Spin-Polarized Positronium Time-of-Flight Spectroscopy for Probing Spin-Polarized Surface Electronic States.

The energy spectrum of positronium atoms generated at a solid surface reflects the electron density of states (DOS) associated solely with the first surface layer. Using spin-polarized positrons, the spin-dependent surface DOS can be studied. For this purpose, we have developed a spin-polarized positronium time-of-flight spectroscopy apparatus based on a ^{22}Na positron source and an electrostatic beam transportation system, which enables the sampling of topmost surface electrons around the Γ point and near the Fermi level. We applied this technique to nonmagnetic Pt(111) and W(001), ferromagnetic Ni(111), Co(0001) and graphene on them, Co_{2}FeGa_{0.5}Ge_{0.5} (CFGG) and Co_{2}MnSi (CMS). The results showed that the electrons of Ni(111) and Co(0001) surfaces have characteristic negative spin polarizations, while these spin polarizations vanished upon graphene deposition, suggesting that the spin polarizations of graphene on Ni(111) and Co(0001) were mainly induced at the Dirac points that were out of range in the present measurement. The CFGG and CMS surfaces also exhibited only weak spin polarizations suggesting that the half-metallicity expected for these bulk states was not maintained at the surfaces.

Structure determination of the rutile-TiO2(110)-(1 × 2) surface using total-reflection high-energy positron diffraction (TRHEPD).

The exact structure of the rutile-TiO2(110)-(1 × 2) surface, which had been under debate over the past 30 years, was investigated using the newly developed technique of total-reflection high-energy positron diffraction (TRHEPD), which is a positron counterpart of reflection high-energy electron diffraction (RHEED). The rocking-curves for the 00-spot obtained from the experimental diffraction patterns were compared to the curves for various models calculated with a full-dynamical theory. It was found that the rocking-curves matched those for a surface consisting of a Ti2O3 configuration, originally suggested by Onishi and Iwasawa [H. Onishi and Y. Iwasawa, Surf. Sci., 1994, 313, L783], but with a further modification of atomic positions close to the ones proposed by Wang et al. [Q. Wang, A. R. Oganov, Q. Zhu and X. F. Zhou, Phys. Rev. Lett., 2014, 113, 266101]. This result demonstrates that TRHEPD can distinguish between the existence and absence of the oxygen atoms on the topmost surface, and between the Ti atoms residing in positions at the interstitial-vertical sites and those at interstitial-horizontal sites.

Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation.

Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeutic agents such as clopidogrel. Polymorphisms in CYP2C19 are associated with large interindividual variations in the therapeutic efficacy of clopidogrel. This study evaluated the in vitro oxidation of clopidogrel by 21 CYP2C19 variants harboring amino acid substitutions. These CYP2C19 variants were heterologously expressed in COS-7 cells, and the kinetic parameters of clopidogrel 2-oxidation were estimated. Among the 21 CYP2C19 variants, 12 (that is, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.14, CYP2C19.16, CYP2C19.19, CYP2C19.22, CYP2C19.24 and CYP2C19.25) showed no or markedly low activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro assessment provided insights into the specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpreting the results of in vivo studies.

Charge-to-Spin Conversion and Spin Diffusion in Bi/Ag Bilayers Observed by Spin-Polarized Positron Beam.

Charge-to-spin conversion induced by the Rashba-Edelstein effect was directly observed for the first time in samples with no magnetic layer. A spin-polarized positron beam was used to probe the spin polarization of the outermost surface electrons of Bi/Ag/Al2O3 and Ag/Bi/Al2O3 when charge currents were only associated with the Ag layers. An opposite surface spin polarization was found between Bi/Ag/Al2O3 and Ag/Bi/Al2O3 samples with the application of a charge current in the same direction. The surface spin polarizations of both systems decreased exponentially with the outermost layer thickness, suggesting the occurrence of spin diffusion from the Bi/Ag interface to the outermost surfaces. This work provides a new technique to measure spin diffusion length.

22q11.2 deletion carriers and schizophrenia-associated novel variants.

The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

IgG4-related skin disease.

