Observation of room-temperature polar skyrmions.

Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO3)n/(SrTiO3)n suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses1-3. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.

Observation of polar vortices in oxide superlattices.

The complex interplay of spin, charge, orbital and lattice degrees of freedom provides a plethora of exotic phases and physical phenomena. In recent years, complex spin topologies have emerged as a consequence of the electronic band structure and the interplay between spin and spin-orbit coupling in materials. Here we produce complex topologies of electrical polarization--namely, nanometre-scale vortex-antivortex (that is, clockwise-anticlockwise) arrays that are reminiscent of rotational spin topologies--by making use of the competition between charge, orbital and lattice degrees of freedom in superlattices of alternating lead titanate and strontium titanate layers. Atomic-scale mapping of the polar atomic displacements by scanning transmission electron microscopy reveals the presence of long-range ordered vortex-antivortex arrays that exhibit nearly continuous polarization rotation. Phase-field modelling confirms that the vortex array is the low-energy state for a range of superlattice periods. Within this range, the large gradient energy from the vortex structure is counterbalanced by the corresponding large reduction in overall electrostatic energy (which would otherwise arise from polar discontinuities at the lead titanate/strontium titanate interfaces) and the elastic energy associated with epitaxial constraints and domain formation. These observations have implications for the creation of new states of matter (such as dipolar skyrmions, hedgehog states) and associated phenomena in ferroic materials, such as electrically controllable chirality.

Phase coexistence and electric-field control of toroidal order in oxide superlattices.

Systems that exhibit phase competition, order parameter coexistence, and emergent order parameter topologies constitute a major part of modern condensed-matter physics. Here, by applying a range of characterization techniques, and simulations, we observe that in PbTiO3/SrTiO3 superlattices all of these effects can be found. By exploring superlattice period-, temperature- and field-dependent evolution of these structures, we observe several new features. First, it is possible to engineer phase coexistence mediated by a first-order phase transition between an emergent, low-temperature vortex phase with electric toroidal order and a high-temperature ferroelectric a1/a2 phase. At room temperature, the coexisting vortex and ferroelectric phases form a mesoscale, fibre-textured hierarchical superstructure. The vortex phase possesses an axial polarization, set by the net polarization of the surrounding ferroelectric domains, such that it possesses a multi-order-parameter state and belongs to a class of gyrotropic electrotoroidal compounds. Finally, application of electric fields to this mixed-phase system permits interconversion between the vortex and the ferroelectric phases concomitant with order-of-magnitude changes in piezoelectric and nonlinear optical responses. Our findings suggest new cross-coupled functionalities.

Full Electroresistance Modulation in a Mixed-Phase Metallic Alloy.

We report a giant, ∼22%, electroresistance modulation for a metallic alloy above room temperature. It is achieved by a small electric field of 2 kV/cm via piezoelectric strain-mediated magnetoelectric coupling and the resulting magnetic phase transition in epitaxial FeRh/BaTiO_{3} heterostructures. This work presents detailed experimental evidence for an isothermal magnetic phase transition driven by tetragonality modulation in FeRh thin films, which is in contrast to the large volume expansion in the conventional temperature-driven magnetic phase transition in FeRh. Moreover, all the experimental results in this work illustrate FeRh as a mixed-phase model system well similar to phase-separated colossal magnetoresistance systems with phase instability therein.

Immunological impression cytology of the conjunctival epithelium in patients with thyroid orbitopathy-related dry eye.

Thyroid orbitopathy (TO) is an autoimmune disease that is complicated by ocular surface disorders, leading to discomfort. Dry eye is very prevalent in patients with TO. Recent studies on the pathogenesis of dry eye have focused on the inflammatory process, and some supporting evidence has been discovered. Because TO is a disorder of autoimmune origin, we assumed that the association between TO and dry eye is related to inflammation. Inflammation of the ocular surface in TO-related dry eye has not been well studied. In this study, we assessed cellular inflammation of the ocular surface and the cytokine profiles in patients with TO-related dry eye. Conjunctival impression cytology (CIC) was assessed with an immunofluorescent assay. TO-related dry eye was diagnosed by using the Schirmer test, tear break-up time, thyroid function, and clinical signs. CIC was combined with immunological staining of interleukin-1a (IL-1a), IL-1b, and IL- 6. The immunological impression cytology (IC) grade was compared to the clinical activity score of TO. All TO patients with dry eye were positive for IL-1a, IL-1b, and IL-6. However, the normal controls were also positive for IL-1a. A trend was observed between the clinical inflammatory score and immunological IC grade. This study was the first to delineate the immunological IC of TO-related dry eye. Our study aimed to investigate the pathogenesis of dry eye in TO. Our findings suggest that the conjunctival cytokines IL-1a, IL-1b, and IL-6 may play a role. The results of this study will be useful for future studies of additional inflammatory cytokines, and the levels of these cytokines could be used as an outcome to assess the efficacy of treatment, such as anti-cytokine or immunosuppression therapy, in patients with TO-related dry eye or other ocular surface inflammatory disorders.

