Unveiling unconventional magnetism at the surface of Sr2RuO4.

Materials with strongly correlated electrons often exhibit interesting physical properties. An example of these materials is the layered oxide perovskite Sr2RuO4, which has been intensively investigated due to its unusual properties. Whilst the debate on the symmetry of the superconducting state in Sr2RuO4 is still ongoing, a deeper understanding of the Sr2RuO4 normal state appears crucial as this is the background in which electron pairing occurs. Here, by using low-energy muon spin spectroscopy we discover the existence of surface magnetism in Sr2RuO4 in its normal state. We detect static weak dipolar fields yet manifesting at an onset temperature higher than 50 K. We ascribe this unconventional magnetism to orbital loop currents forming at the reconstructed Sr2RuO4 surface. Our observations set a reference for the discovery of the same magnetic phase in other materials and unveil an electronic ordering mechanism that can influence electron pairing with broken time reversal symmetry.

Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Nodal superconducting exchange coupling.

A superconducting spin valve consists of a thin-film superconductor between two ferromagnetic layers. A change of magnetization alignment shifts the superconducting transition temperature (ΔΤc) due to an interplay between the magnetic exchange energy and the superconducting condensate. The magnitude of ΔΤc scales inversely with the superconductor thickness (dS) and is zero when dS exceeds the superconducting coherence length (ξ). Here, we report a superconducting spin-valve effect involving a different underlying mechanism in which magnetization alignment and ΔΤc are determined by nodal quasiparticle excitation states on the Fermi surface of the d-wave superconductor YBa2Cu3O7-δ sandwiched between insulating layers of ferromagnetic Pr0.8Ca0.2MnO3. We observe ΔΤc values that approach 2 K with the sign of ΔΤc oscillating with dS over a length scale exceeding 100ξ and, for particular values of dS, the superconducting state reinforces an antiparallel magnetization alignment. These results pave the way to all-oxide superconducting memory in which superconductivity modulates the magnetic state.

Fraunhofer patterns in magnetic Josephson junctions with non-uniform magnetic susceptibility.

The development of superconducting memory and logic based on magnetic Josephson junctions relies on an understanding of junction properties and, in particular, the dependence of critical current on external magnetic flux (i.e. Fraunhofer patterns). With the rapid development of Josephson junctions with various forms of inhomogeneous barrier magnetism, Fraunhofer patterns are increasingly complex. In this paper we model Fraunhofer patterns for magnetic Josephson junctions in which the barrier magnetic susceptibility is position- and external-magnetic-field dependent. The model predicts anomalous Fraunhofer patterns in which local minima in the Josephson critical current can be nonzero and non-periodic with external magnetic flux due to an interference effect between magnetised and demagnetised regions.

Magnetic Exchange Fields and Domain Wall Superconductivity at an All-Oxide Superconductor-Ferromagnet Insulator Interface.

At a superconductor-ferromagnet (S/F) interface, the F layer can introduce a magnetic exchange field within the S layer, which acts to locally spin split the superconducting density of states. The effect of magnetic exchange fields on superconductivity has been thoroughly explored at S-ferromagnet insulator (S/FI) interfaces for isotropic s-wave S and a thickness that is smaller than the superconducting coherence length. Here we report a magnetic exchange field effect at an all-oxide S/FI interface involving the anisotropic d-wave high temperature superconductor praseodymium cerium copper oxide (PCCO) and the FI praseodymium calcium manganese oxide (PCMO). The magnetic exchange field in PCCO, detected via magnetotransport measurements through the superconducting transition, is localized to the PCCO/PCMO interface with an average magnitude that depends on the presence or absence of magnetic domain walls in PCMO. The results are promising for the development of all-oxide superconducting spintronic devices involving unconventional pairing and high temperature superconductors.

Visible light emission from a silica microbottle resonator by second- and third-harmonic generation.

