal phase in SrRuO3 (SRO) thin films is presented, arising from the strain-controlled oxygen octahedral rotation (OOR) pattern. For compressively strained SRO films grown on SrTiO3 substrate, oxygen octahedral network relaxation is accompanied by structural phase separation into strained tetragonal and bulk-like orthorhombic phases, and the asymmetric OOR evolution across the phase boundary allows formation of the polar phase, while bulk metallic and ferromagnetic properties are maintained. From the results, it is expected that other oxide perovskite thin films will also yield similar structural environments with variation of OOR patterns, and thereby provide promising opportunities for atomic scale control of material properties through strain engineering.

Cooperative activation of PI3K by Ras and Rho family small GTPases.

Phosphoinositide 3-kinases (PI3Ks) and Ras and Rho family small GTPases are key regulators of cell polarization, motility, and chemotaxis. They influence each other's activities by direct and indirect feedback processes that are only partially understood. Here, we show that 21 small GTPase homologs activate PI3K. Using a microscopy-based binding assay, we show that K-Ras, H-Ras, and five homologous Ras family small GTPases function upstream of PI3K by directly binding the PI3K catalytic subunit, p110. In contrast, several Rho family small GTPases activated PI3K by an indirect cooperative positive feedback that required a combination of Rac, CDC42, and RhoG small GTPase activities. Thus, a distributed network of Ras and Rho family small GTPases induces and reinforces PI3K activity, explaining past challenges to elucidate the specific relevance of different small GTPases in regulating PI3K and controlling cell polarization and chemotaxis.

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability.

Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

First Observation of Ferroelectricity in ∼1 nm Ultrathin Semiconducting BaTiO3 Films.

The requirements of multifunctionality in thin-film systems have led to the discovery of unique physical properties and degrees of freedom, which exist only in film forms. With progress in growth techniques, one can decrease the film thickness to the scale of a few nanometers (∼nm), where its unique physical properties are still pronounced. Among advanced ultrathin film systems, ferroelectrics have generated tremendous interest. As a prototype ferroelectric, the electrical properties of BaTiO3 (BTO) films have been extensively studied, and it has been theoretically predicted that ferroelectricity sustains down to ∼nm thick films. However, efforts toward determining the minimum thickness for ferroelectric films have been hindered by practical issues surrounding large leakage currents. In this study, we used ∼nm thick BTO films, exhibiting semiconducting characteristics, grown on a LaAlO3/SrTiO3 (LAO/STO) heterostructure. In particular, we utilized two-dimensional electron gas at the LAO/STO heterointerface as the bottom electrode in these capacitor junctions. We demonstrate that the BTO film exhibits ferroelectricity at room temperature, even when it is only ∼2 unit-cells thick, and the total thickness of the capacitor junction can be reduced to less than ∼4 nm. Observation of ferroelectricity in ultrathin semiconducting films and the resulting shrunken capacitor thickness will expand the applicability of ferroelectrics in the next generation of functional devices.

The core regulatory network in human cells.

In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved, essential and non-disease, non-druggable genes compared to the peripheral genes. Overall, our study provides an insight into how all human cells share a common function and generate tissue-specific functional traits by transmitting and processing information through regulatory network.

Identification and characterization of the leaf specific networks of inner and rosette leaves in Brassica rapa.

Inner and rosette leaves of Chinese cabbage (Brassica rapa) have different characteristics in terms of nutritional value, appearance, taste, color and texture. Many researchers have utilized differentially expressed genes for exploring the difference between inner and rosette leaves of Brassica rapa. The functional characteristics of a gene, however, is determined by complex interactions between genes. Hence, a noble network approach is required for elucidating such functional difference that is not captured by gene expression profiles alone. In this study, we measured gene expression in the standard cabbage genome by RNA-Sequencing and constructed rosette and inner leaf networks based on the gene expression profiles. Furthermore, we compared the topological and functional characteristics of these networks. We found significant functional difference between the rosette and inner leaf networks. Specifically, we found that the genes in the rosette leaf network were associated with homeostasis and response to external stimuli whereas the genes in the inner leaf network were mainly related to the glutamine biosynthesis processes and developmental processes with hormones. Overall, the network approach provides an insight into the functional difference of the two leaves.

Overcoming the Fundamental Barrier Thickness Limits of Ferroelectric Tunnel Junctions through BaTiO3/SrTiO3 Composite Barriers.

