Multifaceted properties of Andreev bound states: interplay of symmetry and topology.

Andreev bound states (ABSs) ubiquitously emerge as a consequence of non-trivial topological structures of the order parameter of superfluids and superconductors and significantly contribute to thermodynamics and low-energy quantum transport phenomena. We here share the current status of our knowledge on their multifaceted properties such as Majorana fermions and odd-frequency pairing. A unified concept behind ABSs originates from a soliton state in the one-dimensional Dirac equation with mass domain wall and interplay of ABSs with symmetry and topology enrich their physical characteristics. We make an overview of ABSs with a special focus on superfluid 3He. The quantum liquid confined to restricted geometries serves as a rich repository of noteworthy quantum phenomena, such as the mass acquisition of Majorana fermions driven by spontaneous symmetry breaking, topological quantum criticality, Weyl superfluidity and the anomalous magnetic response. The marriage of the superfluid 3He and nano-fabrication techniques will take one to a new horizon of topological quantum phenomena associated with ABSs.This article is part of the theme issue 'Andreev bound states'.

High rate capability by sulfur-doping into LiFePO4 matrix.

Enhanced electrochemical performance of LiFePO4 for Li-ion batteries has been anticipated by anion doping at the O-site rather than cation doping at the Fe-site. We report on the electrochemical performance of S-doped LiFePO4 nanoparticles synthesized by a solvothermal method using thioacetamide as a sulfur source. S-doping into the LiFePO4 matrix expands the lattice due to the larger ionic radius of S2- than that of O2-. The lattice parameters a and b increase by around 0.2% with sulfur content, while that of c remains almost unchanged with only 0.03% increase. The S-doping also contributes to the suppression of antisite defects (Fe occupying Li sites), which facilitates the easy migration of Li in the diffusion channels without blockage. Owing to these effects of S-doping, the S-doped LiFePO4 nanoparticles show enhanced electrochemical properties with a high discharge capacity of ∼113 mA h g-1 even at a high rate of 10C.

Wnt/ß-catenin activation and macrophage induction during liver cancer development following steatosis.

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/ß-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/ß-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/ß-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/ß-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/ß-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

Factors associated with mothers not vaccinating their children against mumps in Japan.

OBJECTIVES: In Japan, mumps immunization is not mandatory, and the prevalence of mumps immunization among eligible children is only about 30%, raising concerns about increased risk of meningitis, encephalitis and deafness caused by mumps. In 2011, to understand why families are not voluntarily immunizing their children against mumps, we surveyed mothers who were university graduates to examine the factors and barriers influencing mumps vaccination in Japan. STUDY DESIGN: A cross sectional design. METHODS: We sent questionnaires including questions on demographic data and vaccination status, barriers and factors for immunizations to university alumnae to recruit participants. Data were analysed by Student's t-test for continuous variables and by univariate and multivariate analysis to obtain the odds ratio and adjusted odds ratio. RESULTS: Two hundred and twenty-six mothers with children responded with an average (range) age of 44.7 years (SD = 5.02; 30-55 years). Adjusted odds ratios (aOR) from logistic regression analysis identified fear of harmful side-effects (aOR, 2.55; 95% CI, 1.10 to 5.89), the vaccination not being mandatory (aOR, 3.30; 95% CI, 1.41 to 7.72), perceived non-efficacy (aOR, 6.21; 95% CI, 1.85 to 20.91) and being busy (aOR, 3.30; 95% CI, 1.21 to 9.01) were significantly and inversely associated with mumps vaccination. Recommendations from family doctors (aOR, 0.35; 95% CI, 0.17 to 0.71), living abroad when their children would be vaccinated (aOR, 0.10; 95% CI, 0.02 to 0.68) and the maternal age (aOR, 0.91; 95% CI, 0.85 to 0.96) were significant and positively associated with vaccination. CONCLUSIONS: In the absence of mandatory vaccinations, a public education campaign about mumps, their potential consequences and the nature and value of vaccination could improve the prevalence of mumps vaccination among children and prevent the consequences of this disease.

