Photovoltaic effect by soft phonon excitation.

SignificanceThe quantum-mechanical geometric phase of electrons provides various phenomena such as the dissipationless photocurrent generation through the shift current mechanism. So far, the photocurrent generations are limited to above or near the band-gap photon energy, which contradicts the increasing demand of the low-energy photonic functionality. We demonstrate the photocurrent through the optical phonon excitations in ferroelectric BaTiO3 by using the terahertz light with photon energy far below the band gap. This photocurrent without electron-hole pair generation is never explained by the semiclassical treatment of electrons and only arises from the quantum-mechanical geometric phase. The observed photon-to-current conversion efficiency is as large as that for electronic excitation, which can be well accounted for by newly developed theoretical formulation of shift current.

Efficient Endocytosis of the Human Lactoferrin N-Lobe Enhances Its Antiproliferative Activity against Human Cancer Cells.

Human lactoferrin (hLF) is a glycosylated globular iron-binding protein with high functional versatility that elicits anticancer, neuroprotective, and anti-inflammatory effects. Some of the diverse functions of hLF are induced after its internalization into various cells via cell surface endocytosis receptors, such as proteoglycans, which contain glycosaminoglycan (GAG) chains. We have previously demonstrated that an hLF derivative comprising the N-terminal half of hLF (referred to as the N-lobe) is internalized by intestinal enterocyte Caco-2 cells. However, the relationship between the intracellular uptake of the N-lobe and its pharmacological activity remains poorly understood. Here, we report that the N-lobe is efficiently internalized by lung cancer cells via endocytic pathways, suppressing their proliferation. Moreover, the N-lobe showed higher intracellular uptake than hLF. We found that the N-lobe was internalized into the human lung cancer cell lines PC-14 and PC-3 via clathrin- and/or caveolae-mediated endocytosis. Intracellular uptake of the N-lobe was inhibited when an equimolar concentration of chondroitin sulfate (CS)-E, a GAG subtype involved in malignant transformation and tumor metastasis, was added. The inhibitory effect of the N-lobe on PC-14 cell proliferation decreased with the addition of CS-E in a dose-dependent manner, suggesting that the CS-recognizing sequence on the N-lobe is necessary for its internalization or that the CS proteoglycan on cancer cells acts as an endocytosis receptor. These results suggest that the efficient endocytic uptake of the N-lobe is important for its antiproliferation effects on lung cancer cell lines. Thus, the N-lobe presents a promising drug candidate for cancer treatment.

Defect tolerant zero-bias topological photocurrent in a ferroelectric semiconductor.

Lattice defect is a major cause of energy dissipation in conventional electric current due to the drift and diffusion motions of electrons. Different nature of current emerges when noncentrosymmetric materials are excited by light. This current, called the shift current, originates from the change in the Berry connection of electrons' wave functions during the interband optical transition. Here, we demonstrate the defect tolerance of shift current using single crystals of ferroelectric semiconductor antimony sulfoiodide (SbSI). Although the dark conductance spreads over several orders of magnitude in each crystal due to the difference in the density of defect levels, the observed shift current converges to an identical value. We also reveal that the shift current is scarcely disturbed by the surface defects while they drastically suppress the conventional photocurrent. The defect tolerance is a manifestation of the topological nature of shift current, which will be a crucial advantage in optoelectronic applications.

Bulk Photovoltaic Effect Along the Nonpolar Axis in Organic-Inorganic Hybrid Perovskites.

The origin of the bulk photovoltaic effect (BPVE) was considered as a built-in electric field formed by the macroscopic polarization of materials. Alternatively, the "shift current mechanism" has been gradually accepted as the more appropriate description of the BPVE. This mechanism implies that the photocurrent generated by the BPVE is a topological current featuring an ultrafast response and dissipation-less nature, which is very attractive for photodetector applications. Meanwhile, the origin of the BPVE in organic-inorganic hybrid perovskites (OIHPs) has not been discussed and is still widely accepted as the classical mechanism without any experimental evidence. Herein, we observed the BPVE along the nonpolar axis in OIHPs, which is inconsistent with the classical explanation. Furthermore, based on the nonlinear optical tensor correlation, we substantiated that the BPVE in OIHPs is originated in the shift current mechanism.