We report the first observation of nonlinear harmonic generation and sum frequency generation (SFG) coupled with stimulated Raman scattering (SRS) via the second-order (χ(2)) and the third-order (χ(3)) nonlinearities in a silica microbottle resonator. The visible light emission due to third-harmonic generation (THG) was observed in both the output of a tapered fiber and the optical microscope images, which can be used to identify the axial mode profiles. SFG enabled by three- and four-wave mixing processes between the pump light and the light generated via SRS was also observed. Second-harmonic generation (SHG) and the SFG are enabled by χ(2) induced in silica by surface effects and multipole excitations.

Roles of M2 and M3 muscarinic receptors in the generation of rhythmic motor activity in mouse small intestine.

BACKGROUND: The roles of M2 and M3 muscarinic receptor subtypes in the regulation of gut motor activity were investigated. METHODS: We simultaneously recorded changes in the intraluminal pressure (IP) and longitudinal tension (LT) in small intestinal segments from M2 or M3 receptor knockout (KO) and wild-type (WT) mice. KEY RESULTS: In the WT preparations, luminal distension induced a continuous rhythmic contractile activity that was characterized by synchronous rises in IP and LT, occurring periodically at a constant interval. Tetrodotoxin completely abolished the response, whereas atropine either abolished or attenuated it. In the majority of the M2 KO preparations, however, no rhythmic activity was observed in response to the luminal distention, even though networks of enteric neurons and interstitial cells of Cajal (ICC) seemed to be intact. Where rhythmic activity did occur in M2 KO preparations, it was atropine resistant. In the M3 KO preparations, the IP and LT were synchronously changed by the luminal distention, but the changes occurred at irregular intervals. The W/W(v) mutant preparations, which lack ICC in the myenteric plexus (ICC-MY), showed results similar to those of the M3 KO preparations. In some of the M2 /M3 double-KO preparations, rhythmic activity was not observed, but in the others, an atropine-resistant rhythmicity appeared. CONCLUSIONS & INFERENCES: These results suggest that M2 and M3 muscarinic receptors differentially regulate the intestinal motor activity: M2 receptors play an essential role in the generation of rhythmic motor activity, and M3 receptors have a modulatory role in controlling the periodicity of the rhythmic activity together with the ICC-MY.

Turbulence effect on cloud radiation.

The effect of turbulent clustering of water droplets on radiative transfer is investigated by means of both a three-dimensional direct numerical simulation of particle-laden homogeneous isotropic turbulence and a radiative transfer simulation based on a Monte Carlo photon tracing method. The results show that turbulent clustering causes the formation of void regions of droplets and hence increases the direct transmittance. This effect decreases as the turbulent Reynolds number increases and is estimated to be negligibly small under the conditions in real clouds.

Immunohistochemical and functional studies for M3 muscarinic receptors and cyclo-oxygenase-2 expressed in the mouse atrium.

In mouse atrium, M2 and M3 muscarinic receptors (M2R and M3R) are involved in biphasic (negative and positive) inotropic actions of muscarinic agonists, and the positive inotropic action is reduced by indomethacin. The aim of our study was to determine the localization of M2R, M3R and cyclo-oxygenase (COX) in mouse atrium and to characterize muscarinic receptor-mediated positive inotropy. M2R immunoreactivity was found only on atrial myocardium, but M3R immunoreactivity was localized on both the myocardium and endocardial endothelium. COX-1 and COX-2 immunoreactivities were identified in both myocardial and endocardial endothelium. In electrically stimulated left atria, carbachol caused M2R-mediated negative inotropy followed by M3R-mediated positive inotropy. Removal of atrial endothelium reduced the positive inotropy without affecting the negative inotropy, suggesting that stimulation of endothelial M3R mediates the positive inotropy. N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398, COX-2 inhibitor) decreased the carbachol-induced positive inotropy; however, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC560, COX-1 inhibitor), 1-[[4,5-bis(4-methoxyphenyl)-2-thiazolyl]carbonyl]-4-methylpiperazine (FR122047, COX-1 inhibitor) and L-nitroarginine methylester did not affect the inotropic response. M3R activation caused positive chronotropy in spontaneously beating right atria when M2R-mediated negative chronotropy was suppressed and rate of contraction was low, <350 beats min⁻¹. Our results indicate that although M3Rs are located on both myocardial cells and endocardial endothelial cells, only endothelial M3Rs mediate positive inotropy in response to muscarinic agonists via activation of COX-2 in the mouse atrium. M3R-mediated positive chronotropy counteracting M2R-mediated negative chronotropy was also demonstrated.

