Evidence for a spinon Fermi surface in a triangular-lattice quantum-spin-liquid candidate.

A quantum spin liquid is an exotic quantum state of matter in which spins are highly entangled and remain disordered down to zero temperature. Such a state of matter is potentially relevant to high-temperature superconductivity and quantum-information applications, and experimental identification of a quantum spin liquid state is of fundamental importance for our understanding of quantum matter. Theoretical studies have proposed various quantum-spin-liquid ground states, most of which are characterized by exotic spin excitations with fractional quantum numbers (termed 'spinons'). Here we report neutron scattering measurements of the triangular-lattice antiferromagnet YbMgGaO4 that reveal broad spin excitations covering a wide region of the Brillouin zone. The observed diffusive spin excitation persists at the lowest measured energy and shows a clear upper excitation edge, consistent with the particle-hole excitation of a spinon Fermi surface. Our results therefore point to the existence of a quantum spin liquid state with a spinon Fermi surface in YbMgGaO4, which has a perfect spin-1/2 triangular lattice as in the original proposal of quantum spin liquids.

Multiple Magnetic Bilayers and Unconventional Criticality without Frustration in BaCuSi_{2}O_{6}.

The dimerized quantum magnet BaCuSi_{2}O_{6} was proposed as an example of "dimensional reduction" arising near the magnetic-field-induced quantum critical point (QCP) due to perfect geometrical frustration of its interbilayer interactions. We demonstrate by high-resolution neutron spectroscopy experiments that the effective intrabilayer interactions are ferromagnetic, thereby excluding frustration. We explain the apparent dimensional reduction by establishing the presence of three magnetically inequivalent bilayers, with ratios 3∶2∶1, whose differing interaction parameters create an extra field-temperature scaling regime near the QCP with a nontrivial but nonuniversal exponent. We demonstrate by detailed quantum Monte Carlo simulations that the magnetic interaction parameters we deduce can account for all the measured properties of BaCuSi_{2}O_{6}, opening the way to a quantitative understanding of nonuniversal scaling in any modulated layered system.

HtrA-dependent adherence and invasion of Campylobacter jejuni in human vs avian cells.

The aim of this study was to investigate whether HtrA is responsible for differences in adherence and invasion of Campylobacter jejuni towards human and chicken cell lines. Gentamicin protection assays were performed with either human Caco-2 or chicken 2G4 cells using C. jejuni strain NCTC11168 to compare the adhesion and invasion rates towards these two cell types. The results revealed significant differences in the adhesion and invasion rates between the human and avian cells. Deletion of the Campylobacter htrA gene, coding for the dual function of serine protease and chaperonin with a role in pathogenesis, led to a reduction of the rates in both cell lines. Using a single-amino acid substitution mutant (ΔhtrA/htrAS197A ) that lacked protease activity, but retained chaperonin activity, we show that the first is involved in the invasion of human Caco-2 and chicken 2G4 cells, whereas the latter mutant invaded at lower levels. Adherence towards the chicken cells is higher than towards Caco-2 cells and this is also dependent on HtrA. Together, these data suggest that the proteolytic activity of HtrA is involved in the difference in host response of C. jejuni towards human and chicken-derived cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Campylobacter jejuni is the main cause for bacterial foodborne enterocolitis worldwide. While colonization of the human intestine can lead to severe problems, avian hosts - as the major source of infection - remain unaffected by the bacteria. We showed that the bacterial serine protease and chaperonin HtrA are involved in adhesion and invasion in both species and not responsible for the discrepancy of virulence between the different hosts. In future, HtrA might act as a target for inhibitors to avoid or eradicate colonization in chickens as a less problematic alternative to antibiotics in commercial livestock breeding.

Coexistence of Ferromagnetic and Stripe-Type Antiferromagnetic Spin Fluctuations in YFe_{2}Ge_{2}.