Ferroelectric tunnel junctions (FTJs) have attracted increasing research interest as a promising candidate for nonvolatile memories. Recently, significant enhancements of tunneling electroresistance (TER) have been realized through modifications of electrode materials. However, direct control of the FTJ performance through modifying the tunneling barrier has not been adequately explored. Here, adding a new direction to FTJ research, we fabricated FTJs with BaTiO3 single barriers (SB-FTJs) and BaTiO3/SrTiO3 composite barriers (CB-FTJs) and reported a systematic study of FTJ performances by varying the barrier thicknesses and compositions. For the SB-FTJs, the TER is limited by pronounced leakage current for ultrathin barriers and extremely small tunneling current for thick barriers. For the CB-FTJs, the extra SrTiO3 barrier provides an additional degree of freedom to modulate the barrier potential and tunneling behavior. The resultant high tunability can be utilized to overcome the barrier thickness limits and enhance the overall CB-FTJ performances beyond those of SB-FTJ. Our results reveal a new paradigm to manipulate the FTJs through designing multilayer tunneling barriers with hybrid functionalities.

Robustness and evolvability of the human signaling network.

Biological systems are known to be both robust and evolvable to internal and external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling and attractor landscape analysis to investigate the evolvability and robustness of the human signaling network. Our results show that the human signaling network can be divided into an evolvable core where perturbations change the attractor landscape in state space, and a robust neighbor where perturbations have no effect on the attractor landscape. Using chemical inhibition and overexpression of nodes, we validated that perturbations affect the evolvable core more strongly than the robust neighbor. We also found that the evolvable core has a distinct network structure, which is enriched in feedback loops, and features a higher degree of scale-freeness and longer path lengths connecting the nodes. In addition, the genes with high evolvability scores are associated with evolvability-related properties such as rapid evolvability, low species broadness, and immunity whereas the genes with high robustness scores are associated with robustness-related properties such as slow evolvability, high species broadness, and oncogenes. Intriguingly, US Food and Drug Administration-approved drug targets have high evolvability scores whereas experimental drug targets have high robustness scores.

Biphasic RLR-IFN-ß response controls the balance between antiviral immunity and cell damage.

In RNA virus-infected cells, retinoic acid-inducible gene-I-like receptors (RLRs) sense foreign RNAs and activate signaling cascades to produce IFN-α/ß. However, not every infected cell produces IFN-α/ß that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-ß-GFP reporter system, we observed bimodal IFN-ß production in the uniformly stimulated cell population with intracellular dsRNA. Mathematical simulation proposed the strength of autocrine loop via RLR as one of the contributing factor for biphasic IFN-ß expression. Bimodal IFN-ß production with intracellular dsRNA was disturbed by blockage of IFN-α/ß secretion or by silencing of the IFN-α/ß receptor. Amplification of RLRs was critical in the generation of bimodality of IFN-ß production, because IFN-ß(high) population expressed more RLRs than IFN-ß(low) population. In addition, bimodality in IFN-ß production results in biphasic cellular response against infection, because IFN-ß(high) population was more prone to apoptosis than IFN-ß(low) population. These results suggest that RLR-mediated biphasic cellular response may act to restrict the number of cells expressing IFN-ß and undergoing apoptosis in the infected population.

The co-regulation mechanism of transcription factors in the human gene regulatory network.

The co-regulation of transcription factors (TFs) has been widely observed in various species. Why is such a co-regulation mechanism needed for transcriptional regulation? To answer this question, the following experiments and analyses were performed. First, examination of the human gene regulatory network (GRN) indicated that co-regulation was significantly enriched in the human GRN. Second, mathematical simulation of an artificial regulatory network showed that the co-regulation mechanism was related to the biphasic dose-response patterns of TFs. Third, the relationship between the co-regulation mechanism and the biphasic dose-response pattern was confirmed using microarray experiments examining different time points and different doses of the toxicant tetrachlorodibenzodioxin. Finally, two mathematical models were constructed to mimic highly co-regulated networks (HCNs) and little co-regulated networks (LCNs), and we found that HCNs were more robust to parameter perturbation than LCNs, whereas LCNs were faster in adaptation to environmental changes than HCNs.

A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network.

Regulator of calcineurin 1 (RCAN1) is a key regulator of the calcineurin-NFAT signaling network in organisms ranging from yeast to human, but its functional role is still under debate because different roles of RCAN1 have been suggested under various experimental conditions. To elucidate the mechanisms underlying the RCAN1 regulatory system, we used a systems approach by combining single-cell experimentation with in silico simulations. In particular, we found that the nuclear export of GSK3ß, which switches on the facilitative role of RCAN1 in the calcineurin-NFAT signaling pathway, is promoted by PI3K signaling. Based on this, along with integrated information from previous experiments, we developed a mathematical model in which the functional role of RCAN1 changes in a dose-dependent manner: RCAN1 functions as an inhibitor when its levels are low, but as a facilitator when its levels are high. Furthermore, we identified a hidden incoherent regulation switch that mediates this role change, which entails negative regulation through RCAN1 binding to calcineurin and positive regulation through sequential phosphorylation of RCAN1.