The impact of joint range of motion limitations on health-related quality of life in patients with haemophilia A: a prospective study.

In patients with haemophilia A, repeated occurrences of haemarthrosis and synovitis lead to limitations in range of motion (ROM) of major joints. However, the effect of limitations in joint ROM on health-related quality of life (HRQOL) in these patients has not been studied previously. The aim of this study was to assess the impact of ROM limitations of 10 major joints (bilateral shoulders, elbows, hips, knees and ankles), combined with other possibly influential factors, on HRQOL in patients with haemophilia A. The ROM limitations in 13 movements and pain intensity of the 10 major joints were measured. The socio-demographic and clinical data were recorded. Short-Form 36 was used as the HRQOL measurement. Eighteen patients (mean age: 36.9 years) were included. Hip ROM limitations, knee ROM limitations and hip pain intensity predicted physical functioning scale (P < 0.001; adjusted R2 = 0.553). Shoulder ROM limitations and age predicted role limitation were due to emotional problems scale (P < 0.001; adjusted R2 = 0.373). Elbow ROM limitations and haemophilia severity predicted mental health scale (P = 0.001; adjusted R2 = 0.320). Hip ROM limitations predicted social functioning scale (P = 0.041; adjusted R2 = 0.091). Educational level and elbow ROM limitations predicted vitality scale (P < 0.001; adjusted R2 = 0.416). The ROM limitations of hip, knee, shoulder and elbow could be predictors for HRQOL in patients with haemophilia A. Improving ROM of major joints could be an appropriate treatment strategy to enhance HRQOL in these patients.

Malignancy-associated chylothorax: a 20-year study of 18 patients from a single institution.

Malignancy-associated chylothorax is a rare manifestation with uncertain characteristics and clinical significance. We segregated 18 patients into malignant lymphoma (n= 11) and solid malignancy (n= 7) groups to analyse the characteristics, treatment response and prognostic value of malignancy-associated chylothorax. Diagnosis of chylothorax was confirmed by a triglyceride concentration of >110 mg/dL or by the presence of chylomicrons in the pleural effusion. Concentrations of glucose, protein and lactate dehydrogenase did not differ significantly between the malignant lymphoma and solid malignancy groups. Although not statistically significant (P= 0.25), 90.9% malignant lymphoma patients and 57.1% solid malignancy patients had exudates. The cytology diagnostic rate in the malignant lymphoma and solid malignancy groups was 20.0% and 33.3% respectively (P > 0.99). After chemotherapy, six malignant lymphoma patients achieved complete remission, with simultaneous chylothorax disappearance. The overall survival rate at 12 and 24 months in the malignant lymphoma group was 54.5% and 36.4% respectively, while that in the solid malignancy group was 35.7% and 0% respectively. Malignant lymphoma was the chief cause of chylothorax in our cohort. Effective lymphoma treatment, lacking supplementary interventions, is essential for treating chylothorax in malignant lymphoma patients. Chylothorax indicates extremely limited life expectancy for solid malignancy patients.

Caffeic acid phenethyl ester inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using a local delivery system.

Over the last two decades, significant advances have been made in percutaneous coronary intervention (PCI) for the treatment of atherosclerotic plaques. However, restenosis after PCI still challenges both vascular biologists and interventional cardiologists. In this study, we found that caffeic acid phenethyl ester (CAPE) displayed an inhibitory effect on human coronary smooth muscle cell (HCSMC) growth and migration. Flow cytometry analysis showed that the ratio of S phase increased after exposing cells to CAPE for 48-72 h. Pretreatment of cells with CAPE significantly suppressed Cyclin E, CDK2, Cyclin A, and proliferating-cell nuclear antibody expression. We demonstrated that CAPE inhibited AKT 1 and MEK1/2 activation. Using a local infusion system, CAPE was able to regress the intima thickening of the iliac artery in rabbits after balloon injury. The percentage of intimal thickening decreased significantly to 55.0 +/- 0.12 in the group after local CAPE infusion compared to the group after saline infusion (98.3 +/- 0.41%). In conclusion, CAPE can inhibit the proliferation and migration of HCSMCs by inducing cell cycle arrest. Decreased cell cycle genes and associated signaling pathway target gene expression may mediate anti-proliferative and anti-migration effects of CAPE. Furthermore, CAPE prevents intima thickening in rabbits after balloon angioplasty. These results indicate that CAPE may have therapeutic relevance for the prevention of restenosis during PCI in the treatment of coronary artery diseases.