We report neutron scattering measurements of single-crystalline YFe_{2}Ge_{2} in the normal state, which has the same crystal structure as the 122 family of iron pnictide superconductors. YFe_{2}Ge_{2} does not exhibit long-range magnetic order but exhibits strong spin fluctuations. Like the iron pnictides, YFe_{2}Ge_{2} displays anisotropic stripe-type antiferromagnetic spin fluctuations at (π, 0, π). More interesting, however, is the observation of strong spin fluctuations at the in-plane ferromagnetic wave vector (0, 0, π). These ferromagnetic spin fluctuations are isotropic in the (H, K) plane, whose intensity exceeds that of stripe spin fluctuations. Both the ferromagnetic and stripe spin fluctuations remain gapless down to the lowest measured energies. Our results naturally explain the absence of magnetic order in YFe_{2}Ge_{2} and also imply that the ferromagnetic correlations may be a key ingredient for iron-based materials.

Distinct Nature of Static and Dynamic Magnetic Stripes in Cuprate Superconductors.

We present detailed neutron scattering studies of the static and dynamic stripes in an optimally doped high-temperature superconductor, La_{2}CuO_{4+y}. We observe that the dynamic stripes do not disperse towards the static stripes in the limit of vanishing energy transfer. Therefore, the dynamic stripes observed in neutron scattering experiments are not the Goldstone modes associated with the broken symmetry of the simultaneously observed static stripes, and the signals originate from different domains in the sample. These observations support real-space electronic phase separation in the crystal, where the static stripes in one phase are pinned versions of the dynamic stripes in the other, having slightly different periods. Our results explain earlier observations of unusual dispersions in underdoped La_{2-x}Sr_{x}CuO_{4} (x=0.07) and La_{2-x}Ba_{x}CuO_{4} (x=0.095).

Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor.

Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+ imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.

Bound States and Field-Polarized Haldane Modes in a Quantum Spin Ladder.

The challenge of one-dimensional systems is to understand their physics beyond the level of known elementary excitations. By high-resolution neutron spectroscopy in a quantum spin-ladder material, we probe the leading multiparticle excitation by characterizing the two-magnon bound state at zero field. By applying high magnetic fields, we create and select the singlet (longitudinal) and triplet (transverse) excitations of the fully spin-polarized ladder, which have not been observed previously and are close analogs of the modes anticipated in a polarized Haldane chain. Theoretical modeling of the dynamical response demonstrates our complete quantitative understanding of these states.

Positional recurrence maps, a powerful tool to de-correlate static and dynamical disorder in distribution maps from molecular dynamics simulations: the case of Nd2NiO4+d.

In order to investigate the on-site motion of the diffusive species in crystalline solids, we have implemented a code to perform a time-summation of displacements of specific atoms, involving symmetry and adapted projections. The resulting 2D maps have been called 'positional recurrence maps' (PRM). Only displacements are considered, instead of positions, so static deformations are filtered out. In this paper we present the PRM method and show the type of information on the dynamics of selected atoms that can be obtained. We take, as an example, the Nd2NiO4+d system in which we were able to characterize in detail the effects of the dynamical delocalization of the apical oxygen.

Measurement of unique magnetic and superconducting phases in oxygen-doped high-temperature superconductors La(2-x)Sr(x)CuO(4+y).

We present a combined magnetic neutron scattering and muon spin rotation study of the nature of the magnetic and superconducting phases in electronically phase separated La(2-x)Sr(x)CuO(4+y), x=0.04, 0.065, 0.09. For all samples, we find long-range modulated magnetic order below T(N) is approximately equal to Tc=39 K. In sharp contrast to oxygen-stoichiometric La(2-x)Sr(x)CuO(4), we find that the magnetic propagation vector as well as the ordered magnetic moment is independent of Sr content and consistent with that of the "striped" cuprates. Our study provides direct proof that superoxygenation in La(2-x)Sr(x)CuO(4+y) allows the spin stripe ordered phase to emerge and phase separate from superconducting regions with the hallmarks of optimally doped oxygen-stoichiometric La(2-x)Sr(x)CuO(4).

The benefits and risks of stem cell technology.

The potential impact of stem cell technology on medical and dental practice is vast. Stem cell research will not only provide the foundation for future therapies, but also reveal unique insights into basic disease mechanisms. Therefore, an understanding of stem cell technology will be necessary for clinicians in the future. Herein, we give a basic overview of stem cell biology and therapeutics for the practicing clinician.

Heme oxygenase-1 protects against vascular constriction and proliferation.

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.

[Fasanella-Servat procedure for the surgical treatment of acquired ptosis of the upper eyelid]. / Das Fasanella-Servat-Verfahren zur Therapie der erworbenen Ptosis.