Phosphorylation of Dok1 by Abl family kinases inhibits CrkI transforming activity.

The Crk SH2/SH3 adaptor and the Abl nonreceptor tyrosine kinase were first identified as oncoproteins, and both can induce tumorigenesis when overexpressed or mutationally activated. We previously reported the surprising finding that inhibition or knockdown of Abl family kinases enhanced transformation of mouse fibroblasts by CrkI. Abl family inhibitors are currently used or are being tested for treatment of human malignancies, and our finding raised concerns that such inhibitors might actually promote the growth of tumors overexpressing CrkI. Here, we identify the Dok1 adaptor as the key effector for the enhancement of CrkI transformation by Abl inhibition. We show that phosphorylation of tyrosines 295 and 361 of Dok1 by Abl family kinases suppresses CrkI transforming activity, and that upon phosphorylation these tyrosines bind the SH2 domains of the Ras inhibitor p120 RasGAP. Knockdown of RasGAP resulted in a similar enhancement of CrkI transformation, consistent with a critical role for Ras activity. Imaging studies using a FRET sensor of Ras activation revealed alterations in the localization of activated Ras in CrkI-transformed cells. Our results support a model in which Dok1 phosphorylation normally suppresses localized Ras pathway activity in Crk-transformed cells via recruitment and/or activation of RasGAP, and that preventing this negative feedback mechanism by inhibiting Abl family kinases leads to enhanced transformation by Crk.

Iterative tyrosine phosphorylation controls non-canonical domain utilization in Crk.

Crk, the prototypical member of a class of Src homology-2 (SH2) and Src homology-3 (SH3) domain containing proteins that controls the coordinated assembly of signaling complexes, is regulated by phosphorylation of Y221 in the linker region, which forms an intramolecular SH2-pY221 auto-clamp to interrupt SH2-N-terminal SH3 domain (SH3N) signaling. Here, we show using LC-MS/MS and by generating phospho-specific antibodies that, iteratively with Y221, the Crk C-terminal SH3 domain (SH3C) is routinely phosphorylated on Y239 and/or Y251 by several extracellular stimuli known to engage Crk. Although phosphorylation at Y221 auto-inhibits the Crk SH2, phosphorylation of the SH3C generates an unconventional phosphoSH3C-SH3N unit in which the SH3N is fully functional to bind polyproline type II ligands and the phosphoSH3C binds de novo to other SH2 domains. Using high-throughput SH2 domain profiling, artificial neural network and position-specific scoring matrix-based bioinformatics approaches, and unbiased mass spectometry, we found that the phosphoSH3C binds several SH2 domain containing proteins, including specific non-receptor tyrosine kinases-Abl via pY251 and C-terminal Src kinase via pY239. Functionally, we show that the phosphoSH3C modulates the Abl-mediated phenotypes of cell spreading and motility. Together, these studies describe a versatile mechanism wherein phosphorylation of Crk at Y221 is not an off switch but redirects signaling from the SH2-SH3N axis to a phosphoSH3C-SH3N axis, with the SH3N as a common denominator.

Anisotropy of the superconducting state in Sr2RuO4.

Despite intense studies the exact nature of the order parameter in superconducting Sr2RuO4 remains unresolved. We have used small-angle neutron scattering to study the vortex lattice in Sr2RuO4 with the field applied close to the basal plane, taking advantage of the transverse magnetization. We measured the intrinsic superconducting anisotropy between the c axis and the Ru-O basal plane (~60), which greatly exceeds the upper critical field anisotropy (~20). Our result imposes significant constraints on possible models of triplet pairing in Sr2RuO4 and raises questions concerning the direction of the zero spin projection axis.

Twofold spontaneous symmetry breaking in the heavy-fermion superconductor UPt3.

