Landau renormalizations of superfluid density in the heavy-fermion superconductor CeCoIn5.

The formation of heavy-fermion bands can occur by means of the conversion of a periodic array of local moments into itinerant electrons via the Kondo effect and the huge consequent Fermi-liquid renormalizations. Leggett predicted for liquid (3)He that Fermi-liquid renormalizations change in the superconducting state, leading to a temperature dependence of the London penetration depth Λ quite different from that in BCS theory. Using Leggett's theory, as modified for heavy fermions, it is possible to extract from the measured temperature dependence of Λ in high quality samples both Landau parameters F(0)(s) and F(1)(s); this has never been accomplished before. A modification of the temperature dependence of the electronic specific heat C(el), related to that of Λ, is also expected. We have carefully determined the magnitude and temperature dependence of Λ in CeCoIn(5) by muon spin relaxation rate measurements to obtain F(0)(s) = 36 ± 1 and F(1)(s) = 1.2 ± 0.3, and we find a consistent change in the temperature dependence of C(el). This, the first determination of F(1)(s) with a value ≪ F(0)(s) in a heavy-fermion compound, tests the basic assumption of the theory of heavy fermions, that the frequency dependence of the self-energy is much more important than its momentum dependence.

Direct observation of the quantum critical point in heavy fermion CeRhSi3.

We report on muon spin rotation studies of the noncentrosymmetric heavy fermion antiferromagnet CeRhSi3. A drastic and monotonic suppression of the internal fields, at the lowest measured temperature, was observed upon an increase of external pressure. Our data suggest that the ordered moments are gradually quenched with increasing pressure, in a manner different from the pressure dependence of the Néel temperature. At 23.6 kbar, the ordered magnetic moments are fully suppressed via a second-order phase transition, and T(N) is zero. Thus, we directly observed the quantum critical point at 23.6 kbar hidden inside the superconducting phase of CeRhSi3.

Magnetic transition and spin fluctuations in the unconventional antiferromagnetic compound Yb3Pt4.

Muon spin rotation and relaxation measurements have been carried out on the unconventional antiferromagnet Yb3Pt4. Oscillations are observed below T(N) = 2.22(1) K, consistent with the antiferromagnetic (AFM) Néel temperature observed in bulk experiments. In agreement with neutron diffraction experiments the oscillation frequency ω(µ)(T)/2π follows an S = 1/2 mean-field temperature dependence, yielding a quasistatic local field of 1.71(2) kOe at T = 0. A crude estimate gives an ordered moment of ∼ 0.66 µ(B) at T = 0, comparable to 0.81 µ(B) from neutron diffraction. As T-->T(N) from above the dynamic relaxation rate λ(d) exhibits no critical slowing down, consistent with a mean-field transition. In the AFM phase a T-linear fit to λ(d)(T), appropriate to a Fermi liquid, yields highly enhanced values of λ(d)/T and the Korringa constant K(µ)(2)T/λ(d), with K(µ) the estimated muon Knight shift. A strong suppression of λ(d) by applied field is observed in the AFM phase. These properties are consistent with the observed large Sommerfeld-Wilson and Kadowaki-Woods ratios in Yb3Pt4 (although the data do not discriminate between Fermi-liquid and non-Fermi-liquid states), and suggest strong enhancement of q≈0 spin correlations between large-Fermi-volume band quasiparticles in the AFM phase of Yb3Pt4.

Direct search for a ferromagnetic phase in a heavily overdoped nonsuperconducting copper oxide.

The doping of charge carriers into the CuO(2) planes of copper oxide Mott insulators causes a gradual destruction of antiferromagnetism and the emergence of high-temperature superconductivity. Optimal superconductivity is achieved at a doping concentration p beyond which further increases in doping cause a weakening and eventual disappearance of superconductivity. A potential explanation for this demise is that ferromagnetic fluctuations compete with superconductivity in the overdoped regime. In this case, a ferromagnetic phase at very low temperatures is predicted to exist beyond the doping concentration at which superconductivity disappears. Here we report on a direct examination of this scenario in overdoped La(2-x)Sr(x)CuO(4) using the technique of muon spin relaxation. We detect the onset of static magnetic moments of electronic origin at low temperature in the heavily overdoped nonsuperconducting region. However, the magnetism does not exist in a commensurate long-range ordered state. Instead it appears as a dilute concentration of static magnetic moments. This finding places severe restrictions on the form of ferromagnetism that may exist in the overdoped regime. Although an extrinsic impurity cannot be absolutely ruled out as the source of the magnetism that does occur, the results presented here lend support to electronic band calculations that predict the occurrence of weak localized ferromagnetism at high doping.

