Extreme mobility enhancement of two-dimensional electron gases at oxide interfaces by charge-transfer-induced modulation doping.

Two-dimensional electron gases (2DEGs) formed at the interface of insulating complex oxides promise the development of all-oxide electronic devices. These 2DEGs involve many-body interactions that give rise to a variety of physical phenomena such as superconductivity, magnetism, tunable metal-insulator transitions and phase separation. Increasing the mobility of the 2DEG, however, remains a major challenge. Here, we show that the electron mobility is enhanced by more than two orders of magnitude by inserting a single-unit-cell insulating layer of polar La(1-x)Sr(x)MnO3 (x = 0, 1/8, and 1/3) at the interface between disordered LaAlO3 and crystalline SrTiO3 produced at room temperature. Resonant X-ray spectroscopy and transmission electron microscopy show that the manganite layer undergoes unambiguous electronic reconstruction, leading to modulation doping of such atomically engineered complex oxide heterointerfaces. At low temperatures, the modulation-doped 2DEG exhibits Shubnikov-de Haas oscillations and fingerprints of the quantum Hall effect, demonstrating unprecedented high mobility and low electron density.

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).

Structure and magnetic properties of Cu3Ni2SbO6 and Cu3Co2SbO6 Delafossites with honeycomb lattices.

The crystal structures of two Delafossites, Cu3Ni2SbO6 and Cu3Co2SbO6, are determined by high-resolution synchrotron powder X-ray diffraction. The Ni and Co are ordered with respect to Sb in the layer of edge sharing octahedra, forming magnetic layers with honeycomb geometry. High-resolution electron microscopy confirms ordering, and selected-area electron diffraction patterns identify examples of the stacking polytypes. Low temperature synthetic treatments result in disordered stacking of the layers, but heating just below their melting points results in nearly fully ordered stacking variants. The major variant in both cases is a monoclinic distortion of a 6-layer Delafossite polytype, but a significant amount of a 2-layer polytype is also present for the Ni case. The antiferromagnetic ordering with transitions, at 22.3 and 18.5 K for Ni and Co variants, respectively, is investigated by temperature and field dependent magnetization, as well as specific heat. The sharp magnetic transitions support the presence of well developed 2:1 ordering of the Co:Sb or Ni:Sb ions in the honeycomb layers. Neutron diffraction measurements at 4 K are used to determine the magnetic structures. For both the Ni and Co phases, the propagation vector is k = [100], and can be described as alternating ferromagnetic chains in the metal-oxide plane giving an overall antiferromagntic "zigzag" alignment. While orientation of the magnetic moments of the Co is along the b-axis, the Ni moments are in the ac plane, approximately parallel to the stacking direction. Bulk magnetization properties are discussed in terms of their magnetic structures.

Quantum spin liquid in frustrated one-dimensional LiCuSbO4.

A quantum magnet, LiCuSbO4, with chains of edge-sharing spin-1/2 CuO6 octahedra is reported. While short-range order is observed for T<10 K, no zero-field phase transition or spin freezing occurs down to 100 mK. Specific heat indicates a distinct high-field phase near the 12 T saturation field. Neutron scattering shows incommensurate spin correlations with q=(0.47±0.01)π/a and places an upper limit of 70 µeV on any spin gap. Exact diagonalization of 16-spin easy-plane spin-1/2 chains with competing ferro- and antiferromagnetic interactions (J1=-75 K, J2=34 K) accounts for the T>2 K data.

Spin ½ Delafossite honeycomb compound Cu5SbO6.

Cu(5)SbO(6) is found to have a monoclinic, Delafossite-derived structure consisting of alternating layers of O-Cu(I)-O sticks and magnetic layers of Jahn-Teller distorted Cu(II)O(6) octahedra in an edge sharing honeycomb arrangement with Sb(V)O(6) octahedra. This yields the structural formula Cu(I)(3)Cu(II)(2)Sb(V)O(6). Variants with ordered and disordered layer stacking are observed, depending on the synthesis conditions. The spin ½ Cu(2+) ions form dimers in the honeycomb layer. The magnetic susceptibility measured between 5 and 300 K is characteristic of the presence of a singlet-triplet spin gap of 189 K. High resolution synchrotron X-ray diffraction studies indicate that changes in the intra- or interdimer distances between 300 and 20 K, such as might indicate an increase in strength of the Peierls-like distortion through the spin gap temperature, if present, are very small. A comparison to the NaFeO(2)-type Cu(2+) honeycomb compounds Na(3)Cu(2)SbO(6) and Na(2)Cu(2)TeO(6) is presented.