Contribution of trunk muscularity on sprint run.

This study aimed to investigate how the trunk muscularity is related to sprint running performance. In 23 youth soccer players, the cross-sectional images at the mid level of each of L1-L2, L2-L3, L3-L4, L4-L5, and L5-S1 were obtained using magnetic resonance imaging to determine the cross-sectional areas (CSAs) of rectus abdominis, oblique, psoas major, quadratus lumborum and erector spinae muscles. The times taken to sprint over 20 m were measured, and the mean velocity of running was calculated for each of the 2 distances (V (10 m) and V (20 m)) and for the distance from 10 m to 20 m (V (10-20 m)). The CSA values of the 5 slice levels for all muscles except for the quadratus lumborum and those of the 3 slice levels (L1-L2, L2-L3 and L3-L4) for the quadratus lumborum were averaged and expressed relative to the two-third power of body mass (CSA/BM (2/3)). The CSA/BM (2/3) values of the erector spinae and quadratus lumborum were selected as significant contributors to predict V (10 m) ( R(2)=0.450), V (20 m) ( R(2)=0.504) and V (10-20 m) ( R(2)=0.420). The current results indicate that the muscularity of the erector spinae and quadratus lumborum contributes to achieving a high performance in sprint running over distances of less than 20 m.

Engulfment of spermatozoa by cumulus cells and the role of CD36.

The function of cumulus cells after sperm penetration is not well understood. The present study examined the phagocytic action of cumulus cells on sperm after dispersion of cumulus-oocyte complexes. In a co-incubation system of cauda sperm and cumulus cells, the sperm heads were beginning to vanish after 2.5h and 77%±1.34 of sperm heads had disappeared at 30 h. Most of the sperm heads were engulfed by cumulus cells. Immunofluorescent studies showed that cumulus cells were expressing the CD36 molecule, and sperm were exposing phosphatidylserine (PS). Anti-CD36 antibody and annexin V inhibited the engulfment of sperm by cumulus cells by 26.0% and 40.5%, respectively. These results suggested that the cumulus cells recognized the PS molecules on sperm via CD36 and this molecular interaction possibly triggered the phagocytosis of sperm by cumulus cells. These results suggest that cumulus cells might play a role in inhibiting undesired immune reactions induced by sperm antigens.

Gene expression profile during ovarian folliculogenesis.

Assisted reproductive technologies have progressed significantly and have provided successful treatment for many infertile couples. However, more advanced technologies are required for severe infertility such as premature ovarian failure and ovarian impairment due to adjuvant therapy for cancer. Ovarian tissue cryopreservation followed by in vitro growth of isolated follicles is a feasible proposition for such patients. Close coordination of communication among follicle cells including oocytes, granulosa and theca cells is required for follicle growth. Crucial factors may regulate the gonadotropin-independent and -dependent follicle growth stages. To facilitate development of a culture system for early growing follicles, DNA microarray analysis of mouse ovaries recovered at 7, 10, 13, 16 and 19 days of age was performed to identify factors required for the growth of early-stage follicles. These studies showed strong intensity of zona pellucida glycoproteins, bone morphogenic protein-15 (BMP-15) and growth differentiation factor (GDF-9) in 7 days old mice, which gradually declined in 19 days old mice. KIT, KIT ligand, anti-müllerian hormone (AMH) and platelet-derived growth factor (PDGF), known as granulosa cell secreted factors, also showed relatively high expression. These studies will facilitate our understanding of the regulatory factors involved in folliculogenesis and thereby enable establishment of in vitro culture system for ovarian follicles.

CD52 expression is induced in the mouse uterus at the time of embryo implantation.