Harnessing the chondroitin sulfate-binding characteristics of human lactoferrin to neutralize neurite outgrowth inhibition.

Human lactoferrin (hLF) is a glycosaminoglycan (GAG)-binding protein involved in various biological functions. It consists of two globular functional domains, referred to as the N- and C-lobes. Both heparin (HP) and heparan sulfate (HS) bind to the N-lobe domain of hLF. Although some biological functions of hLF such as neuroprotective effects and cancer growth inhibition are regulated by its binding to HS, the binding characteristics of hLF with other GAG subtypes, and their effects on biological activities are still poorly understood. Here, we report that hLF binds to chondroitin sulfate (CS)-E, a GAG subtype involved in various neurodegenerative diseases. The α-helical content of hLF, which is an indicator of changes in the secondary structure of hLF, increased in the presence of CS-C, CS-D, or CS-E, but not in the presence of HP, HS, CS-A, or CS-B. This structural change was also observed in the N-lobe, the N-terminal half region of the hLF. Additionally, the thermal stability of the N-lobe showed a dose-dependent improvement in the presence of CS-E, but not in the presence of HP. This indicates that the binding mode of hLF/N-lobe to CS-E may differ from that of HP. hLF was also found to neutralize CS-E-induced inhibition of neurite outgrowth and neuronal growth cone collapse, which are neurodegenerative responses to spinal cord injury, in cultured dorsal root ganglion neurons. Thus, hLF is a promising drug candidate for the treatment of CS-E-induced neurodegenerative diseases such as spinal cord injury.

Noncentrosymmetric Columnar Liquid Crystals with the Bulk Photovoltaic Effect for Organic Photodetectors.

The bulk photovoltaic effect (BPVE) has drawn intensive attention due to its unique features that cannot be accessed with the conventional photovoltaic effect. However, the BPVE is observed in noncentrosymmetric materials and has been studied mainly for inorganic materials. Here, we report a simple subphthalocyanine (SubPc) derivative that assembles into a noncentrosymmetric columnar liquid crystal with the help of a DC E-field. These columnar assemblies exhibit the BPVE over a wide range of wavelengths up to 650 nm. Furthermore, just by sandwiching this columnar assembly between two ITO electrodes, the resultant device reaches a light-on/off ratio, Ilight/Idark, as high as 6.6 × 103, indicating that the polar columnar assemblies with SubPcs are promising for photodetectors.

Reproductive interference by alien hornet Vespa velutina threatens the native populations of Vespa simillima in Japan.

The yellow-legged hornet Vespa velutina has become one of the major alien species in European and East Asian countries. As in its homeland, the invading V. velutina is reported as the major predator of honeybees and is becoming a threat to beekeeping in Europe. However, it remains unknown how V. velutina might affect native hornets when it invades Asia, where a large number of Vespa species are distributed. Thus, by analyzing the mitochondrial cytochrome c oxidase subunit I gene, we investigated whether interspecific mating occurs between V. velutina and Japanese native Vespa spp. Our results showed that the alien V. velutina causes reproductive interference in Japanese native hornet Vespa simillima. Forty-three percent of native V. simillima queens had the sperm of V. velutina males, and among the all V. simillima queens analyzed, 28% only had V. velutina sperm. We did not find evidence of V. velutina queens having the sperm of V. simillima males. These findings suggest that reproductive interference by V. velutina males poses a threat to the native V. simillima populations. A decline of V. simillima may also negatively affect other insects that interact with V. simillima.

Cellular Uptake and Release of Intact Lactoferrin and Its Derivatives in an Intestinal Enterocyte Model of Caco-2 Cells.