Screening of point charge impurities in highly anisotropic metals: application to mu+-spin relaxation in underdoped cuprate superconductors.

We calculate the screening charge density distribution due to a point charge, such as that of a positive muon (mu+), placed between the planes of a highly anisotropic layered metal. In underdoped hole cuprates the screening charge converts the charge density in the metallic-plane unit cells in the vicinity of the mu+ to nearly its value in the insulating state. The current-loop-ordered state observed by polarized neutron diffraction then vanishes in such cells, and also in nearby cells over a distance of order the intrinsic correlation length of the loop-ordered state. This strongly suppresses the magnetic field at the mu+ site. We estimate this suppressed field in underdoped YBa2Cu3O6+x and La2-xSrxCuO4, and find consistency with the observed approximately 0.2 G field in the former case and the observed upper bound of approximately 0.2 G in the latter case. This resolves the controversy between the neutron diffraction and mu-spin relaxation experiments.

Expression of anti-Müllerian hormone (AMH) in equine granulosa-cell tumors and in normal equine ovaries.

Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS), is expressed by granulosa cells in females of many mammalian species, and circulating AMH concentrations have been used to monitor granulosa-cell tumors (GCT) in women. The objective was to characterize expression of AMH in equine GCT, and in normal equine ovaries, based upon immunohistochemistry (IHC), using a polyclonal primary antibody directed against human AMH. Equine GCT (n=27) and normal equine ovaries (n=10) were examined by IHC. In addition, sera from four mares with GCT were characterized for AMH bioactivity, based upon suppression of Müllerian duct development in the fetal rat. Immunolabeling with alpha-AMH was localized to granulosa cells in equine GCT, as well as within antral follicles in normal ovaries. Expression of AMH first appeared in granulosa cells of small growing follicles and was most intense in small antral follicles; large antral or atretic follicles had reduced immunolabeling. Omission of the primary antibody or incubation of the primary antibody with the corresponding blocking peptide eliminated immunolabeling of granulosa cells in GCT and in normal antral follicles, confirming the specificity of the immunolabel. Sera from mares with GCT had increased AMH bioactivity compared to control sera. In conclusion, AMH was strongly expressed by granulosa cells in equine GCT and in normal antral follicles. Therefore, anti-Müllerian hormone may be a useful biomarker for detection of GCT in the horse.

Mullerian inhibiting substance levels at the time of HCG administration in IVF cycles predict both ovarian reserve and embryo morphology.

BACKGROUND: Pre-antral and early antral follicles secrete Müllerian inhibiting substance (MIS), suggesting that MIS may directly reflect ovarian reserve. Since little is known about how ovarian reserve affects oocyte quality, we attempt here to assess the predictive value of MIS on embryo morphology and IVF outcome. To do so, we measured MIS at the time of HCG administration 36 h prior to oocyte retrieval. METHODS: A total of 257 patients undergoing IVF were prospectively recruited. We measured MIS levels by enzyme-linked immunosorbent assay at the time of HCG, and compared the MIS values to day 3 FSH levels in the prediction of embryo morphology and IVF outcome. RESULTS: The distribution of MIS levels was skewed, with a median of 2.7 ng/ml (range 0 to 28.5 ng/ml). MIS values at the time of HCG administration inversely correlated with basal FSH levels (P = 0.002), and both correlated significantly with patient age, number of mature follicles, number of oocytes retrieved and serum estradiol levels. MIS levels correlated significantly with a greater number of 6-cell embryos and better embryo morphology score, while basal FSH levels did not correlate with these outcome variables. MIS levels > or =2.7 ng/ml portended improved oocyte quality as reflected in a higher implantation rate (P = 0.001) and a trend toward a better clinical pregnancy rate (P = 0.084). CONCLUSIONS: MIS levels seem to predict not only ovarian reserve, but also embryo morphology. Measurement of MIS at the time of HCG administration may, therefore, in the future improve management of patients undergoing treatments with assisted reproductive technology.

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model.

Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.

Field dependence of the muon spin relaxation rate in MnSi.

Muon spin rotation/relaxation measurements have been performed in the itinerant helical magnet MnSi at ambient pressure and at 8.3 kbar. We have found the following: (a) the spin-lattice relaxation rate 1/T(1) shows divergence as T1T proportional, variant (T-T(c))(beta) with the power beta larger than 1 near T(c); (b) 1/T(1) is strongly reduced in an applied external field B(L) and the divergent behavior near T(c) is completely suppressed at B(L)> or =4000 G. We discuss that (a) is consistent with the self-consistent renormalization theory and reflects a departure from "mean-field" behavior, while (b) indicates selective suppression of spin fluctuations of the q=0 component by B(L).