"Pure" severe aortic stenosis without concomitant valvular heart diseases: echocardiographic and pathophysiological features.

PURPOSE: In echocardiography the severity of aortic stenosis (AS) is defined by effective orifice area (EOA), mean pressure gradient (mPGAV) and transvalvular flow velocity (maxVAV). The hypothesis of the present study was to confirm the pathophysiological presence of combined left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and pulmonary artery hypertension (PAH) in patients with "pure" severe AS. METHODS AND RESULTS: Patients (n = 306) with asymptomatic (n = 133) and symptomatic (n = 173) "pure" severe AS (mean age 78 ± 9.5 years) defined by indexed EOA < 0.6 cm2 were enrolled between 2014 and 2016. AS patients were divided into 4 subgroups according to mPGAV and indexed left ventricular stroke volume: low flow (LF) low gradient (LG)-AS (n = 133), normal flow (NF) LG-AS (n = 91), LF high gradient (HG)-AS (n = 21) and NFHG-AS (n = 61). Patients with "pure" severe AS showed mean mPGAV of 31.7 ± 9.1 mmHg and mean maxVAV of 3.8 ± 0.6 m/s. Only 131 of 306 patients (43%) exhibited mPGAV > 40 mmHg and maxVAV > 4 m/s documenting incongruencies of the AS severity assessment by Doppler echocardiography. LVH was documented in 81%, DD in 76% and PAH in 80% of AS patients. 54% of "pure" AS patients exhibited all three alterations. Ranges of mPGAV and maxVAV were higher in patients with all three alterations compared to patients with less than three. 224 (73%) patients presented LG-conditions and 82 (27%) HG-conditions. LVH was predominant in NF-AS (p = 0.014) and PAH in LFHG-AS (p = 0.014). Patients' treatment was retrospectively assessed (surgery: n = 100, TAVI: n = 48, optimal medical treatment: n = 156). CONCLUSION: In patients with "pure" AS according to current guidelines the presence of combined LVH, DD and PAH as accepted pathophysiological sequelae of severe AS cannot be confirmed. Probably, the detection of these secondary cardiac alterations might improve the diagnostic algorithm to avoid overestimation of AS severity.

Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism.

OBJECTIVE: Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels. DESIGN: Cross-sectional study. Out-patient clinic. PATIENTS: We investigated 25 unselected patients with KS, recruited from endocrine and fertility clinics. Twenty-five age-matched males served as controls. MEASUREMENTS: Left ventricular systolic long axis function (velocities and strain rate) assessed by tissue Doppler echocardiography related to free testosterone, fasting values of plasma glucose, insulin, homeostasis model assessment (HOMA)-index, cholesterol and triglycerides in addition to dual energy X-ray absorptiometry (DEXA) scan derived assessment of truncal body fat. RESULTS: The long axis function was significantly reduced in patients with KS (peak systolic velocities 4.4 +/- 1.3 vs. 5.3 +/- 1.0 cm/s, P < 0.01 and strain rate -1.3 +/- 0.3 vs.-1.6 +/- 0.3 s(-1), P < 0.01). However, the ventricular dysfunction was mainly attributed KS patients with metabolic syndrome. The peak systolic velocities were significantly correlated to truncal body fat (r = -0.72, P < 0.01) and free testosterone (r = 0.63, P < 0.01), but uncorrelated to plasma glucose, insulin and HOMA-index. CONCLUSION: Systolic long axis function is decreased in patients with KS and metabolic syndrome. The decrease in myocardial systolic function was significantly related to truncal body fat and hypogonadism, but not correlated to insulin sensitivity.

High pulse pressure is not associated with abnormal activation of the renin-angiotensin-aldosterone system in repaired aortic coarctation.

We investigated the relationship between pulse pressure (PP)--a surrogate marker of arterial stiffness-and activity of the renin-angiotensin-aldosterone system (RAAS) in adult patients with repaired coarctation and normal left ventricular (LV) function. A total of 114 patients (44 (26-74) years, 13 (0.1-40) years at repair) and 20 healthy controls were examined with 24-h ambulatory blood pressure monitoring, echocardiography, vasoactive hormone levels and magnetic resonance of the thoracic aorta. Forty-one patients (36%) were taking antihypertensives (28 RAAS inhibitors). Fifty-one had mean 24-h blood pressures >130/80 mm Hg. Hypertension was not associated with age at repair (P=0.257). Patients had higher PP and LV mass compared with controls (52±11 vs. 45±5 mm Hg and 221±71 vs. 154±55 g, respectively; both P<0.05). Differences were more pronounced in the presence of recoarctation, but independently of RAA levels. Even normotensive patients had higher LV mass than controls. LV mass and recoarctation were correlated with PP levels. In conclusion, adult patients with repaired coarctation have increased PP and LV mass compared with controls. PP increased with increasing recoarctation. Hypertension was present also in the absence of recoarctation. These changes could not be explained by abnormal activation of the RAAS.