IgG4-related disease (IgG4-RD) is a recently established clinical entity characterized by high levels of circulating IgG4, and tissue infiltration of IgG4(+) plasma cells. IgG4-RD exhibits a distinctive fibroinflammatory change involving multiple organs, such as the pancreas and salivary and lacrimal glands. The skin lesions of IgG4-RD have been poorly characterized and may stem not only from direct infiltration of plasma cells but also from IgG4-mediated inflammation. Based on the documented cases together with ours, we categorized the skin lesions into seven subtypes: (1) cutaneous plasmacytosis (multiple papulonodules or indurations on the trunk and proximal part of the limbs), (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (plaques and papulonodules mainly on the periauricular, cheek and mandible regions), (3) Mikulicz disease (palpebral swelling, sicca syndrome and exophthalmos), (4) psoriasis-like eruption (strikingly mimicking psoriasis vulgaris), (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura (bilateral asymmetrical palpable purpuric lesions on the lower extremities) and urticarial vasculitis (prolonged urticarial lesions occasionally with purpura) and (7) ischaemic digit (Raynaud phenomenon and digital gangrene). It is considered that subtypes 1-3 are induced by direct infiltration of IgG4(+) plasma cells, while the other types (4-7) are caused by secondary mechanisms. IgG4-related skin disease is defined as IgG4(+) plasma-cell-infiltrating skin lesions that form plaques, nodules or tumours (types 1-3), but may manifest secondary lesions caused by IgG4(+) plasma cells and/or IgG4 (types 4-7).

Unique structures of organelles observed in primary spermatocytes after micro-injection of protein solutions such as immunoglobulin into the lumen of the seminiferous tubules in mice and rats.

Unique membranous structures of intracytoplasmic organelle, sting of a stack of a few flat cisternae about 50 nm in thickness, were found in mouse and rat spermatocytes after micro-injection of immunoglobulin G into the lumina of the seminiferous tubules. Other proteins such as BSA and cytochrome c used in this study also induced the structures. In most cases, the stacks of cisternae were rolled up like cigars or cylinders. The structures varied in length and diameter, the largest one observed in this study being 10.7 µm in length. The structures did not appear when the testes were fixed just after micro-injection and were formed transiently: they were observed in the spermatocytes fixed between 1 and 4 h after injection. Cytochrome c, micro-injected as an inter-cellular tracer, was visualised by a diaminobenzidine reaction. As the reaction product was not contained in the cisternae of the unique structures, the lumen of the cisternae of the organelles was not continuous with the inter-cellular space. A flocculent material of low density was observed in the cisternae of the organelle. Similar material was observed in the lumina of solitary cisternae of the rough endoplasmic reticulum in the spermatocytes, suggesting that the structures derived from endoplasmic reticulum.

Unilateral nephrectomized SHR/NDmcr-cp rat shows a progressive decline of glomerular filtration with tubular interstitial lesions.

In patients with diabetic kidney disease (DKD), the estimated glomerular filtration rate (eGFR) or creatinine clearance rate (Ccr) is always used as an index of decline in renal function. However, there are few animal models of DKD that could be used to evaluate renal function based on GFR or Ccr. For this reason, it is desirable to develop animal models to assess renal function, which could also be used for the evaluation of novel therapeutic agents for DKD. Therefore, we aimed to develop such animal model of DKD by using spontaneously hypertensive rat (SHR)/NDmcr-cp (cp/cp) rats with the characteristics of obese type 2 diabetes and metabolic syndrome. As a result, we have found that unilateral nephrectomy (UNx) caused a chronic Ccr decline, development of glomerular sclerosis, tubular lesions, and tubulointerstitial fibrosis, accompanied by renal anemia. Moreover, losartan-mixed diet suppressed the Ccr decline in UNx-performed SHR/NDmcr-cp rats (UNx-SHR/cp rats), with improvement in renal anemia and histopathological changes. These results suggest that UNx-SHR/cp rats could be used as a DKD model for evaluating the efficacy of therapeutic agents based on suppression of renal function decline.

Pathophysiological analysis of uninephrectomized db/db mice as a model of severe diabetic kidney disease.

Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40% of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db/db mice. In addition, the nephrectomized db /db mice from 10 weeks to 42 weeks were used to assess the efficacy of long-term administration of the angiotensin-II-receptor antagonist losartan. The blood and urinary biochemical parameters, main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104 ± 986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829±500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.