FLJ10540-elicited cell transformation is through the activation of PI3-kinase/AKT pathway.

A significant challenge in the post-genomic era is how to prioritize differentially expressed and uncharacterized novel genes found in hepatocellular carcinoma (HCC) microarray profiling. One such category is cell cycle regulated genes that have only evolved in higher organisms but not in lower eukaryotic cells. Characterization of these genes may reveal some novel human cancer-specific abnormalities. A novel transcript, FLJ10540 was identified. FLJ10540 is overexpressed in HCC as examined by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The patients with higher FLJ10540 expression had a poor survival than those with lower FLJ10540 expression. Functional characterization indicates that FLJ10540 displays a number of characteristics associated with an oncogene, including anchorage-independent growth, enhanced cell growth at low serum levels and induction of tumorigenesis in nude mice. FLJ10540-elicited cell transformation is mediated by activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT pathway. Moreover, FLJ10540 forms a complex with PI3K and can activate PI3K activity, which provides a mechanistic basis for FLJ10540-mediated oncogenesis. Together, using a combination of bioinformatics searches and empirical data, we have identified a novel oncogene, FLJ10540, which is conserved only in higher organisms. The finding raises the possibility that FLJ10540 is a potential new therapeutic target for HCC treatment. These findings may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in cancer cells.

Electrically reversible cracks in an intermetallic film controlled by an electric field.

Cracks in solid-state materials are typically irreversible. Here we report electrically reversible opening and closing of nanoscale cracks in an intermetallic thin film grown on a ferroelectric substrate driven by a small electric field (~0.83 kV/cm). Accordingly, a nonvolatile colossal electroresistance on-off ratio of more than 108 is measured across the cracks in the intermetallic film at room temperature. Cracks are easily formed with low-frequency voltage cycling and remain stable when the device is operated at high frequency, which offers intriguing potential for next-generation high-frequency memory applications. Moreover, endurance testing demonstrates that the opening and closing of such cracks can reach over 107 cycles under 10-µs pulses, without catastrophic failure of the film.

The lipoxygenase inhibitor, baicalein, modulates cell adhesion and migration by up-regulation of integrins and vinculin in rat heart endothelial cells.

BACKGROUND AND PURPOSE: Endothelial cell proliferation, migration and adhesion are necessary for the formation of new blood vessels. We reported previously that baicalein strongly inhibited proliferation of rat heart endothelial cells and here we assess effects on migration and adhesion of these cells. EXPERIMENTAL APPROACH: Effects of baicalein on endothelial migration and adhesion were determined by in vitro wound assays and in modified Boyden chambers. Protein expression and subcellular distribution in rat heart endothelial cells were analysed by immunoblots and immunofluorescence staining. RESULTS: Pretreatment with baicalein for 48 h resulted in a concentration-dependent inhibition of endothelial migration, with an IC(50) of approximately 20 microM. Adhesion assays revealed that baicalein stimulated endothelial cell adhesion to fibronectin and vitronectin, effects blocked by the synthetic peptide Arg-Gly-Asp (RGD). Moreover, treatment with a blocking antibody against integrin alpha5beta1 drastically attenuated baicalein-mediated endothelial adhesion to fibronectin, but not to vitronectin. Furthermore, baicalein-mediated anti-migration effect and adhesion promotion could be partially reversed by the addition of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Western blot analysis indicated that baicalein increased expression levels of integrin-alpha5beta1, -alphavbeta3 and vinculin proteins. Immunofluorescence staining showed that baicalein induced a marked reorganization of actin stress fibres and the recruitment of vinculin and integrins to focal adhesion plaques, with consequently increased formation of focal adhesion contacts. CONCLUSIONS AND IMPLICATIONS: Baicalein markedly inhibited the migration and enhanced the adhesion of rat heart endothelial cells, possibly by up-regulation of the integrins (alpha5beta1 and alphavbeta3) and vinculin and by promotion of actin reorganization and focal adhesion contact formation.

Quantification of flexoelectricity in PbTiO3/SrTiO3 superlattice polar vortices using machine learning and phase-field modeling.