Tuning orbital-selective phase transitions in a two-dimensional Hund's correlated system.

Hund's rule coupling (J) has attracted much attention recently for its role in the description of the novel quantum phases of multi-orbital materials. Depending on the orbital occupancy, J can lead to various intriguing phases. However, experimental confirmation of the orbital occupancy dependency has been difficult as controlling the orbital degrees of freedom normally accompanies chemical inhomogeneities. Here, we demonstrate a method to investigate the role of orbital occupancy in J related phenomena without inducing inhomogeneities. By growing SrRuO3 monolayers on various substrates with symmetry-preserving interlayers, we gradually tune the crystal field splitting and thus the orbital degeneracy of the Ru t2g orbitals. It effectively varies the orbital occupancies of two-dimensional (2D) ruthenates. Via in-situ angle-resolved photoemission spectroscopy, we observe a progressive metal-insulator transition (MIT). It is found that the MIT occurs with orbital differentiation: concurrent opening of a band insulating gap in the dxy band and a Mott gap in the dxz/yz bands. Our study provides an effective experimental method for investigation of orbital-selective phenomena in multi-orbital materials.

Heteroepitaxial Control of Fermi Liquid, Hund Metal, and Mott Insulator Phases in Single-Atomic-Layer Ruthenates.

Interfaces between dissimilar correlated oxides can offer devices with versatile functionalities, and great efforts have been made to manipulate interfacial electronic phases. However, realizing such phases is often hampered by the inability to directly access the electronic structure information; most correlated interfacial phenomena appear within a few atomic layers from the interface. Here, atomic-scale epitaxy and photoemission spectroscopy are utilized to realize the interface control of correlated electronic phases in atomic-scale ruthenate-titanate heterostructures. While bulk SrRuO3 is a ferromagnetic metal, the heterointerfaces exclusively generate three distinct correlated phases in the single-atomic-layer limit. The theoretical analysis reveals that atomic-scale structural proximity effects yield Fermi liquid, Hund metal, and Mott insulator phases in the quantum-confined SrRuO3 . These results highlight the extensive interfacial tunability of electronic phases, hitherto hidden in the atomically thin correlated heterostructure. Moreover, this experimental platform suggests a way to control interfacial electronic phases of various correlated materials.

A design principle underlying the synchronization of oscillations in cellular systems.

Biological oscillations are found ubiquitously in cells and are widely variable, with periods varying from milliseconds to months, and scales involving subcellular components to large groups of organisms. Interestingly, independent oscillators from different cells often show synchronization that is not the consequence of an external regulator. What is the underlying design principle of such synchronized oscillations, and can modeling show that the complex consequences arise from simple molecular or other interactions between oscillators? When biological oscillators are coupled with each other, we found that synchronization is induced when they are connected together through a positive feedback loop. Increasing the coupling strength of two independent oscillators shows a threshold beyond which synchronization occurs within a few cycles, and a second threshold where oscillation stops. The positive feedback loop can be composed of either double-positive (PP) or double-negative (NN) interactions between a node of each of the two oscillating networks. The different coupling structures have contrasting characteristics. In particular, PP coupling is advantageous with respect to stability of period and amplitude, when local oscillators are coupled with a short time delay, whereas NN coupling is advantageous for a long time delay. In addition, PP coupling results in more robust synchronized oscillations with respect to amplitude excursions but not period, with applied noise disturbances compared to NN coupling. However, PP coupling can induce a large fluctuation in the amplitude and period of the resulting synchronized oscillation depending on the coupling strength, whereas NN coupling ensures almost constant amplitude and period irrespective of the coupling strength. Intriguingly, we have also observed that artificial evolution of random digital oscillator circuits also follows this design principle. We conclude that a different coupling strategy might have been selected according to different evolutionary requirements.

Dynamic network rewiring determines temporal regulatory functions in Drosophila melanogaster development processes.