The field-orientation dependent thermal conductivity of the heavy-fermion superconductor UPt3 was measured down to very low temperatures and under magnetic fields throughout the distinct superconducting phases: B and C phases. In the C phase, a striking twofold oscillation of the thermal conductivity within the basal plane is resolved reflecting the superconducting gap structure with a line of node along the a axis. Moreover, we find an abrupt vanishing of the oscillation across a transition to the B phase, as a clear indication of a change of gap symmetries. We also identify extra two line nodes below and above the equator in both B and C phases. From these results together with the symmetry consideration, the gap function of UPt3 is determined as a E(1u) representation characterized by a combination of two line nodes at the tropics and point nodes at the poles.

Phosphorylation of Crk on tyrosine 251 in the RT loop of the SH3C domain promotes Abl kinase transactivation.

Here, we report the identification and characterization of a novel tyrosine phosphorylation site in the carboxy-terminal Src Homology 3 (SH3) (SH3C) domain of the Crk adaptor protein. Y251 is located in the highly conserved RT loop structure of the SH3C, a region of Crk involved in the allosteric regulation of the Abl kinase. Exploiting kinase assays to show that Y251 is phosphorylated by Abl in vitro, we generated affinity-purified antisera against phosphorylated Y251 in Crk and showed that Abl induces phosphorylation at Y251 in vivo, and that the kinetics of phosphorylation at Y251 and the negative regulatory Y221 site in vitro are similar. Y251 on endogenous Crk was robustly phosphorylated in chronic myelogenous leukemia cell lines and in A431 and MDA-MB-468 cells stimulated with epidermal growth factor. Using streptavidin-biotin pull downs and unbiased high-throughput Src Homology 2 (SH2) profiling approaches, we found that a pY251 phosphopeptide binds specifically to a subset of SH2 domains, including Abl and Arg SH2, and that binding of pY251 to Abl SH2 induces transactivation of Abl 1b. Finally, the Y251F Crk mutant significantly abrogates Abl transactivation in vitro and in vivo. These studies point to a yet unrealized positive regulatory role resulting from tyrosine phosphorylation of Crk, and identify a novel mechanism by which an adaptor protein activates a non-receptor tyrosine kinase by SH2 domain displacement.

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy.

Sustained expression of murine interferon (IFN)-γ (Muγ) was found to be effective in preventing tumor metastasis and atopic dermatitis in mouse models. However, our preliminary experiments suggested that the time-dependent decrease in the Muγ expression was not compensated for by repeated injections of Muγ-expressing plasmid. To identify the mechanism underlying this observation, a reporter plasmid was hydrodynamically injected into mice and the levels of the plasmid, mRNA and reporter protein were measured in mice receiving a pre- or co-administration of Muγ-expressing plasmid. Co-injection of Muγ-expressing plasmid had no significant effects on transgene expression from the reporter plasmid. In contrast, pre-injection of Muγ-expressing plasmid greatly inhibited the expression of the reporter protein. Moreover, pre-injection of Muγ-expressing plasmid also reduced the amount of the reporter plasmid in the nuclear fraction of mouse liver to < 10%, and that of reporter mRNA to < 1%. The degree of reduction in the expression of reporter protein was comparable with the reduction in mRNA. These results indicate that the difficulty in regaining the expression level of IFN-γ is due to the impaired delivery of plasmid to the nucleus and to the suppression of transcription from the plasmid.

Proteins that bind the Src homology 3 domain of CrkI have distinct roles in Crk transformation.