An Intact form of lactoferrin (LF) is known to be absorbed from the small intestine and transported into the blood circulation. We reevaluated the cellular uptake and release of LF using an enterocyte model of human small intestinal cells derived from the Caco-2 cell line. In contrast to a previous report, we observed that intact bovine LF was taken up into seven and 21 d-cultured Caco-2 cells and successfully released back into the culture medium, even though the human intestinal LF receptor, intelectin-1, was not immunochemically detectable. Similar observations were made for human LF and its derivatives (the N-terminal half of LF designated N-lobe and Fc fusions). These observations regarding the uptake and release of intact LF in Caco-2 cells were consistent with in vivo observations. Therefore, we propose that the uptake and release of intact LF by Caco-2 cells should be assessed as a potential in vitro model of in vivo LF absorption in human intestines.

Current-Voltage Characteristic and Shot Noise of Shift Current Photovoltaics.

We theoretically study the current-voltage relation, the I-V characteristic, of the photovoltaics due to the shift current, i.e., the photocurrent generated without the external dc electric field in noncentrosymmetric crystals through the Berry connection of the Bloch wave functions. We find that the I-V characteristic and shot noise are controlled by the difference of group velocities between conduction and valence bands, i.e., v_{11}-v_{22}, and the relaxation time τ. Since the shift current itself is independent of these quantities, there are a wide variety of possibilities to design it to maximize the energy conversion rate and also to suppress the noise. We propose that the Landau levels in noncentrosymmetric two-dimensional systems are a promising candidate for energy conversion.

Publisher's Note: Direct Imaging of Dynamic Glassy Behavior in a Strained Manganite Film [Phys. Rev. Lett. 115, 265701 (2015)].

This corrects the article DOI: 10.1103/PhysRevLett.115.265701.

Direct Imaging of Dynamic Glassy Behavior in a Strained Manganite Film.

Complex many-body interaction in perovskite manganites gives rise to a strong competition between ferromagnetic metallic and charge-ordered phases with nanoscale electronic inhomogeneity and glassy behaviors. Investigating this glassy state requires high-resolution imaging techniques with sufficient sensitivity and stability. Here, we present the results of a near-field microwave microscope imaging on the strain-driven glassy state in a manganite film. The high contrast between the two electrically distinct phases allows direct visualization of the phase separation. The low-temperature microscopic configurations differ upon cooling with different thermal histories. At sufficiently high temperatures, we observe switching between the two phases in either direction. The dynamic switching, however, stops below the glass transition temperature. Compared with the magnetization data, the phase separation was microscopically frozen, while spin relaxation was found in a short period of time.

The NMatrix, a new method of presenting statistics, displays the characteristics of medicines with similar effects used in the treatment of lumbar spinal stenosis concisely and clearly, facilitating the selection of appropriate medications.

BACKGROUND: It is often difficult to compare the characteristics of a medicine with those of others based on common standards, whereas the application of rational standards would be expected to facilitate the comparison of medicines with similar effects. The present study was conducted to clarify the characteristics of individual medicines and to examine whether rational standards allow the most appropriate medicines to be chosen. METHODS: Participants diagnosed with lumbar spinal stenosis (LSS) were assessed for QOL and ADL based on the Roland-Morris Disability Questionnaire, JOA score, VAS, and the presence of intermittent claudication (IC). Four medicines--beraprost sodium, ethyl icosapentate (EPA), sarpogrelate hydrochloride, and limaprost alfadex (PGE1)--were prescribed in a random manner. These four medicines were assessed independently in four studies using the same study design and size in each case. Using the NMatrix, the characteristics of the four medicines and the results of mutual comparisons could be displayed concisely and clearly in one matrix based on significance levels. This work involved analyzing pooled data from the four studies. RESULTS: All four medicines improved IC--one of the characteristic symptoms of LSS--by 12 weeks after administration. PGE1 required more time than the other medicines to affect IC. EPA appeared to almost significantly ameliorate some items at every point, though the evidence was insufficient. CONCLUSIONS: The NMatrix concisely and clearly displays the characteristics of "medicines with similar effects" for the treatment of lumbar spinal stenosis, and can help physicians to choose the optimal medicine based on rational criteria for individual patients, according to their symptoms and progress.

Involvement of heparan sulfate 6-O-sulfation in the regulation of energy metabolism and the alteration of thyroid hormone levels in male mice.

