High-Q Magnetic Levitation and Control of Superconducting Microspheres at Millikelvin Temperatures.

We report the levitation of a superconducting lead-tin sphere with 100 µm diameter (corresponding to a mass of 5.6 µg) in a static magnetic trap formed by two coils in an anti-Helmholtz configuration, with adjustable resonance frequencies up to 240 Hz. The center-of-mass motion of the sphere is monitored magnetically using a dc superconducting quantum interference device as well as optically and exhibits quality factors of up to 2.6×10^{7}. We also demonstrate 3D magnetic feedback control of the motion of the sphere. The setup is housed in a dilution refrigerator operating at 15 mK. By implementing a cryogenic vibration isolation system, we can attenuate environmental vibrations at 200 Hz by approximately 7 orders of magnitude. The combination of low temperature, large mass, and high quality factor provides a promising platform for testing quantum physics in previously unexplored regimes with high mass and long coherence times.

NanoSQUID Magnetometry on Individual As-grown and Annealed Co Nanowires at Variable Temperature.

Performing magnetization studies on individual nanoparticles is a highly demanding task, especially when measurements need to be carried out under large sweeping magnetic fields or variable temperature. Yet, characterization under varying ambient conditions is paramount in order to fully understand the magnetic behavior of these objects, e.g., the formation of nonuniform states or the mechanisms leading to magnetization reversal and thermal stability. This, in turn, is necessary for the integration of magnetic nanoparticles and nanowires into useful devices, e.g., spin-valves, racetrack memories, or magnetic tip probes. Here, we show that nanosuperconducting quantum interference devices based on high critical temperature superconductors are particularly well suited for this task. We have successfully characterized a number of individual Co nanowires grown through focused electron beam induced deposition and subsequently annealed at different temperatures. Magnetization measurements performed under sweeping magnetic fields (up to ∼100 mT) and variable temperature (1.4-80 K) underscore the intrinsic structural and chemical differences between these nanowires. These point to significant changes in the crystalline structure and the resulting effective magnetic anisotropy of the nanowires, and to the nucleation and subsequent vanishing of antiferromagnetic species within the nanowires annealed at different temperatures.

Current-Phase Relation of Ballistic Graphene Josephson Junctions.

The current-phase relation (CPR) of a Josephson junction (JJ) determines how the supercurrent evolves with the superconducting phase difference across the junction. Knowledge of the CPR is essential in order to understand the response of a JJ to various external parameters. Despite the rising interest in ultraclean encapsulated graphene JJs, the CPR of such junctions remains unknown. Here, we use a fully gate-tunable graphene superconducting quantum intereference device (SQUID) to determine the CPR of ballistic graphene JJs. Each of the two JJs in the SQUID is made with graphene encapsulated in hexagonal boron nitride. By independently controlling the critical current of the JJs, we can operate the SQUID either in a symmetric or asymmetric configuration. The highly asymmetric SQUID allows us to phase-bias one of the JJs and thereby directly obtain its CPR. The CPR is found to be skewed, deviating significantly from a sinusoidal form. The skewness can be tuned with the gate voltage and oscillates in antiphase with Fabry-Pérot resistance oscillations of the ballistic graphene cavity. We compare our experiments with tight-binding calculations that include realistic graphene-superconductor interfaces and find a good qualitative agreement.

Local Electrical Imaging of Tetragonal Domains and Field-Induced Ferroelectric Twin Walls in Conducting SrTiO_{3}.

We demonstrate electrical mapping of tetragonal domains and electric field-induced twin walls in SrTiO_{3} as a function of temperature and gate bias utilizing the conducting LaAlO_{3}/SrTiO_{3} interface and low-temperature scanning electron microscopy. Conducting twin walls appear below 105 K, and new twin patterns are observed after thermal cycling through the transition or on electric field gating. The nature of the twin walls is confirmed by calculating their intersection angles for different substrate orientations. Numerous walls formed when a large side- or back-gate voltage is applied are identified as field-induced ferroelectric twin walls in the paraelectric tetragonal matrix. The walls persist after switching off the electric field and on thermal cycling below 105 K. These observations point to a new type of ferroelectric functionality in SrTiO_{3}, which could be exploited together with magnetism and superconductivity in a multifunctional context.

Sensitivity of ultracold atoms to quantized flux in a superconducting ring.