The v-Crk oncogene product consists of two protein interaction modules, a Src homology 2 (SH2) domain and a Src homology 3 (SH3) domain. Overexpression of CrkI, the cellular homolog of v-Crk, transforms mouse fibroblasts, and elevated CrkI expression is observed in several human cancers. The SH2 and SH3 domains of Crk are required for transformation, but the identity of the critical cellular binding partners is not known. A number of candidate Crk SH3-binding proteins have been identified, including the nonreceptor tyrosine kinases c-Abl and Arg, and the guanine nucleotide exchange proteins C3G, SOS1 and DOCK180. The aim of this study is to determine which of these are required for transformation by CrkI. We found that short hairpin RNA-mediated knockdown of C3G or SOS1 suppressed anchorage-independent growth of NIH-3T3 cells overexpressing CrkI, whereas knockdown of SOS1 alone was sufficient to suppress tumor formation by these cells in nude mice. Knockdown of C3G was sufficient to revert morphological changes induced by CrkI expression. By contrast, knockdown of Abl family kinases or their inhibition with imatinib enhanced anchorage-independent growth and tumorigenesis induced by Crk. These results show that SOS1 is essential for CrkI-induced fibroblast transformation, and also reveal a surprising negative role for Abl kinases in Crk transformation.

Sign reversal of field-angle resolved heat capacity oscillations in a heavy Fermion superconductor CeCoIn5 and d{x{2}-y{2}} pairing symmetry.

To identify the superconducting gap symmetry in CeCoIn5 (T{c}=2.3 K), we measured the angle-resolved specific heat (C{phi}) in a field rotated around the c axis down to a very low temperature, 0.05T{c}, and made detailed theoretical calculations. In a field of 1 T, a sign reversal of the fourfold angular oscillation in C{phi} was observed at T approximately 0.1T{c} upon entering a quasiclassical regime where the maximum of C{phi} corresponds to the antinodal direction, coinciding with the angle-resolved density of states (ADOS) calculation. The C{phi} behavior, which exhibits minima along the [110] directions, unambiguously allows us to conclude d{x{2}-y{2}} symmetry of this system. The ADOS-quasiclassical region is confined to a narrow T and H domain within T/T{c} approximately 0.1 and 1.5 T (0.13H{c2}).

Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway.

OBJECTIVE: Bezafibrate (BF) has been used to treat biliary damage, particularly in patients with primary biliary cirrhosis (PBC), and its clinical efficacy has been demonstrated. The mechanism of action is thought to involve activation of the PPARalpha-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. METHODS: The levels of serum gamma-glutamyl transpeptidase and alkaline phosphatase, and those of bile components were examined before and after BF administration in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage (PTBD). Hepatic expression of PPARalpha and MDR3 was quantified by real-time PCR in patients with PBC or non-alcoholic fatty liver disease (NAFLD). RESULTS: In patients with obstructive jaundice, BF decreased the serum levels of biliary enzymes and increased the bile concentration of PL. In patients with PBC or NAFLD, the expression levels of MDR3 were already up-regulated before starting the BF treatment. Although BF treatment did not further up-regulate MDR3 expression in NAFLD patients, PPARalpha expression was significantly increased. CONCLUSIONS: BF enhanced the secretion of PL into bile in cholestatic patients undergoing PTBD. However, in patients with PBC or NAFLD, diseases that represent cholesterol overload, MDR3 was already expressed at a high level to compensate for bile acids overproduction, and its expression was hardly affected by BF. In patients with chronic liver diseases such as PBC, BF may induce clinical effects via mechanisms independent of PL secretion.

Microstructure analysis of Nd-Fe-B sintered magnets improved by Tb-metal vapour sorption.

Behaviours of constituent elements in the Nd-Fe-B sintered magnets improved by Tb-metal vapour sorption have been investigated by using an analytical transmission microscopy. It was found that a triple junction of the grain boundaries consists of fine Nd-O crystalline and amorphous phase. The energy dispersive X-ray spectroscopy (EDS) analysis showed that the amorphous phase mainly consists of Co, Nd and Tb. The Tb-treatment causes the formation of the amorphous Co-Nd(Tb) wetting-layer phase which wraps each Nd(2)Fe(14)B grain. The results suggest that the wrapped structure prevents the nucleation of magnetic reversed domains and then improves significantly the coercivity of the magnet.

Role of the Majorana fermion and the edge mode in chiral superfluidity near a p-wave Feshbach resonance.