PURPOSE: The oculoplastic surgeon may choose between several surgical procedures to treat ptosis of the eyelid. One such potential therapeutic option is the Fasanella-Servat procedure. The purpose of our study was to evaluate the postoperative outcome of the Fasanella-Servat procedure in patients with ptosis of the eyelid with regard to objective and subjective criteria. METHODS: The postoperative success of 20 patients (23 eyelids), 11 female and 9 male, with acquired ptosis of the upper eyelid who underwent the Fasanella-Servat procedure between 1995 and 2004 in an eye tertiary care centre, was evaluated. With regard to the type of ptosis, the pre- and postoperative opening of the eyelid, the levator function, and the symmetry between both eyes were analysed statistically. The patients' subjective satisfaction with the functional and cosmetic postoperative outcome was evaluated by means of a nominal questionnaire (scale 1 - 5). The intraoperatively removed tissue was analysed histopathologically for accessory lacrimal glands or levator muscle. RESULTS: The mean preoperative opening of the eyelid was 7.1 mm (min. 4 mm, max. 10 mm) with a mean levator function of 12.6 mm. Postoperatively, the opening of the eyelid improved significantly to 9.3 mm (min. 7 mm; max. 14 mm), while the levator function remained stable. The preoperative asymmetry between both eyes was significantly decreased. 90 % of the patients were satisfied with the cosmetic and functional results. There were no early and late postoperative complications. No side effects were recorded following treatment. The intraoperatively removed tissue showed no evidence of tissue of accessory lacrimal gland or levator muscle. CONCLUSIONS: The Fasanella-Servat procedure remains an effective procedure in treating mild ptosis with few complications and good cosmetic and functional results.

Anomalous water dynamics in brain: a combined diffusion magnetic resonance imaging and neutron scattering investigation.

Water diffusion is an optimal tool for investigating the architecture of brain tissue on which modern medical diagnostic imaging techniques rely. However, intrinsic tissue heterogeneity causes systematic deviations from pure free-water diffusion behaviour. To date, numerous theoretical and empirical approaches have been proposed to explain the non-Gaussian profile of this process. The aim of this work is to shed light on the physics piloting water diffusion in brain tissue at the micrometre-to-atomic scale. Combined diffusion magnetic resonance imaging and first pioneering neutron scattering experiments on bovine brain tissue have been performed in order to probe diffusion distances up to macromolecular separation. The coexistence of free-like and confined water populations in brain tissue extracted from a bovine right hemisphere has been revealed at the micrometre and atomic scale. The results are relevant for improving the modelling of the physics driving intra- and extracellular water diffusion in brain, with evident benefit for the diffusion magnetic resonance imaging technique, nowadays widely used to diagnose, at the micrometre scale, brain diseases such as ischemia and tumours.

Fractionalized excitations in the partially magnetized spin liquid candidate YbMgGaO4.

Quantum spin liquids (QSLs) are exotic states of matter characterized by emergent gauge structures and fractionalized elementary excitations. The recently discovered triangular lattice antiferromagnet YbMgGaO4 is a promising QSL candidate, and the nature of its ground state is still under debate. Here we use neutron scattering to study the spin excitations in YbMgGaO4 under various magnetic fields. Our data reveal a dispersive spin excitation continuum with clear upper and lower excitation edges under a weak magnetic field (H = 2.5 T). Moreover, a spectral crossing emerges at the Γ point at the Zeeman-split energy. The corresponding redistribution of the spectral weight and its field-dependent evolution are consistent with the theoretical prediction based on the inter-band and intra-band spinon particle-hole excitations associated with the Zeeman-split spinon bands, implying the presence of fractionalized excitations and spinon Fermi surfaces in the partially magnetized QSL state in YbMgGaO4.

9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation.

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.

Adaptins: the final recount.