We report on the magnetic trapping of an ultracold ensemble of (87)Rb atoms close to a superconducting ring prepared in different states of quantized magnetic flux. The niobium ring of 10 µm radius is prepared in a flux state n Φ(0), where Φ(0)=h/2e is the flux quantum and n varying between ±6. An atomic cloud of 250 nK temperature is positioned with a harmonic magnetic trapping potential at ∼18 µm distance below the ring. The inhomogeneous magnetic field of the supercurrent in the ring contributes to the magnetic trapping potential of the cloud. The induced deformation of the magnetic trap impacts the shape of the cloud, the number of trapped atoms, as well as the center-of-mass oscillation frequency of Bose-Einstein condensates. When the field applied during cooldown of the chip is varied, the change of these properties shows discrete steps that quantitatively match flux quantization.

Phase retrapping in a pointlike φ Josephson junction: the butterfly effect.

We consider a φ Josephson junction, which has a bistable zero-voltage state with the stationary phases ψ = ±φ. In the nonzero voltage state the phase "moves" viscously along a tilted periodic double-well potential. When the tilting is reduced quasistatically, the phase is retrapped in one of the potential wells. We study the viscous phase dynamics to determine in which well (-φ or +φ) the phase is retrapped for a given damping, when the junction returns from the finite-voltage state back to the zero-voltage state. In the limit of low damping, the φ Josephson junction exhibits a butterfly effect-extreme sensitivity of the destination well on damping. This leads to an impossibility to predict the destination well.

Reversal mechanism of an individual Ni nanotube simultaneously studied by torque and SQUID magnetometry.

Using an optimally coupled nanometer-scale SQUID, we measure the magnetic flux originating from an individual ferromagnetic Ni nanotube attached to a Si cantilever. At the same time, we detect the nanotube's volume magnetization using torque magnetometry. We observe both the predicted reversible and irreversible reversal processes. A detailed comparison with micromagnetic simulations suggests that vortexlike states are formed in different segments of the individual nanotube. Such stray-field free states are interesting for memory applications and noninvasive sensing.

Guidelines for the management of third and fourth degree perineal tears after vaginal birth from the Austrian Urogynecology Working Group.

The purpose of this guideline is to provide a decision aid for diagnosis, treatment, and follow-up of patients with major perineal tears and thus minimize the risk of persistent symptoms. In 2007, the "Guideline for the management of third and fourth degree perineal tears after vaginal birth" was established by members of the Austrian Urogynecologic Working Group (AUB). The guideline was updated in 2011, including literature published up to 30 November 2011. The DELPHI method was used to reach consensus. Evidence-based and consensus-based statements were defined for epidemiology, risk factors, classification, diagnosis, surgery, and follow-up of major perineal lacerations at vaginal birth.

Immunology in the Clinic Review Series; focus on host responses: T cell responses to herpes simplex viruses.

Herpes virus infections are chronic and co-exist with acquired immune responses that generally prevent severe damage to the host, while allowing periodic shedding of virus and maintenance of its transmission in the community. Herpes simplex viruses type 1 and 2 (HSV-1, HSV-2) are typical in this regard and are representative of the viral subfamily Alphaherpesvirinae, which has a tropism for neuronal and epithelial cells. This review will emphasize recent progress in decoding the physiologically important CD8(+) and CD4(+) T cell responses to HSV in humans. The expanding data set is discussed in the context of the search for an effective HSV vaccine as therapy for existing infections and to prevent new infections.

Experimental evidence of a φ Josephson junction.

We demonstrate experimentally the existence of Josephson junctions having a doubly degenerate ground state with an average Josephson phase ψ=±φ. The value of φ can be chosen by design in the interval 0<φ<π. The junctions used in our experiments are fabricated as 0-π Josephson junctions of moderate normalized length with asymmetric 0 and π regions. We show that (a) these φ Josephson junctions have two critical currents, corresponding to the escape of the phase ψ from -φ and +φ states, (b) the phase ψ can be set to a particular state by tuning an external magnetic field, or (c) by using a proper bias current sweep sequence. The experimental observations are in agreement with previous theoretical predictions.

Josephson junction with a magnetic-field tunable ground state.

We consider an asymmetric 0-π Josephson junction consisting of 0 and π regions of different lengths L(0) and L(π). As predicted earlier this system can be described by an effective sine-Gordon equation for the spatially averaged phase ψ so that the effective current-phase relation of this system includes a negative second harmonic ∝sin(2ψ). If its amplitude is large enough, the ground state of the junction is doubly degenerate ψ=±φ, where φ depends on the amplitudes of the first and second harmonics. We study the behavior of such a junction in an applied magnetic field H and demonstrate that H induces an additional term ∝Hcosψ in the effective current-phase relation. This results in a nontrivial ground state tunable by magnetic field. The dependence of the critical current on H allows for revealing the ground state experimentally.

HLA-DQB1 codon 57 is critical for peptide binding and recognition.