The visualization of chiral p-wave superfluidity in Fermi gases near p-wave Feshbach resonances is theoretically examined. It is proposed that the superfluidity becomes detectable in the entire BCS-BEC regimes through (i) vortex visualization by the density depletion inside the vortex core and (ii) intrinsic angular momentum in vortex-free states. It is revealed that both (i) and (ii) are closely connected with the Majorana zero energy mode of the vortex core and the edge mode, which survive until the strong coupling BCS regime is approached from the weak coupling limit and vanish in the Bose-Einstein condensation regime.

Majorana bound state in rotating superfluid 3He-A between parallel plates.

A concrete and experimentally feasible example for testing the putative Majorana zero-energy state bound in a vortex is theoretically proposed for a parallel plate geometry of superfluid 3He-A phase. We examine the experimental setup in connection with ongoing rotating cryostat experiments. The theoretical analysis is based on the well-established Ginzburg-Landau functional, supplemented by microscopic calculations of the Bogoliubov-de Gennes equation, both of which allow the precise location of the parameter regions of the Majorana state to be found in realistic situations.

Kelvin waves of quantized vortex lines in trapped Bose-Einstein condensates.

We have theoretically investigated Kelvin waves of quantized vortex lines in trapped Bose-Einstein condensates. Counterrotating perturbation induces an elliptical instability to the initially straight vortex line, driven by a parametric resonance between a quadrupole mode and a pair of Kelvin modes of opposite momenta. Subsequently, Kelvin waves rapidly decay to longer wavelengths emitting sound waves in the process. We present a modified Kelvin wave dispersion relation for trapped superfluids and propose a simple method to excite Kelvin waves of specific wave number.

Bulk electronic structure of the antiferromagnetic superconducting phase in ErNi2B2C.

We have performed temperature- (T-)dependent laser-photoemission spectroscopy of the antiferromagnetic (AF) superconductor ErNi2B2C to study the electronic-structure evolution reflecting the interplay between antiferromagnetism and superconductivity. The spectra at the superconducting (SC) phase show a very broad spectral shape. A T-dependent SC gap shows a sudden deviation from the BCS prediction just below TN. This observation can be explained well by the theoretical model and thus represents the characteristic bulk electronic structure of the AF SC phase for the first time.

Field-angle-dependent specific heat measurements and gap determination of a heavy fermion superconductor URu2Si2.

To identify the superconducting gap structure in URu2Si2, we perform field-angle-dependent specific heat measurements for the two principal orientations in addition to field rotations, and a theoretical analysis based on microscopic calculations. The Sommerfeld coefficient gamma(H)'s in the mixed state exhibit a distinctly different field dependence. This comes from point nodes and the substantial Pauli paramagnetic effect of URu2Si2. These two features combined give rise to a consistent picture of superconducting properties, including a possible first order transition of Hc2 at low temperatures.

Therapeutic control of hepatitis C virus: the role of neutralizing monoclonal antibodies.

Liver failure associated with hepatitis C virus (HCV) accounts for a substantial portion of liver transplantation. Although current therapy helps some patients with chronic HCV infection, adverse side effects and a high relapse rate are major problems. These problems are compounded in liver transplant recipients as reinfection occurs shortly after transplantation. One approach to control reinfection is the combined use of specific antivirals together with HCV-specific antibodies. Indeed, a number of human and mouse monoclonal antibodies to conformational and linear epitopes on HCV envelope proteins are potential candidates, since they have high virus neutralization potency and are directed to epitopes conserved across diverse HCV genotypes. However, a greater understanding of the factors contributing to virus escape and the role of lipoproteins in masking virion surface domains involved in virus entry will be required to help define those protective determinants most likely to give broad protection. An approach to immune escape is potentially caused by viral infection of immune cells leading to the induction hypermutation of the immunoglobulin gene in B cells. These effects may contribute to HCV persistence and B cell lymphoproliferative diseases.