CD52 is a GPI anchor protein present in lymphocytes, the epithelial cells of the epididymis and sperm. It has been reported that male reproductive tract CD52 induces antibodies interfering with sperm function and causes infertility. CD52 is also expressed in ovulated cumulus cells in female reproductive tissues. In the present study, we examined the distribution and the mechanism of regulation of CD52 in the uterus. CD52 expression was evaluated in uterine tissue recovered at 0.5, 4.5, 8.5 and 12.5dpc (days post-coitum). Immunohistochemistry, RT-PCR, Western blotting and gel shift analysis were performed to determine localization and transcriptional regulation of CD52. Cd52 mRNA and CD52 protein were found to increase simultaneously from 0.5 to 4.5dpc. Gel shift analysis revealed that NKX2.2, a transcriptional factor, binds to the promoter region of the Cd52 gene. CD52 and NKX2.2 were co-localized in the endometrium of the uterus. Pathway analysis using Ingenuity pathway analysis predicted that Cd52 is associated with genes involved in the formation of uterosomes which are necessary for embryo attachment. These findings suggest that CD52 synthesis is regulated by NKX2.2 at a transcriptional level, and that Cd52 may be a member of the network of genes regulating uterine receptivity for embryo implantation.

Biochemical property and immunogenicity of mouse male reproductive tract CD52 (mrt-CD52).

Male reproductive tract CD52 (mrt-CD52) is known to be a pathogenic antigen for immunological infertility. Although human CD52 has been extensively investigated, the properties of mouse CD52 are not well elucidated. This study was conducted, therefore, to examine the tissue distribution, molecular composition and immunogenicity of mouse mrt-CD52. Immunohistological studies with an antibody to a synthetic peptide showed that mouse CD52 was localized mainly in the cauda epididymis and vas deferens, but not in the testis, liver, kidney or spleen. The molecule was composed of Asn (N)-linked and The/Ser (O)-linked carbohydrates as well as a glycosylphosphatidyl (GPI) anchor portion. Purified mrt-CD52 preparations produced antibodies by subcutaneous and intranasal immunization in both male and female mice. These antisera showed sperm-immobilizing activities with complement to mouse sperm. The research indicated mouse CD52 had similar biochemical and immunological properties to human CD52. This animal experiment is a good model for investigating human mrt-CD52 antibody detected in infertile patients.

Roles of M2 and M3 muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice.

BACKGROUND AND PURPOSE: The functional roles of M(2) and M(3) muscarinic receptors in neurogenic cholinergic contractions in gastrointestinal tracts remain to be elucidated. To address this issue, we studied cholinergic nerve-induced contractions in the ileum using mutant mice lacking M(2) or M(3) receptor subtypes. EXPERIMENTAL APPROACH: Contractile responses to transmural electrical (TE) stimulation were isometrically recorded in ileal segments from M(2)-knockout (KO), M(3)-KO, M(2)/M(3)-double KO, and wild-type mice. KEY RESULTS: TE stimulation at 2-50 Hz frequency-dependently evoked a fast, brief contraction followed by a slower, longer one in wild-type, M(2)-KO or M(3)-KO mouse preparations. Tetrodotoxin blocked both the initial and later contractions, while atropine only inhibited the initial contractions. The initial cholinergic contractions were significantly greater in wild-type than M(2)-KO or M(3)-KO mice; the respective mean amplitudes at 50 Hz were 91, 74 and 68 % of 70mM K(+)-induced contraction. Pretreatment with pertussis toxin blocked the cholinergic contractions in M(3)-KO but not in M(2)-KO mice. Cholinergic contractions also remained in wild-type preparations, but their sizes were reduced by 20-30 % at 10-50 Hz. In M(2)/M(3)-double KO mice, TE stimulation evoked only slow, noncholinergic contractions, which were significantly greater in sizes than in any of the other three mouse strains. CONCLUSION AND IMPLICATIONS: These results demonstrate that M(2) and M(3) receptors participate in mediating cholinergic contractions in mouse ileum with the latter receptors assuming a greater role. Our data also suggest that the lack of both M(2) and M(3) receptors causes upregulation of noncholinergic excitatory innervation of the gut smooth muscle.

Muscarinic cationic current in gastrointestinal smooth muscles: signal transduction and role in contraction.