The association of specific HLA-DQ alleles with autoimmunity is correlated with discrete polymorphisms in the HLA-DQ sequence that are localized within sites suitable for peptide recognition. The polymorphism at residue 57 of the DQB1 polypeptide is of particular interest since it may play a major structural role in the formation of a salt bridge structure at one end of the peptide-binding cleft of the DQ molecules. This polymorphism at residue 57 is a recurrent feature of HLA-DQ evolution, occurring in multiple distinct allelic families, which implies a functional selection for maintaining variation at this position in the class II molecule. We directly tested the amino acid polymorphism at this site as a determinant for peptide binding and for antigen-specific T cell stimulation. We found that a single Ala-->Asp amino acid 57 substitution in an HLA-DQ3.2 molecule regulated binding of an HSV-2 VP-16-derived peptide. A complementary single-residue substitution in the peptide abolished its binding to DQ3.2 and converted it to a peptide that can bind to DQ3.1 and DQ3.3 Asp-57-positive MHC molecules. These binding studies were paralleled by specific T cell recognition of the class II-peptide complex, in which the substituted peptide abolished T cell reactivity, which was directed to the DQ3.2-peptide complex, whereas the same T cell clone recognized the substituted peptide presented by DQ3.3, a class II restriction element differing from DQ3.2 only at residue 57. This structural and functional complementarity for residue 57 and a specific peptide residue identifies this interaction as a key controlling determinant of restricted recognition in HLA-DQ-specific immune response.

Coherent terahertz emission of intrinsic Josephson junction stacks in the hot spot regime [corrected].

We report on THz emission measurements and low temperature scanning laser imaging of Bi2Sr2CaCu2O8 intrinsic Josephson junction stacks. Coherent emission is observed at large dc input power, where a hot spot and a standing wave, formed in the "cold" part of the stack, coexist. By changing bias current and bath temperature, the emission frequency can be varied by more than 40%; the variation matches the Josephson-frequency variation with voltage. The linewidth of radiation is much smaller than expected from a purely cavity-induced synchronization. Thus, an additional mechanism seems to play a role. Some scenarios, related to the presence of the hot spot, are discussed.

Magnetic vortex nucleation and annihilation in bi-stable ultra-small ferromagnetic particles.

Vortex-mediated magnetization reversal in individual ultra-small (∼100 nm) ferromagnetic particles at low temperatures is studied by nanoSQUID magnetometry. At zero applied bias field, the flux-closure magnetic state (vortex) and the quasi uniform configuration are bi-stable. This stems from the extremely small size of the nanoparticles that lies very close to the limit of single-domain formation. The analysis of the temperature-dependent (from 0.3 to 70 K) hysteresis of the magnetization allows us to infer the nature of the ground state magnetization configuration. The latter corresponds to a vortex state as also confirmed by electron holography experiments. Based on the simultaneous analysis of the vortex nucleation and annihilation data, we estimate the magnitude of the energy barriers separating the quasi single-domain and the vortex state and their field dependence. For this purpose, we use a modified power-law scaling of the energy barriers as a function of the applied bias field. These studies are essential to test the thermal and temporal stability of flux-closure states stabilized in ultra-small ferromagnets.

Multicenter study of QuantiFERON®-TB Gold Plus in patients with active tuberculosis.

SETTING: QuantiFERON®-TB Gold Plus (QFT-Plus), recently approved for use in the United States, is a new-generation QuantiFERON assay that differs from its predecessors in that it uses an additional antigen tube containing peptides to elicit both CD8+ and CD4+ T-lymphocyte responses. OBJECTIVE: To assess the sensitivity of QFT-Plus compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) in participants with active TB. DESIGN: Adult patients with active TB at three US and two Japanese sites were eligible for this study if they had culture-confirmed TB and were either untreated or had received 14 days of anti-tuberculosis treatment. RESULTS: We enrolled 164 participants, nine of whom had indeterminate results. Excluding indeterminate values, there were 150 QFT-GIT-positive results among 159 tests and 146 QFT-Plus-positive results among 157 tests, with sensitivities of respectively 94.3% (95%CI 89.5-97.4) and 93.02% (95%CI 87.8-96.5%). The estimated sensitivities for the two tests were not significantly different (P = 0.16). Overall test agreement was 98.7%, with a κ statistic of 0.89 (95%CI 0.75-1.00). CONCLUSION: In this multisite study, we found that QFT-Plus had similar sensitivity to QFT-GIT in adult patients with active TB.

Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes.