Here, we report that male heparan sulfate 6-O-sulfotransferase-2 (Hs6st2) knockout mice showed increased body weight in an age-dependent manner even when fed with a normal diet and showed a phenotype of impaired glucose metabolism and insulin resistance. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mitochondrial uncoupling proteins Ucp1 and Ucp3 was reduced in the interscapular brown adipose tissue (BAT) of male Hs6st2 knockout mice, suggesting reduced energy metabolism. The serum level of thyroid-stimulating hormone was significantly higher and that of thyroxine was lower in the knockout mice. When cultures of brown adipocytes from wild-type and Hs6st2 knockout mice isolated and differentiated in vitro were treated with FGF19 (fibroblast growth factor 19) or FGF21 in the presence or the absence of heparitinase I, phosphorylation of p42/p44 mitogen-activated protein (MAP) kinase was reduced. Heparan sulfate (HS) 6-O-sulfation was reduced not only in BAT but also in the thyroid tissue of the knockout mice. Thus, 6-O-sulfation in HS seems to play an important role in mediating energy metabolism by controlling thyroid hormone levels and signals from the FGF19 subfamily proteins, and the alteration of the HS composition may result in metabolic syndrome phenotypes such as altered glucose and insulin tolerance.

Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho.

Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10-100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors.

Iron facilitator LS081 reduces hypoxia-inducible factor-1α protein and functions as anticancer agent in hepatocellular carcinoma.

Hypoxia inducible factor-1α (HIF-1α) has a central role in cellular oxygen-sensing, and its overexpression in many types of cancer is considered important in tumor progression. Thus, targeting HIF-1α production and activity has been of great therapeutic interest. In normoxic conditions, HIF-1α is hydroxylated by oxygen-dependent prolyl-hydroxylases, which require ferrous iron for its activity. The tumor suppressor protein von Hippel Lindau binds to the hydroxylated HIF-1α, which is then ubiquitinated and degraded by proteasomes. We focused on the physiological degradation machinery of HIF-1α mediated by prolyl hydroxylases. Previously, we identified a small molecule, LS081, that is capable of stimulating iron uptake into cells. In the present study, we aimed to inhibit the expression of HIF-1α protein and growth of hepatocellular carcinoma by using the iron-facilitating activity of LS081. In the human hepatocellular carcinoma cell lines Hep3B and HepG2, a combination of LS081 and ferric ammonium citrate (LS081/FeAC) inhibited HIF-1α protein expression but did not inhibit HIF-1α mRNA expression. A mutated HIF-1α protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS081 and FeAC. Furthermore, the iron-facilitating activity of LS081 resulted in Hep3B and HepG2 growth inhibition in vitro and in vivo. These results indicate that the iron-facilitating activity of LS081 inhibits HIF-1α expression through prolyl-hydroxylation of HIF-1α and might have a therapeutic effect in the treatment of hepatocellular carcinoma.

Transient photoinduced 'hidden' phase in a manganite.

Photoinduced phase transitions are of special interest in condensed matter physics because they can be used to change complex macroscopic material properties on the ultrafast timescale. Cooperative interactions between microscopic degrees of freedom greatly enhance the number and nature of accessible states, making it possible to switch electronic, magnetic or structural properties in new ways. Photons with high energies, of the order of electron volts, in particular are able to access electronic states that may differ greatly from states produced with stimuli close to equilibrium. In this study we report the photoinduced change in the lattice structure of a charge and orbitally ordered Nd(0.5)Sr(0.5)MnO(3) thin film using picosecond time-resolved X-ray diffraction. The photoinduced state is structurally ordered, homogeneous, metastable and has crystallographic parameters different from any thermodynamically accessible state. A femtosecond time-resolved spectroscopic study shows the formation of an electronic gap in this state. In addition, the threshold-like behaviour and high efficiency in photo-generation yield of this gapped state highlight the important role of cooperative interactions in the formation process. These combined observations point towards a 'hidden insulating phase' distinct from that found in the hitherto known phase diagram.

[Complete heart block induced by insertion of a pulmonary artery catheter].