The identification of network motifs has been widely considered as a significant step towards uncovering the design principles of biomolecular regulatory networks. To date, time-invariant networks have been considered. However, such approaches cannot be used to reveal time-specific biological traits due to the dynamic nature of biological systems, and hence may not be applicable to development, where temporal regulation of gene expression is an indispensable characteristic. We propose a concept of a "temporal sequence of network motifs", a sequence of network motifs in active sub-networks constructed over time, and investigate significant network motifs in the active temporal sub-networks of Drosophila melanogaster. Based on this concept, we find a temporal sequence of network motifs which changes according to developmental stages and thereby cannot be identified from the whole static network. Moreover, we show that the temporal sequence of network motifs corresponding to each developmental stage can be used to describe pivotal developmental events.

Defect Engineering in A2 BO4 Thin Films via Surface-Reconstructed LaSrAlO4 Substrates.

Ruddlesden-Popper oxides (A2 BO4 ) have attracted significant attention regarding their potential application in novel electronic and energy devices. However, practical uses of A2 BO4 thin films have been limited by extended defects such as out-of-phase boundaries (OPBs). OPBs disrupt the layered structure of A2 BO4 , which restricts functionality. OPBs are ubiquitous in A2 BO4 thin films but inhomogeneous interfaces make them difficult to suppress. Here, OPBs in A2 BO4 thin films are suppressed using a novel method to control the substrate surface termination. To demonstrate the technique, epitaxial thin films of cuprate superconductor La2- x Srx CuO4 (x = 0.15) are grown on surface-reconstructed LaSrAlO4 substrates, which are terminated with self-limited perovskite double layers. To date, La2- x Srx CuO4 thin films are grown on LaSrAlO4 substrates with mixed-termination and exhibit multiple interfacial structures resulting in many OPBs. In contrast, La2- x Srx CuO4 thin films grown on surface-reconstructed LaSrAlO4 substrates energetically favor only one interfacial structure, thus inhibiting OPB formation. OPB-suppressed La2- x Srx CuO4 thin films exhibit significantly enhanced superconducting properties compared with OPB-containing La2- x Srx CuO4 thin films. Defect engineering in A2 BO4 thin films will allow for the elimination of various types of defects in other complex oxides and facilitate next-generation quantum device applications.

A system-level investigation into the cellular toxic response mechanism mediated by AhR signal transduction pathway.

MOTIVATION: Viewing a cellular system as a collection of interacting parts can lead to new insights into the complex cellular behavior. In this study, we have investigated aryl hydrocarbon receptor (AhR) signal transduction pathway from such a system-level perspective. AhR detects various xenobiotics, such as drugs or endocrine disruptors (e.g. dioxin), and mediates transcriptional regulation of target genes such as those in the cytochrome P450 (CYP450) family. On binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), however, AhR becomes abnormally activated and conveys toxic effects on cells. Despite many related studies on the TCDD-mediated toxicity, quantitative system-level understanding of how TCDD-mediated toxicity generates various toxic responses is still lacking. RESULTS: Here, we present a manually curated TCDD-mediated AhR signaling pathway including crosstalks with the hypoxia pathway that copes with oxygen deficiency and the p53 pathway that induces a DNA damage response. Based on the integrated pathway, we have constructed a mathematical model and validated it through quantitative experiments. Using the mathematical model, we have investigated: (i) TCDD dose-dependent effects on AhR target genes; (ii) the crosstalk effect between AhR and hypoxia signals; and (iii) p53 inhibition effect of TCDD-liganded AhR. Our results show that cellular intake of TCDD induces AhR signaling pathway to be abnormally up-regulated and thereby interrupts other signaling pathways. Interruption of hypoxia and p53 pathways, in turn, can incur various hazardous effects on cells. Taken together, our study provides a system-level understanding of how AhR signal mediates various TCDD-induced toxicities under the presence of hypoxia and/or DNA damage in cells.

Observation of metallic electronic structure in a single-atomic-layer oxide.

Correlated electrons in transition metal oxides exhibit a variety of emergent phases. When transition metal oxides are confined to a single-atomic-layer thickness, experiments so far have shown that they usually lose diverse properties and become insulators. In an attempt to extend the range of electronic phases of the single-atomic-layer oxide, we search for a metallic phase in a monolayer-thick epitaxial SrRuO3 film. Combining atomic-scale epitaxy and angle-resolved photoemission measurements, we show that the monolayer SrRuO3 is a strongly correlated metal. Systematic investigation reveals that the interplay between dimensionality and electronic correlation makes the monolayer SrRuO3 an incoherent metal with orbital-selective correlation. Furthermore, the unique electronic phase of the monolayer SrRuO3 is found to be highly tunable, as charge modulation demonstrates an incoherent-to-coherent crossover of the two-dimensional metal. Our work emphasizes the potentially rich phases of single-atomic-layer oxides and provides a guide to the manipulation of their two-dimensional correlated electron systems.