Muon spin relaxation and isotropic pairing in superconducting PrOs4Sb12.

Transverse-field muon-spin rotation measurements in the vortex-lattice of the heavy-fermion (HF) superconductor PrOs4Sb12 yield a temperature dependence of the magnetic penetration depth lambda indicative of an isotropic or nearly isotropic energy gap. This is not seen to date in any other HF superconductor and is a signature of isotropic pairing symmetry, possibly related to a novel nonmagnetic "quadrupolar Kondo" HF mechanism in PrOs4Sb12. The T=0 relaxation rate sigma(s)(0)=0.91(1) micros(-1) yields an estimated magnetic penetration depth lambda(0)=3440(20) A, which is considerably shorter than in other HF superconductors.

29Si NMR and hidden order in URu2Si2.

Below T(N) approximately 17 K the 29Si NMR line in URu2Si2 exhibits a previously unobserved field-independent nearly isotropic contribution to the linewidth, which increases to approximately 12 G as T-->0. We argue that this feature does not arise from static freezing of the U-spin magnetization, but is due to coupling between 29Si spins and a hidden order parameter. We discuss time-reversal symmetry-breaking orbital antiferromagnetism and indirect nuclear spin-spin interactions as possible coupling mechanisms. Further NMR experiments and theoretical calculations are suggested.

Müllerian inhibiting substance inhibits testosterone synthesis in adult rats.

Müllerian inhibiting substance (MIS) is a gonadal hormone that causes regression of the Müllerian ducts during male sexual differentiation. Postnatally, MIS inhibits the proliferation and differentiation of immature Leydig cells, and transgenic mice that overexpress MIS have decreased serum testosterone concentrations. To elucidate the effects of MIS on androgen regulation in the postnatal testis, we examined testosterone synthesis in adult Sprague-Dawley rats following intratesticular and intraperitoneal injections of MIS. Intratesticular MIS injection achieved high local concentrations of MIS (574.0 +/- 60.0 ng/mL) at 4 hours, with a corresponding decline in serum testosterone concentrations to 0.7 +/- 0.1 ng/mL, compared to 1.1 +/- 0.2 ng/mL with intraperitoneal MIS and 1.6 +/- 0.1 ng/mL with intratesticular vehicle (IT-Veh) (P < .001). Intratesticular administration of MIS (IT-MIS) resulted in much higher serum and testicular interstitial fluid MIS concentrations than the intraperitoneal route. To directly examine the testosterone production rate in MIS-treated animals, we isolated Leydig cells from MIS and vehicle-injected testes. Primary Leydig cells exposed to MIS had a lower testosterone production rate and decreased expression of p450c17 (hydroxylase/lyase) and luteinizing hormone (LH) receptor mRNAs than that of vehicle-injected controls or the noninjected contralateral testis. In conclusion, intratesticular administration of MIS caused a decline in serum testosterone concentrations by decreasing the rate of testosterone biosynthesis, confirming that MIS can regulate adult Leydig cell androgen production. The ability of MIS to down-regulate mRNA expression of the p450c17 and LH receptor genes suggests that this effect is mediated transcriptionally. These data indicate that, in addition to its role in embryonic differentiation of the male reproductive tract, MIS has a regulatory function in the postnatal testis. We conclude that one such function is for MIS to directly inhibit adult Leydig cell steroidogenesis.

Glassy spin dynamics in non-fermi-liquid UCu5-xPdx, x = 1.0 and 1.5.

Local f-electron spin dynamics in the non-Fermi-liquid heavy-fermion alloys UCu5-xPdx, x = 1.0 and 1.5, have been studied using muon spin-lattice relaxation. The sample-averaged asymmetry function G(t) indicates strongly inhomogeneous spin fluctuations and exhibits the scaling G(t,H) = G(t/H(gamma)) expected from glassy dynamics. At 0.05 K gamma(x = 1.0) = 0.35+/-0.1, but gamma(x = 1.5) = 0.7+/-0.1. This is in contrast to inelastic neutron scattering results, which yield gamma = 0.33 for both concentrations. There is no sign of static magnetism approximately greater than 10(-3)(B)/U ion in either material above 0.05 K. Our results strongly suggest that both alloys are quantum spin glasses.

Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary epithelial cells in vivo.

Müllerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro through interference with cell cycle progression and induction of apoptosis, a process associated with NFkappaB activation and up-regulation of one of its important target genes, IEX-1S (Segev, D. L., Ha, T., Tran, T. T., Kenneally, M., Harkin, P., Jung, M., MacLaughlin, D. T., Donahoe, P. K., and Maheswaran, S. (2000) J. Biol. Chem. 275, 28371-28379). Here we demonstrate that MIS activates the NFkappaB signaling cascade, induces IEX-1S mRNA, and inhibits the growth of MCF10A, an immortalized human breast epithelial cell line with characteristics of normal cells. In vivo, an inverse correlation was found to exist between various stages of mammary growth and MIS type II receptor expression. Receptor mRNA significantly diminished during puberty, when the ductal system branches and invades the adipose stroma and during the expansive growth at lactation, but it was up-regulated during involution, a time of regression and apoptosis. Peripartum variations in MIS type II receptor expression correlated with NFkappaB activation and IEX-1S mRNA expression. Administration of MIS to female mice induced NFkappaB DNA binding and IEX-1S mRNA expression in the breast. Furthermore, exposure to MIS in vivo increased apoptosis in the mouse mammary ductal epithelium. Thus, MIS may function as an endogenous hormonal regulator of NFkappaB signaling and growth in the breast.

Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo.

Techniques of tissue engineering and cell and molecular biology were used to create a biodegradable scaffold for transfected cells to produce complex proteins. Mullerian Inhibiting Substance (MIS) causes regression of Mullerian ducts in the mammalian embryo. MIS also causes regression in vitro of ovarian tumor cell lines and primary cells from ovarian carcinomas, which derive from Mullerian structures. In a strategy to circumvent the complicated purification protocols for MIS, Chinese hamster ovary cells transfected with the human MIS gene were seeded onto biodegradable polymers of polyglycolic acid fibers and secretion of MIS confirmed. The polymer-cell graft was implanted into the right ovarian pedicle of severe combined immunodeficient mice. Serum MIS in the mice rose to supraphysiologic levels over time. One week after implantation of the polymer-cell graft, IGROV-1 human tumors were implanted under the renal capsule of the left kidney. Growth of the IGROV-1 tumors was significantly inhibited in the animals with a polymer-cell graft of MIS-producing cells, compared with controls. This novel MIS delivery system could have broader applications for other inhibitory agents not amenable to efficient purification and provides in vivo evidence for a role of MIS in the treatment of ovarian cancer.

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents.

Müllerian Inhibiting Substance (MIS) expression is inversely proportional to the serum concentration of testosterone in males after birth and in vitro studies have shown that MIS can lower testosterone production by Leydig cells. Also, mice overexpressing MIS exhibited Leydig cell hypoplasia and lower levels of serum testosterone, but it is not clear whether this is a result of MIS affecting the development of Leydig cells or their capacity to produce testosterone. To examine the hypothesis that MIS treatment will result in decreased testosterone production by mature Leydig cells in vivo, we treated luteinizing hormone (LH)-stimulated adult male rats and mice with MIS and demonstrated that it can lead to a several-fold reduction in testosterone in serum and in testicular extracts. There was also a slight decrease in 17-OH-progesterone compared to the more significant decrease in testosterone, suggesting that MIS might be regulating the lyase activity of cytochrome P450c17 hydroxylase/lyase (Cyp17), but not its hydroxylase activity. Northern analysis showed that, in both MIS-treated rats and mice, the mRNA for Cyp17, which catalyzes the committed step in androgen synthesis, was down-regulated. In rats, the mRNA for cytochrome P450 side-chain cleavage (P450scc) was also down-regulated by MIS. This was not observed in mice, indicating that there might be species-specific regulation by MIS of the enzymes involved in the testosterone biosynthetic pathway. Our results show that MIS can be used in vivo to lower testosterone production by mature rodent Leydig cells and suggest that MIS-mediated down-regulation of the expression of Cyp17, and perhaps P450scc, contributes to that effect.

Observation of two time scales in the ferromagnetic manganite La1-xCaxMnO3, x approximately 0.3.

We report new zero-field muon spin relaxation and neutron spin echo measurements in ferromagnetic (FM) (La,Ca)MnO3 which suggest at least two spatially separated regions possessing very different Mn-ion spin dynamics. One region displays diffusive relaxation, "critical slowing down" near T(C) and an increasing volume fraction below T(C), suggesting overdamped FM spin waves below T(C). The second region possesses more slowly fluctuating spins, a linewidth independent of q, and a decreasing volume fraction below T(C). The estimated length scale for the inhomogeneity is

A time-less function for mouse timeless.

The timeless (tim) gene is essential for circadian clock function in Drosophila melanogaster. A putative mouse homolog, mTimeless (mTim), has been difficult to place in the circadian clock of mammals. Here we show that mTim is essential for embryonic development, but does not have substantiated circadian function.