Adaptins are subunits of adaptor protein (AP) complexes involved in the formation of intracellular transport vesicles and in the selection of cargo for incorporation into the vesicles. In this article, we report the results of a survey for adaptins from sequenced genomes including those of man, mouse, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, the plant Arabidopsis thaliana, and the yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. We find that humans, mice, and Arabidopsis thaliana have four AP complexes (AP-1, AP-2, AP-3, and AP-4), whereas D. melanogaster, C. elegans, S. cerevisiae, and S. pombe have only three (AP-1, AP-2, and AP-3). Additional diversification of AP complexes arises from the existence of adaptin isoforms encoded by distinct genes or resulting from alternative splicing of mRNAs. We complete the assignment of adaptins to AP complexes and provide information on the chromosomal localization, exon-intron structure, and pseudogenes for the different adaptins. In addition, we discuss the structural and evolutionary relationships of the adaptins and the genetic analyses of their function. Finally, we extend our survey to adaptin-related proteins such as the GGAs and stonins, which contain domains homologous to the adaptins.

Avenacin Production in Creeping Bentgrass (Agrostis stolonifera) and Its Influence on the Host Range of Gaeumannomyces graminis.

Avenacinase activity has been shown to be a key factor determining the host range of Gaeumannomyces graminis on oats (Avena sativa). G. graminis var. avenae produces avenacinase, which detoxifies the oat root saponin avenacin, enabling it to infect oats. G. graminis var. tritici does not produce avenacinase and is unable to infect oats. G. graminis var. avenae is also reported to incite take-all patch on creeping bentgrass (Agrostis stolonifera). It is unknown whether creeping bentgrass produces avenacin and if the avenacin-avenacinase interaction influences G. graminis pathogenicity on creeping bentgrass. The root extracts of six creeping bentgrass cultivars were analyzed by fluorimetry, thin-layer chromatography, and high performance liquid chromatography for avenacin content. Avenacin was not detected in any creeping bentgrass cultivars, and pathogenicity assays confirmed that both G. graminis var. avenae and G. graminis var. tritici can infect creeping bentgrass and wheat (Triticum aestivum), but only G. graminis var. avenae incited disease on oats. These results are consistent with the root analyses and confirm that avenacinase activity is not required for creeping bentgrass infection by G. graminis.

A novel retinoic acid receptor-selective retinoid, ALRT1550, has potent antitumor activity against human oral squamous carcinoma xenografts in nude mice.

We have identified a novel retinoid, ALRT1550, that potently and selectively activates retinoic acid receptors (RARs). ALRT1550 binds RARs with Kd values of approximately equal to 1-4 nM, and retinoid X receptors with low affinities (Kd approximately equal to 270-556 nM). We studied the effects of ALRT1550 on cellular proliferation in squamous carcinoma cells. ALRT1550 inhibited in vitro proliferation of UMSCC-22B cells in a concentration-dependent manner with an IC50 value of 0.22 +/- 0.1 (SE) nM. 9-cis-Retinoic acid (ALRT1057), a pan agonist retinoid that activates RARs and retinoid X receptors, inhibited proliferation with an IC50 value of 81 +/- 29 nM. In vivo, as tumor xenografts in nude mice, UMSCC-22B formed well-differentiated squamous carcinomas, and oral administration (daily, 5 days/week) of ALRT1550, begun 3 days after implanting tumor cells, inhibited tumor growth by up to 89% in a dose-dependent manner over the range of 3-75 micrograms/kg. ALRT1550 (30 micrograms/kg) also inhibited growth of established tumors by 72 +/- 3% when tumors were allowed to grow to approximately equal to 100 mm3 before dosing began. In comparison, 9-cis retinoic acid at 30 mg/kg inhibited growth of established tumors by 73 +/- 5%. Interestingly, retinoids did not appear to alter tumor morphologies in UMSCC-22B tumors. Notably, ALRT1550 produced a therapeutic index of approximately equal to 17 in this model, indicating a separation between doses that inhibited tumor growth and that induced symptoms of hypervitaminosis A. In summary, ALRT1550 potently inhibits cellular proliferation in vitro and in vivo in this squamous cell carcinoma tumor model. These data support additional study of ALRT1550 for its potential for improving anticancer therapy in human clinical trials.

Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity.

BACKGROUND AND PURPOSE: Sphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases. EXPERIMENTAL APPROACH: The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6-trinitrobenzenesulfonic acid colitis and CD4(+) CD45RB(hi) T cell adoptive transfer colitis) was assessed. KEY RESULTS: RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models. CONCLUSIONS AND IMPLICATIONS: S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.