Flexoelectricity refers to electric polarization generated by heterogeneous mechanical strains, namely strain gradients, in materials of arbitrary crystal symmetries. Despite more than 50 years of work on this effect, an accurate identification of its coupling strength remains an experimental challenge for most materials, which impedes its wide recognition. Here, we show the presence of flexoelectricity in the recently discovered polar vortices in PbTiO3/SrTiO3 superlattices based on a combination of machine-learning analysis of the atomic-scale electron microscopy imaging data and phenomenological phase-field modeling. By scrutinizing the influence of flexocoupling on the global vortex structure, we match theory and experiment using computer vision methodologies to determine the flexoelectric coefficients for PbTiO3 and SrTiO3. Our findings highlight the inherent, nontrivial role of flexoelectricity in the generation of emergent complex polarization morphologies and demonstrate a viable approach to delineating this effect, conducive to the deeper exploration of both topics.

Hidden Magnetic States Emergent Under Electric Field, In A Room Temperature Composite Magnetoelectric Multiferroic.

The ability to control a magnetic phase with an electric field is of great current interest for a variety of low power electronics in which the magnetic state is used either for information storage or logic operations. Over the past several years, there has been a considerable amount of research on pathways to control the direction of magnetization with an electric field. More recently, an alternative pathway involving the change of the magnetic state (ferromagnet to antiferromagnet) has been proposed. In this paper, we demonstrate electric field control of the Anomalous Hall Transport in a metamagnetic FeRh thin film, accompanying an antiferromagnet (AFM) to ferromagnet (FM) phase transition. This approach provides us with a pathway to "hide" or "reveal" a given ferromagnetic region at zero magnetic field. By converting the AFM phase into the FM phase, the stray field, and hence sensitivity to external fields, is decreased or eliminated. Using detailed structural analyses of FeRh films of varying crystalline quality and chemical order, we relate the direct nanoscale origins of this memory effect to site disorder as well as variations of the net magnetic anisotropy of FM nuclei. Our work opens pathways toward a new generation of antiferromagnetic - ferromagnetic interactions for spintronics.

Differential expression of vascular endothelial growth factor, placenta growth factor and their receptors in placentae from pregnancies complicated by placenta accreta.

Placenta accreta is a pregnancy complication characterized by the presence of life-threatening uteroplacental neovascularization. The factors involving its development are unknown. Vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptors (VEGFR) have important roles in vascular remodeling. We have investigated the differential expression of these proteins in placentae from placenta accreta (cases) and normal placentation (controls). Immunohistochemically, the expression of VEGFR-2 in the syncytiotrophoblast was significantly lower in cases than in controls during both the second and third trimesters (P = 0.005 and 0.002, respectively). However, VEGFR-2 expression in the cytotrophoblastic and extravillous trophoblastic cells and VEGFR-1, -3 and Ki-67 in the trophoblast populations were not significantly different between controls and cases (P > 0.05). Ki-67 immunostaining also showed that endothelial cells of the larger vessels were stained weaker in normal placenta than in placenta accreta. The majority of VEGFR-2 expression, as demonstrated by Western blot or reverse transcription polymerase chain reaction, was consistent with the immunohistochemical findings in the syncytiotrophoblast. Furthermore, enzyme-linked immunosorbent assay in the placental lysates showed that the women with placenta accreta demonstrated significantly higher VEGF (P = 0.001) and lower soluble VEGFR-2 (P = 0.015) concentrations than did women with normal pregnancy. PlGF and soluble VEGFR-1 levels did not show any significance in study groups (P > 0.05). These observations suggest that the participation of up-regulated VEGF and down-regulated VEGFR-2 (both membrane-bound and soluble forms) may be associated with the development of placenta accreta.

Large resistivity modulation in mixed-phase metallic systems.

In numerous systems, giant physical responses have been discovered when two phases coexist; for example, near a phase transition. An intermetallic FeRh system undergoes a first-order antiferromagnetic to ferromagnetic transition above room temperature and shows two-phase coexistence near the transition. Here we have investigated the effect of an electric field to FeRh/PMN-PT heterostructures and report 8% change in the electrical resistivity of FeRh films. Such a 'giant' electroresistance (GER) response is striking in metallic systems, in which external electric fields are screened, and thus only weakly influence the carrier concentrations and mobilities. We show that our FeRh films comprise coexisting ferromagnetic and antiferromagnetic phases with different resistivities and the origin of the GER effect is the strain-mediated change in their relative proportions. The observed behaviour is reminiscent of colossal magnetoresistance in perovskite manganites and illustrates the role of mixed-phase coexistence in achieving large changes in physical properties with low-energy external perturbation.

