Noise-resilient edge modes on a chain of superconducting qubits.

Inherent symmetry of a quantum system may protect its otherwise fragile states. Leveraging such protection requires testing its robustness against uncontrolled environmental interactions. Using 47 superconducting qubits, we implement the one-dimensional kicked Ising model, which exhibits nonlocal Majorana edge modes (MEMs) with [Formula: see text] parity symmetry. We find that any multiqubit Pauli operator overlapping with the MEMs exhibits a uniform late-time decay rate comparable to single-qubit relaxation rates, irrespective of its size or composition. This characteristic allows us to accurately reconstruct the exponentially localized spatial profiles of the MEMs. Furthermore, the MEMs are found to be resilient against certain symmetry-breaking noise owing to a prethermalization mechanism. Our work elucidates the complex interplay between noise and symmetry-protected edge modes in a solid-state environment.

Realizing topologically ordered states on a quantum processor.

The discovery of topological order has revised the understanding of quantum matter and provided the theoretical foundation for many quantum error­correcting codes. Realizing topologically ordered states has proven to be challenging in both condensed matter and synthetic quantum systems. We prepared the ground state of the toric code Hamiltonian using an efficient quantum circuit on a superconducting quantum processor. We measured a topological entanglement entropy near the expected value of ­ln2 and simulated anyon interferometry to extract the braiding statistics of the emergent excitations. Furthermore, we investigated key aspects of the surface code, including logical state injection and the decay of the nonlocal order parameter. Our results demonstrate the potential for quantum processors to provide insights into topological quantum matter and quantum error correction.

Accurately computing the electronic properties of a quantum ring.

A promising approach to study condensed-matter systems is to simulate them on an engineered quantum platform1-4. However, the accuracy needed to outperform classical methods has not been achieved so far. Here, using 18 superconducting qubits, we provide an experimental blueprint for an accurate condensed-matter simulator and demonstrate how to investigate fundamental electronic properties. We benchmark the underlying method by reconstructing the single-particle band structure of a one-dimensional wire. We demonstrate nearly complete mitigation of decoherence and readout errors, and measure the energy eigenvalues of this wire with an error of approximately 0.01 rad, whereas typical energy scales are of the order of 1 rad. Insight into the fidelity of this algorithm is gained by highlighting the robust properties of a Fourier transform, including the ability to resolve eigenenergies with a statistical uncertainty of 10-4 rad. We also synthesize magnetic flux and disordered local potentials, which are two key tenets of a condensed-matter system. When sweeping the magnetic flux we observe avoided level crossings in the spectrum, providing a detailed fingerprint of the spatial distribution of local disorder. By combining these methods we reconstruct electronic properties of the eigenstates, observing persistent currents and a strong suppression of conductance with added disorder. Our work describes an accurate method for quantum simulation5,6 and paves the way to study new quantum materials with superconducting qubits.

Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals.

5-Hydroxymethylcytosine (5hmC) is a recently characterized epigenetic mark that is particularly abundant in brain tissue and that regulates gene transcription. We have recently begun to understand the important role of 5hmC in brain development, plasticity and disease, but there are currently little data on 5hmC alterations in psychiatric illnesses. Here we report what we believe to be the first genome-wide analysis of 5hmC in the depressed brain. Using AbaSI sequencing, we investigated 5hmC in the prefrontal cortex of depressed (N=19) and psychiatrically healthy controls (N=19). Consistent with previous global 5hmC analyses in other phenotypes, and likely owing to the inter-individual variability in 5hmC content, the distribution of 5hmC across chromosomes and genomic features was not different between groups. We did, however, find 550 CpGs with suggestive evidence of differential hydroxymethylation. Of these, we validated CpGs in the gene body of myosin XVI (MYO16) and insulin-degrading enzyme using targeted oxidative bisulfite sequencing. Furthermore, the enrichment of 5hmC was also associated with changes in the expression of these two genes in depressed suicides. Together, our results present a novel mechanism linking increased 5hmC to depression and provide a framework for future research in this field.

TACI-Ig prevents the development of airway hyperresponsiveness in a murine model of asthma.