We report a case of complete heart block induced by insertion of a pulmonary artery catheter (PAC). A 74-year-old man was scheduled for off-pump coronary artery bypass grafting. The preoperative electrocardiogram revealed complete left bundle-branch block (LBBB). General anesthesia was induced with intravenous administration of midazolam 5.3 mg, fentanyl 110 microg and rocuronium 32 mg. General anesthesia was maintained with oxygen, air and sevoflurane. After a PAC was inserted via the right internal jugular vein and when it entered the right ventricle, complete heart block (CHB) associated with severe bradycardia occurred. Cardiopulmonary bypass (CPB) was required during the surgery and temporary epicardial pacing was instituted for weaning from CPB. Cardiac rhythm was restored to complete LBBB without any treatment postoperatively, but CHB recurred 9 seconds after the removal of PAC. The electrophysiologic study performed afterward showed an intact conduction pathway. Right bundle-branch block (RBBB) is one of complications induced by pulmonary artery catheterization. In the patients with underlying LBBB, transient RBBB produces CHB that could produce hemodynamic compromise. Therefore, we should carefully consider the indication of PAC in the patients with preexisting LBBB.

Real-space observations of 60-nm skyrmion dynamics in an insulating magnet under low heat flow.

Thermal-current induced electron and spin dynamics in solids -dubbed "caloritronics"- have generated widespread interest in both fundamental physics and spintronics applications. Here, we examine the dynamics of nanometric topological spin textures, skyrmions driven by a temperature gradient ∇T or heat flow, that are evaluated through in-situ real-space observations in an insulating helimagnet Cu2OSeO3. We observe increases of the skyrmion velocity and the Hall angle with increasing ∇T above a critical value of ~ 13 mK/mm, which is two orders of magnitude lower than the ∇T required to drive ferromagnetic domain walls. A comparable magnitude of ∇T is also observed to move the domain walls between a skyrmion domain and the non-topological conical-spin domain from cold to hot regions. Our results demonstrate the efficient manipulation of skyrmions by temperature gradients, a promising step towards energy-efficient "green" spintronics.

Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease.

In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-beta (Abeta) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Abeta40 and Abeta42 were used for immunocytochemical analyses, Abeta42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Abeta-oligomer. In comparison to the Abeta42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Abeta42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=- 0.61, p<0.02). Together with recent evidence that the Abeta peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Abeta may be a compensatory response in neurons to oxidative stress in Alzheimer disease.

Albumin fusion at the N-terminus or C-terminus of human lactoferrin leads to improved pharmacokinetics and anti-proliferative effects on cancer cell lines.

Human lactoferrin (hLF), a soluble factor of the innate immune system, exhibits various biological functions and therefore has potential as a therapeutic protein. However, the clinical applications of hLF are limited by its low stability in blood. We therefore attempted to resolve this by producing recombinant hLF fused to human serum albumin (HSA). Two HSA-fused hLFs with different fusion orientations (hLF-HSA and HSA-hLF) were produced in Chinese hamster ovary (CHO) DG44 cells. hLF-HSA revealed higher thermal stability, resistance to peptic degradation, and stability during the process of cellular uptake and release in an intestinal enterocyte model (Caco-2 cells) than HSA-hLF. The lower stability of HSA-hLF is presumably due to the steric hindrance imposed by HSA fusion to the N-terminus of hLF. Both HSA fusion proteins, especially HSA-hLF, displayed improved pharmacokinetic properties despite the lower protein stability of HSA-hLF. hLF-HSA and HSA-hLF exhibited approximately 3.3- and 20.7-fold longer half-lives (64.0 and 403.6 min), respectively, than holo-rhLF (19.5 min). Both HSA fusion proteins were found to exert enhanced growth inhibition effects on cancer cells in vitro, but not normal cells. Their enhanced growth inhibitory activities were considered to be due to the synergetic effects of hLF and HSA because hLF alone or HSA alone failed to exert such an effect. Altogether, Fusion of HSA to hLF yielded superior pharmacokinetics and anti-proliferative activities against cancer cells. HSA-fused hLF is a novel candidate for further application of hLF as biopharmaceuticals for intravenous administration.