Synthesis and antibacterial evaluation of certain quinolone derivatives.

A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities. Preliminary results indicated that most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Among them, 1-(4-amino-2-fluorophenyl)-6-fluoro-1,4-dihydro-7-[4-[2-(4-methoxyphenyl)-2-hydroxyiminoethyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid (11d) and its ketone precursor 10d exhibited significant activities against Klebsiella pneumoniae, methicillin-resistant S. aureus, erythromycin- and ampicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. Due to strong cytotoxicities of 11d (a mean log GI(50) of -5.40), compound 10d, with good antibacterial activities and low cytotoxicities (a mean log GI(50) of -4.67), is a more potential drug candidate.

Suppression of the tumorigenicity of human hepatoma hep3B cells by long-term retinoic acid treatment.

We cultured human hepatoma Hep3B cells in the presence of RA (10(-5) M) for 30 days; the expression of both alpha-fetoprotein and hepatitis B virus surface antigen were suppressed over 70% at the transcriptional level by RA treatment. The doubling time of RA treated Hep3B cells was slightly different from the control cells when they were cultured in 5% fetal calf serum/DMEM medium. However, cultured under serum-free conditions, the control Hep3B cells still grow, but the RA treated cells could not attach to the substratum of the culture plate and stopped growing. In vivo assay indicated that RA treatment completely suppressed the tumorigenicity of Hep3B cells in nude mice.

Retinoic acid-induced apoptosis is prevented by serum albumin and enhanced by Lipiodol in human hepatoma Hep3B cells.

The effects of retinoic acid (RA) on the cell growth and viability of human hepatoma Hep3B cells were examined. We showed that removal of serum in the presence of RA results in cell death in a dose-dependent manner in human hepatoma Hep3B cells. Time-course cell death analysis showed that RA at a dose of 10 microM induces a rapid (48-72 h) fall in cell viability (>95%). The drug-induced cell death was RA-specific, since three RA analogs (retinol, retinal and retinol acetate) did not show any cytocidal activity at an equimolar dose. Fluorescence microscopy and DNA fragmentation analysis showed that Hep3B cells treated with RA underwent a death process highly reminiscent of apoptosis, with chromatin condensation, nuclear fragmentation and the presence of a 180-200 bp DNA fragment ladder. Additionally, we found that RA-induced apoptosis was reduced by 70-80% when the medium was supplemented with serum albumin (human and bovine) at a concentration of 0.05%. However, a variety of known growth factors were ineffective in preventing RA-induced apoptosis. Preincubating serum and serum albumin with Lipiodol restored the apoptotic effects of RA demonstrated in serum-free systems. These data suggest that the binding of RA by serum albumin may have reduced the bioavailability of RA, restricting its apoptotic effects on Hep3B cells. Blocking RA-albumin interactions with a lipid lymphographic contrast medium (Lipiodol) may improve the bioavailability of RA and significantly enhance its apoptotic effect on human hepatoma Hep3B cells.

Proteolysis of integrin alpha5 and beta1 subunits involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells.

Our previous report demonstrated that all-trans-retinoic acid (ATRA) induces detachment and death under serum starvation in several human tumor cell lines. In this study, we examined the influence of cell-extracellular matrix interaction on the ability of ATRA to induce apoptosis. Plating of human hepatoma Hep3B cells onto poly-hydroxyethylmethacrylate-coated plates in the absence of serum resulted in the acceleration of ATRA-induced apoptosis. In contrast, ATRA-induced apoptosis was significantly suppressed by plating cells onto Matrigel-coated plates but not suppressed by culturing onto collagen-, laminin-, vitronectin-, or fibronectin-coated plates. Exogenously added soluble collagen, laminin, fibronectin, vitronectin or Matrigel failed to suppress ATRA-induced apoptosis. Results from the adhesion assay indicated that the cell attachment to fibronectin was significantly inhibited by ATRA. Treatment with perturbing antibody against integrin alpha5 or beta1 subunits resulted in promotion of ATRA-induced apoptosis. Moreover, the proteolytic cleavage of alpha5beta1 integrin and focal adhesion kinase (FAK) proteins is linked to the early phase of the ATRA-induced apoptotic process. Furthermore, ATRA-induced detachment, death, and cleavage of alpha5beta1 integrin and FAK were drastically suppressed by plating cells onto Matrigel-coated plates. These findings provide evidence that abrogation of cell adhesion, through proteolysis of alpha5beta1 integrin and FAK, is closely linked to ATRA-induced apoptosis in Hep3B cells.