1 The muscarinic receptor plays a key role in the parasympathetic nervous control of various peripheral tissues including gastrointestinal tract. The neurotransmitter acetylcholine, via activating muscarinic receptors that exist in smooth muscle, produces its contraction. 2 There is the opening of cationic channels as an underlying mechanism. The opening of cationic channels results in influxes of Ca2+ via the channels into the cell and also via voltage-dependent Ca2+ channels which secondarily opened in response to the depolarization, providing an amount of Ca2+ for activation of the contractile proteins. 3 Electrophysiological and pharmacological studies have shown that the cationic channels as well as muscarinic receptors exist in many visceral smooth muscle cells. However, the activation mechanisms of the cationic channels are still unclear. 4 In this article, we summarize the current knowledge of the muscarinic receptor-operated cationic channels, focusing on the receptor subtype, G protein and other signalling molecules that are involved in activation of these channels and on the molecular characteristics of the channel. This will improve strategies aimed at developing new selective pharmacological agents and understanding the activation mechanism and functions of these channels in physiological systems.

[Effects of octreotide acetate on intractable chylothorax after surgery for congenital heart diseases].

We experienced 2 infants in whom octreotide acetate was effective on intractable chylothorax after surgery for congenital heart diseases. They were 8- and 5-month-old. They were diagnosed as having corrected transposition of the great arteries (TGA) and tetralogy of Fallot respectively, and underwent bidirectional Glenn anastomosis and right modified Blalock Taussig shunt. Chylothorax was revealed on the 11th and the 1st postoperative day, and was not improved by any conventional therapy in either case. Then octreotide acetate was infused continuously with 0.1-0.6 micorg/kg/hour for 24 and 7 days. Chylothorax disappeared completely without any complications such as disturbance of blood sugar level or growth retardation. Octreotide acetate was effective and safe even in infants in intractable chylothorax after surgery for congenital heart diseases, as long as used for short period.

Volatile female odors activate the accessory olfactory system of male mice without physical contact.

We previously reported that male mice are more attracted to volatile odors from intact female mice than from ovariectomized female mice. In the present study, we investigated male attraction to volatile odors from soiled bedding collected from the cages of estrous or ovariectomized female mice. There was no difference in the total time spent sniffing volatile odors from estrous and ovariectomized female mice, suggesting that female mice emit volatile odors which are not excreted into bedding. To test this possibility, we investigated c-Fos expression in the mitral cell layer and granule cell layer of the accessory olfactory bulb 60 min after exposure of male mice to volatile odors without physical contact. Volatile odors from an estrous female mouse significantly increased the total number of c-Fos positive cells in each of the rostral and caudal granule cell layer, but not in the mitral cell layer. After exposure to volatile odors from estrous bedding, the total number of c-Fos positive cells did not increase. Volatile odors from a male mouse did not increase the total number of c-Fos positive cells. Volatile odors from an ovariectomized female mouse increased c-Fos expression only in the caudal granule cell layer. These results suggest that female mice emit specific volatile odors which are not excreted into bedding, and that the volatile odors activate the accessory olfactory system of male mice without physical contact. To characterize the female-specific volatile odors, we conducted habituation-dishabituation tests. Whereas sham-operated male mice discriminated between volatile odors of estrous and ovariectomized female mice, vomeronasal organ-removed male mice did not. These results suggest that male mice discriminated whether or not female mice were ovariectomized, by volatile odors via the accessory olfactory system, and that the female-specific volatile odors are involved in reproduction.

[Effects of additional pulmonary blood flow after bidirectional Glenn procedure].

Thirteen cases of functional single ventricle who had undergone bidirectional Glenn procedure were divided into 2 groups according to presence (5) or absence (8) of additional pulmonary blood flow. Additional flow was preserved in cases with relatively small pulmonary artery index (PA index), and their sources were antegrade pulmonary blood flow (2), and Blalock-Taussig (BT) shunt (3). In the control group, PA index was reduced to about 70% of the preoperative value, while in the additional group, pulmonary artery growth was recognized without significant elevation of mean pulmonary artery pressure. However, atrioventricular valve regurgitation progressed and systemic ventricular volume did not decrease after Glenn in the additional group. Therefore special consideration for the timing of Fontan procedure is mandatory.