BACKGROUND: Increased levels of serum IgE are associated with greater asthma prevalence and disease severity. IgE depletion using an anti-IgE monoclonal antibody has met with success in the treatment of moderate-to-severe and severe persistent allergic asthma. OBJECTIVE: To test whether B cell-targeted therapy is a more effective treatment for airway hyperresponsiveness (AHR) in a murine model compared with IgE-depletion. METHODS: We delivered soluble mTACI-Ig, a receptor for the B cell survival factors BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), or anti-IgE to allergen-sensitized mice before airway challenge with allergen. RESULTS: mTACI-Ig treatment reduced circulating mature B cell levels in the blood, while anti-IgE treatment had no effect on B cell counts. Both mTACI-Ig and anti-IgE decreased the levels of total and allergen-specific IgE in the serum. Histopathologic analysis of lungs showed a reduction in disease severity scores for both treatment groups, but results were more pronounced in mTACI-Ig-treated mice. Neutrophil and eosinophil numbers in the bronchoalveolar lavage (BAL) were significantly reduced following mTACI-Ig treatment, but not after anti-IgE delivery. BLyS and APRIL blockade also resulted in a significant decrease in IL-4 and eotaxin mRNA and IL-4 and KC protein levels in total lung homogenates and BAL fluid, respectively. Finally, mTACI-Ig treatment was more effective than anti-IgE treatment in reducing AHR to inhaled antigen. CONCLUSIONS: Our data demonstrate that delivery of mTACI-Ig is a more effective treatment than anti-IgE mAb in a murine model of AHR.

TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS.

BLyS and APRIL have similar but distinct biological roles, mediated through two known TNF receptor family members, TACI and BCMA. We show that mice treated with TACI-Ig and TACI-Ig transgenic mice have fewer transitional T2 and mature B cells and reduced levels of circulating immunoglobulin. TACI-Ig treatment inhibits both the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis. In BLyS-deficient mice, B cell development is blocked at the transitional T1 stage such that virtually no mature B cells are present, while B-1 cell numbers are relatively normal. These findings further elucidate the roles of BLyS and APRIL in modulating B cell development and suggest that BLyS is required for the development of most but not all mature B cell populations found in the periphery.

Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.

Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

Rhizobium etli CE3 carries vir gene homologs on a self-transmissible plasmid.

RosR is a transcriptional regulator important for determining cell-surface characteristics and nodulation competitiveness in Rhizobium etli CE3. We identified a 15-kb region that contains genes with similarity to members of the virB, virC, virG, and virE operons of Agrobacterium tumefaciens and demonstrated that RosR directly regulates one operon in this region. These genes were located on plasmid pa of R. etli CE3, which is self-transmissible between R. etli and A. tumefaciens.

TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.

Paraplegia due to ossification of ligamenta flava in X-linked hypophosphatemia. A case report.

STUDY DESIGN: Spinal canal decompression at the most prominent of multiple posterior calcified thoracic lesions in a case of X-linked hypophosphatemia was undertaken for treatment and diagnosis purposes, as well as to assess possible nature of the pathophysiology underlying the presenting deficits. OBJECTIVES: To discuss the clinical assessment diagnostic and treatment aspects of this rare coincidence of ossification of ligamenta flava in the patient with the skeletal deformities of X-linked hypophosphatemia. SUMMARY OF BACKGROUND DATA: The patient with the stigmata and chemical findings of an X-linked hypophosphatemia presented with paraplegia and multiple calcified posterior spinal thoracic lesions. This was studied with magnetic resonance imaging and electrophysiologic studies of the spinal sensory pathways of the legs. These data constituted the preoperative information required to assess later results of surgical intervention. METHODS: Presurgical clinical, imaging and electrophysiologic studies and laboratory and pathologic investigations of the surgical specimens. RESULTS: Resolution of the paraplegia with walking and return to work in a physically demanding job for the last 4 or 5 years of postoperative follow-up after surgical decompression of the spinal cord only at the worst and highest of the effected spinal levels. CONCLUSION: The coincidence of X-linked hypophosphatemia and ossification of ligamenta flava has been reported only in two or three cases in the literature. Removal of the offending ossifying lesion is known to result in resolution of the clinical deficits but similar lesions at other spinal levels are suspected of producing recurrences. The return of function and of the corresponding electrophysiologic correlates indicate a neurono-apractic nature of the neurologic symptoms.

Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase.

The csk gene encodes a nonreceptor protein tyrosine kinase that acts in part by regulating the activity of src-family protein tyrosine kinases. Since the src-family kinases p56lck and p59fyn play pivotal roles during lymphocyte development, it seemed plausible that p50csk might contribute to these regulatory circuits. Using a gene targeting approach, mouse embryonic stem cell lines lacking functional csk genes were generated. These csknull embryonic stem cells proved capable of contributing to many adult tissues, notably heart and brain. However, although csknull progenitors colonized the developing thymus, T and B cell differentiation were both blocked at very early stages. This represented a relatively selective interdiction of lymphocyte maturation, since csknull hematopoietic progenitors supported the development of normal-appearing MAC-1+ blood leukocytes, and the successful maturation of granulocyte/macrophage-colony-forming units from fetal liver progenitors. We conclude that p50csk regulates normal lymphocyte differentiation, but that it almost certainly does so by acting on targets other than p56lck and p59fyn.

Involvement of p21ras distinguishes positive and negative selection in thymocytes.

Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR). To test the importance of p21ras in the control of thymocyte development, we generated mice expressing a dominant-negative p21ras protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter. Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21ras in mediating TCR-derived signals in mature CD4+8- or CD8+4- thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4+8+ thymocytes of mice expressing dominant-negative p21ras. Analysis of thymocyte development in mice made doubly transgenic for the H-Y-specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21H-rasN17. Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes. In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21H-rasN17. These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable.

CD28-mediated costimulation is necessary for optimal proliferation of murine NK cells.

CD28, a cell surface molecule expressed on all murine T cells, plays a critical role in T cell activation. We show here that NK-1.1+ cells, a subpopulation of SCID splenocytes, and IL-2-activated NK cells express CD28, although at lower levels than alpha beta T cells. Optimal proliferation of highly purified asialo GM1+ NK cells from the SCID spleen was observed in response to stimulation with IL-2 and PMA, together with anti-CD28 or L-B7+ cells. Thus, in addition to IL-2, murine NK cells require CD28-mediated costimulatory signals for optimal proliferation. IL-2-activated NK cells produced enhanced levels of IFN-gamma and TNF in response to stimulation with anti-CD28 and PMA. On the other hand, we were unable to demonstrate that CD28 signaling had any effect on NK-mediated cytotoxicity. We conclude that the CD28 costimulatory pathway is functional in NK cells and plays an important role in their proliferation and cytokine production.

Sarcoidosis of the peripheral nervous system.

The clinical and electrophysiologic data of four new patients with sarcoidosis involving the peripheral nerves are presented and the subject is reviewed. Two had a symmetric polyneuropathy and two had polyradiculopathy. These plus the few cases in the literature indicate that the findings on electromyography are most consistent with axonal neuropathy, in a multifocal pattern. Needle electrolyography was more useful than nerve conduction studies in identifying lesions.

T cell receptor-triggered activation of intraepithelial lymphocytes in vitro.

Intraepithelial lymphocytes (IEL) of the mouse small intestine were examined for their potential to respond to TCR signalling in vitro. Purified IEL subsets were activated using mAbs specific for CD3, TCR alpha beta or TCR gamma delta. Thy-1+ IEL, regardless of TCR type, proliferated equally well in response to anti-TCR mAb with or without exogenous IL-2. In contrast, Thy-1- TCR alpha beta, CD8 beta- IEL required exogenous IL-2 for proliferation. No such requirement was observed for Thy-1- TCR gamma delta IEL proliferation. IEL proliferation in the absence of added IL-2 was due to an IL-2 secretion/IL-2 receptor (IL-2R) autocrine pathway, since mAbs specific for IL-2 and IL-2R inhibited IEL proliferation. Thy-1+ CD8 beta- CD4+CD8+ IEL were unresponsive to TCR-induced proliferation but exhibited high levels of cytolytic activity upon TCR-triggering. Thy-1- non-cytolytic IEL were induced to express Thy-1 and cytolytic activity following activation in vitro. In addition, the involvement of the co-stimulatory molecule CD28 in IEL activation was tested. CD28 was weakly expressed by fresh IEL and anti-CD28 mAb had no effect on TCR-triggered proliferation. However, anti-TCR stimulation increased CD28 expression on a subset of TCR alpha beta IEL and the addition of anti-CD28 mAb resulted in increased IL-2 production, but not in increased proliferation. Our results indicate that IEL, including the purported extrathymic CD8 beta- subset, can respond to TCR-driven signals via proliferation and/or cytolytic activity.

Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn.

Considerable evidence supports the hypothesis that the nonreceptor protein tyrosine kinase p59fyn participates in signal transduction from the T cell receptor (TCR). To examine this hypothesis in detail, we have produced mice that lack the thymic isoform of p59fyn but retain expression of the brain isoform of the protein. fynTnull mice exhibit a remarkably specific lymphoid defect: thymocytes are refractile to stimulation through the TCR with mitogen or antigen, while peripheral T cells, following what appears to be a normal maturation sequence, reacquire significant signaling capabilities. These data confirm that p59fynT plays a pivotal role in TCR signal transduction and demonstrate that additional developmentally regulated signaling components also contribute to TCR-induced lymphocyte activation.

Identification and distribution of the costimulatory receptor CD28 in the mouse.

T cell activation requires Ag-specific stimulation mediated by the TCR as well as an additional stimulus provided by Ag presenting cells. On human T cells, it has been shown that antibodies to the Ag CD28 can provide a potent amplification signal for cytokine production and proliferation. Here we describe the production of a mAb to the murine homologue of CD28, and the use of this antibody to examine the function and distribution of CD28 in the mouse. Anti-murine CD28 synergizes with TCR-mediated signals to greatly enhance lymphokine production and proliferation of T cells, and the CD28 signal is not blocked by cyclosporin A. In the peripheral lymphoid organs and in the blood of the mouse, all CD4+ and CD8+ T cells express CD28. In the thymus, CD28 expression is highest on immature CD3-, CD8+ and CD4+8+ cells, and on CD4-8- cells that express alpha beta and tau delta TCR. The level of CD28 on mature CD4+ and CD8+ alpha beta TCR+ thymocytes is two- to fourfold lower than on the immature cells. The potent costimulatory function of CD28 on mature T cells, together with the high level of expression on CD4+8+ thymocytes, suggest that this costimulatory receptor might play an important role in T cell development and activation.

CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.

Occupancy of the T-cell antigen receptor is insufficient to induce T-cell activation optimally; a second co-stimulatory signal is required. Exposure of T-cell clones to complexes of antigen with major histocompatibility complex molecules in the absence of the co-stimulatory signal induces a state of clonal anergy. This requirement for two stimuli for T-cell activation could have an important role in vivo in establishing peripheral tolerance to antigens not encountered in the thymus. The receptor on T cells required for the co-stimulatory stimulus involved in the prevention of anergy has not been identified. The human T-cell antigen CD28 provides a signal that can synergize with T-cell antigen receptor stimulation in activating T cells to proliferate and secrete lymphokines. Here we report that a monoclonal antibody against the murine homologue of CD28 (ref. 7; J.A.G. et al., manuscript in preparation) can provide a co-stimulatory signal to naive CD4+ T cells and to T-cell clones. Moreover, we demonstrate that this co-stimulatory signal can block the induction of anergy in T-cell clones.

Establishing brain death in South Carolina: a clinician's guide.

With recent technological and medical advances, basic cardiopulmonary function can now be prolonged in many patients. Concurrently, organ transplantations have become more common and interest in living wills has increased. As a result, the South Carolina physician is increasingly obligated to determine whether a patient receiving cardiopulmonary support is dead due to irreversible cessation of brain function (ICBF) (brain dead). Here we review the bedside clinical valuation of brain death (ICBF), the adjunctive use of the EEG and other tests, and the South Carolina laws pertaining to this complex decision.