Schizophrenia with the 22q11.2 deletion and additional genetic defects: case history.

The 22q11.2 deletion is the most prominent known genetic risk factor for schizophrenia, but its penetrance is at most approximately 50% suggesting that additional risk factors are required for disease progression. We examined a woman with schizophrenia with this deletion for such risk factors. She had high plasma pentosidine levels ('carbonyl stress') and a frameshift mutation in the responsible gene, GLO1. She also had a constant exotropia, so we examined the PHOX2B gene associated with both schizophrenia and strabismus, and detected a 5-alanine deletion. We propose that the combination of these genetic defects may have exceeded the threshold for the manifestation of schizophrenia.

Localisation of RA175 (Cadm1), a cell adhesion molecule of the immunoglobulin superfamily, in the mouse testis, and analysis of male infertility in the RA175-deficient mouse.

RA175, a member of the immunoglobulin superfamily, plays an important role in cell adhesion, and RA175 gene-deficient mice (RA175(-/-) ) show oligoastheno-teratozoospermia. To understand the function of RA175, location in the testis and the morphological features of its spermatogenic cells in RA175(-/-) mice were investigated. Immunohistochemical studies revealed that RA175 immunoreactivity was observed on the cell surface of the spermatogenic cells at specific stages. A strong reaction was detected from type A spermatogonia to pachytene spermatocytes at stage IV and from step 6 to step 16 spermatids during spermatogenesis. From pachytene spermatocytes at stage VI to step 4 spermatids, the reaction was not detected by the enzyme-labelled antibody method and was faintly detected by the indirect immunofluorescence method. Abnormal vacuoles in the seminiferous epithelium, showing exfoliation of germ cells, and ultrastructural abnormality of the elongate spermatids were revealed in the RA175(-/-) testes. Other members of the immunoglobulin superfamily such as basigin, nectin-2 and nectin-3, which have an important role in spermatogenesis, were immunohistochemically detected in the RA175(-/-) testis. These observations indicate a unique expression pattern of RA175 in the testis and provide clues regarding the mechanism of male infertility in the testis.

High-density magnetic-vacancy inclusion in Co2MnGa single crystal probed by spin-polarized positron annihilation spectroscopy.

Co2MnGa is a Weyl semimetal exhibiting giant anomalous Hall and Nernst effects. Using spin-polarized positron annihilation spectroscopy, we examined a Bridgman-grown Co2MnGa single crystal with a nearly perfectL21-ordered structure and a reference Co2MnAl polycrystal with a Mn-Al-disorderedB2 structure. We found that a large amount of magnetic vacancies (more than 100 ppm) were included in the Co2MnGa crystal but not the Co2MnAl crystal. We discuss possible reasons for the inclusion of vacancies, the role of vacancies in the development of the ordered structure, and the electronic states associated with the vacancies. Toward the development of Co2MnGa-based devices, the manners for reducing vacancies as well as the influence of vacancies on the electrical transport properties should be considered.

Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer.

PURPOSE: Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. METHODS: Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). RESULTS: The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). CONCLUSIONS: Tryptophan metabolites may have a potential for predicting the efficacy of ICIs. REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry 000026140.

Positronium formation at 4H SiC(0001) surfaces.

Positronium formation at 4H SiC(0001) surfaces were investigated upon the removal of natural oxide layers by hydrofluoric acid etching and heat treatment at 1000 K in ultra-high vacuum. Two types of positronium were observed in the positronium time-of-flight (PsTOF) measurements irrespective of conduction type and surface polarity. One type formed the major part of the PsTOF spectrum with a maximum energy of 4.7 ± 0.3 eV. This energy exceeded the theoretical value calculated with valence electrons. The PsTOF spectrum shape was different from those of metal surfaces, suggesting that the surface state electrons or conduction electrons need to be considered as the positronium source. Another positronium appeared at 1000 K in the tail of the PsTOF spectrum with a maximum energy of 0.2-0.5 eV. This thermally-assisted athermal positronium may be formed via the surface state positrons and electrons.

Molecular dissection of the Rho-associated protein kinase (p160ROCK)-regulated neurite remodeling in neuroblastoma N1E-115 cells.