CD8+ cytotoxic T lymphocytes (CTL) clones with specificity for herpes simplex virus (HSV) were derived from two donors with genital HSV-2 infection. These CTL clones specifically lysed HSV-infected autologous B lymphoblastoid cells, but not HSV-infected fibroblasts. Exogenous peptide loading sensitized both cell types to lysis by an HSV-specific CTL clone of known specificity. HSV infection rendered fibroblasts refractory to peptide sensitization. HSV infection also rendered fibroblasts and keratinocytes insensitive to lysis by allospecific CD8+ CTL clones. Lysis of B lymphoblastoid cells in this system was only slightly reduced by HSV infection. Reduction of fibroblast allospecific lysis was dose and time dependent and was blocked by acyclovir, indicating the involvement of a late HSV gene product. HSV caused a reduction of fibroblast cell surface HLA class I antigen, at least in part due to reduction of synthesis of heavy chain-beta 2 microglobulin heterodimers. These results suggest that HSV-induced blockade of antigen presentation by cutaneous cells to CD8+ CTL may be a mechanism by which HSV limits or evades the immune response of the host.

Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes.

The mechanisms involved in host clearance of symptomatic mucocutaneous herpes simplex virus (HSV) infection are unclear. We studied the functional properties of bulk cultures of skin-infiltrating lymphocytes from normal skin and serial biopsies of recurrent genital HSV-2 lesions, and compared HSV-specific and NK responses with viral clearance. HSV-specific CD4+ or CD8+ T cells were rarely detected in lymphocytes cultured from normal skin. The total lymphocyte count and HSV-specific and NK-like effector cell activities were markedly higher in cultures derived from lesional skin. HSV-specific CD4+ proliferative responses and NK-like cytotoxic responses were present at all stages of herpetic lesions, including biopsies early in the disease course. In contrast, cytotoxic T lymphocyte activity was generally low among cells derived from early culture-positive lesions, and increased during lesion evolution. Viral clearance from the lesion site was associated with a high level of local cytolytic activity towards HSV-infected cells. The phenotypes of cells with HSV-specific cytotoxic responses varied between patients, having CD4+ and CD8+ components. Immunotherapeutic approaches to HSV should be directed at improving in vivo cytolytic activity to HSV.

Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment.

HIV-1-infected patients treated early with combination antiretrovirals respond favorably, but not all maintain viral suppression and improved HIV-specific Th function. To understand if genetic factors contribute to this variation, we prospectively evaluated over 18 months 21 early-treated patients stratified by alleles of class II haplotypes. All seven subjects with the DRB1*13-DQB1*06 haplotype, but only 21% of other subjects, maintained virus suppression at every posttreatment measurement. Following HIV-1 p24 antigen stimulation, PBMCs from patients with this haplotype demonstrated higher mean lymphoproliferation and IFN-gamma secretion than did cells from patients with other haplotypes. Two DRB1*13-restricted Gag epitope regions were identified, a promiscuous one that bound its putative restriction element with nanomolar affinity, and another that mapped to a highly conserved region. These findings suggest that class II molecules, particularly the DRB1*13 haplotype, have an important impact on virologic and immunologic responses. The advantage of the haplotype may relate to selection of key HIV-1 Th1 epitopes in highly conserved regions with avid binding to class II molecules. Eliciting responses to the promiscuous epitope region may be beneficial in vaccine strategies.

A high-resolution combined scanning laser and widefield polarizing microscope for imaging at temperatures from 4 K to 300 K.

Polarized light microscopy, as a contrast-enhancing technique for optically anisotropic materials, is a method well suited for the investigation of a wide variety of effects in solid-state physics, as, for example, birefringence in crystals or the magneto-optical Kerr effect (MOKE). We present a microscopy setup that combines a widefield microscope and a confocal scanning laser microscope with polarization-sensitive detectors. By using a high numerical aperture objective, a spatial resolution of about 240 nm at a wavelength of 405 nm is achieved. The sample is mounted on a 4He continuous flow cryostat providing a temperature range between 4 K and 300 K, and electromagnets are used to apply magnetic fields of up to 800 mT with variable in-plane orientation and 20 mT with out-of-plane orientation. Typical applications of the polarizing microscope are the imaging of the in-plane and out-of-plane magnetization via the longitudinal and polar MOKE, imaging of magnetic flux structures in superconductors covered with a magneto-optical indicator film via the Faraday effect, or imaging of structural features, such as twin-walls in tetragonal SrTiO3. The scanning laser microscope furthermore offers the possibility to gain local information on electric transport properties of a sample by detecting the beam-induced voltage change across a current-biased sample. This combination of magnetic, structural, and electric imaging capabilities makes the microscope a viable tool for research in the fields of oxide electronics, spintronics, magnetism, and superconductivity.