A critical role for the small GTPase Rho and one of its targets, p160ROCK (a Rho-associated coiled coil-forming protein kinase), in neurite remodeling was examined in neuroblastoma N1E-115 cells. Using wild-type and a dominant-negative form of p160ROCK and a p160ROCK-specific inhibitor, Y-27632, we show here that p160ROCK activation is necessary and sufficient for the agonist-induced neurite retraction and cell rounding. The neurite retraction was accompanied by elevated phosphorylation of myosin light chain and the disassembly of the intermediate filaments and microtubules. Y-27632 blocked both neurite retraction and the elevation of myosin light chain phosphorylation in a similar concentration-dependent manner. On the other hand, suppression of p160ROCK activity by expression of a dominant-negative form of p160ROCK induced neurites in the presence of serum by inducing the reassembly of the intermediate filaments and microtubules. The neurite outgrowth by the p160ROCK inhibition was blocked by coexpression of dominant-negative forms of Cdc42 and Rac, indicating that p160ROCK constitutively and negatively regulates neurite formation at least in part by inhibiting activation of Cdc42 and Rac. The assembly of microtubules and intermediate filaments to form extended processes by inhibitors of the Rho-ROCK pathway was also observed in Swiss 3T3 cells. These results indicate that Rho/ROCK-dependent tonic inhibition of cell process extension is exerted via activation of the actomysin-based contractility, in conjunction with a suppression of assembly of intermediate filaments and microtubules in many cell types including, but not exclusive to, neuronal cells.

Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

The actin cytoskeleton undergoes extensive remodeling during cell morphogenesis and motility. The small guanosine triphosphatase Rho regulates such remodeling, but the underlying mechanisms of this regulation remain unclear. Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM-kinase. Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK. ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM-kinase, which in turn was activated to phosphorylate cofilin. Overexpression of LIM-kinase in HeLa cells induced the formation of actin stress fibers in a Y-27632-sensitive manner. These results indicate that phosphorylation of LIM-kinase by ROCK and consequently increased phosphorylation of cofilin by LIM-kinase contribute to Rho-induced reorganization of the actin cytoskeleton.

Saccades and prefrontal hemodynamics in basketball players.

We investigated saccade performance and prefrontal hemodynamics in basketball players with different skill levels. Subjects were 27 undergraduate basketball players and 13 non-athlete undergraduates (control group: CON). The players were divided into two groups: those who had played in the National Athletic Meet during high school or played regularly (n=13, elite group: ELI) and those who were bench warmers (n=14, skilled group: SKI). Horizontal eye movement and oxy-, deoxy-, and total-hemoglobin (Hb) concentration in the prefrontal cortex during pro- and anti-saccade were measured using electro-oculography and near-infrared spectroscopy, respectively. Only error rate in anti-saccade was less in ELI (4.8+/-4.0%) than SKI (13.7+/-12.6%) and CON (13.9+/-8.3%) (p<0.05). In ELI alone, oxy- (-0.15+/-0.18 mmol*mm) and total-Hb (-0.12+/-0.15 mmol*mm) during anti-saccade decreased significantly compared with that during rest (p<0.05), while those in CON significantly increased (oxy-Hb: 0.17+/-0.15 mmol*mm, total-Hb: 0.14+/-0.14 mmol*mm) (p<0.05). These results suggest that inhibition of eye movement to a visual target changes from voluntary to automatic through the motor learning of basketball.

A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons.

We tested the contribution of the small GTPase Rho and its downstream target p160ROCK during the early stages of axon formation in cultured cerebellar granule neurons. p160ROCK inhibition, presumably by reducing the stability of the cortical actin network, triggered immediate outgrowth of membrane ruffles and filopodia, followed by the generation of initial growth cone-ike membrane domains from which axonal processes arose. Furthermore, a potentiation in both the size and the motility of growth cones was evident, though the overall axon elongation rate remained stable. Conversely, overexpression of dominant active forms of Rho or ROCK was suggested to prevent initiation of axon outgrowth. Taken together, our data indicate a novel role for the Rho/ROCK pathway as a gate critical for the initiation of axon outgrowth and the control of growth cone dynamics.