Empirical parameterization of a model for predicting peptide helix/coil equilibrium populations.

A modification of the Lifson-Roig formulation of helix/coil transitions is presented; it (1) incorporates end-capping and coulombic (salt bridges, hydrogen bonding, and side-chain interactions with charged termini and the helix dipole) effects, (2) helix-stabilizing hydrophobic clustering, (3) allows for different inherent termination probabilities of individual residues, and (4) differentiates helix elongation in the first versus subsequent turns of a helix. Each residue is characterized by six parameters governing helix formation. The formulation of the conditional probability of helix initiation and termination that we developed is essentially the same as one presented previously (Shalongo W, Stellwagen, E. 1995. Protein Sci 4:1161-1166) and nearly the mathematical equivalent of the new capping formulation incorporated in the model presented by Rohl et al. (1996. Protein Sci 5:2623-2637). Side-chain/side-chain interactions are, in most cases, incorporated as context dependent modifications of propagation rather than nucleation parameters. An alternative procedure for converting [theta]221 values to experimental fractional helicities () is presented. Tests of the program predictions suggest this method may have some advantages both for designed peptides and for the analysis of secondary structure preferences that could drive the formation of molten-globule intermediates on protein folding pathways. The model predicts the fractional helicity of 385 peptides with a root-mean-square deviation (RMSD) of 0.050 and locates (with precise definition of the termini in many cases) helices in proteins as well as competing methods. The propagation and nucleation parameters were derived from NMR data and from the CD data for a 79 peptide "learning set" for which an excellent fit resulted (RMSD = 0.0295). The current set of parameter corrections for capping boxes, helix dipole interactions, and side-chain/side-chain interactions (coulombic, hydrogen bonding and hydrophobic clustering), although still under development provide a significant improvement in both helix/coil equilibrium prediction for peptides and helix location in protein sequences. This is clearly evident in the rms deviations between CD measures and calculated values of fractional helicity for different classes of peptides before and after applying the corrections: for peptides lacking capping boxes and i/i + 3 and i/i + 4 side-chain/side-chain interactions RMSD = 0.044 (n = 164) versus RMSD = 0.054 (0.172 without the corrections, n = 221) for peptides that required context-dependent corrections of the parameters. If we restrict the analysis to N-acylated peptides with helix stabilizing side-chain/side-chain interactions (including N-capping boxes), the degree to which our corrections account for the stabilizing interaction can be judged from the change in helicity underestimation, (calc-CD): -0.15 +/- 0.10, which is reduced to -0.018 +/- 0.048 (n = 191) upon applying the corrections.

Efforts toward deriving the CD spectrum of a 3(10) helix in aqueous medium.

There have been two recent reports suggesting that 3(10) helices can be distinguished from alpha helices by circular dichroism. The differentiating feature is stated to be a [theta]222:[theta]208 ratio (R2) distinctly smaller than unity. This has been reported for a C(alpha)alpha'-disubstituted homooctamer [Toniolo et al. (1996), J. Am. Chem. Soc. 118, 2744-2745] and for alanine-rich systems of 16-21 residue length with modest fractional helicity [Millhauser (1995) Biochemistry 34, 3873-3877]. We report here the changes in the CD spectrum produced by inserting aminoisobutyric acid (Aib) residues into the helical domain of human pancreatic amylin. In order to examine this effect at comparable net fractional helicities, CD spectra were measured for each species during the course of a helicity titration by trifluoroethanol addition. The addition of five Aib residues gave results of particular interest. At low net fractional helicity, this Aib-rich system displays a diminished pi-->pi* (circa 208 nm) rotational strength versus the less Aib-rich species. However, NMR data and comparisons of CD difference spectra suggest that fluoroalcohol-induced extension of the short Aib-rich helix is in the form of an alpha helix. Given the diminished intensity of the minimum at 208 nm at low net helicity when 3(10) conformations should contribute, we urge extreme caution in using a [theta]222:[theta]208 ratio smaller than unity as a diagnostic for 3(10) helices.

Does the solid-state structure of endothelin-1 provide insights concerning the solution-state conformational equilibrium?

Additional NMR data (local NOE ratios and chemical shifts) for endothelin-1 supporting the existence of a relatively regular helix initiated abruptly at Lys9 (with Asp8 as an N-cap) and extending in all cases to Cys15 (and in a frayed form to Asp18 in some analogs) is presented. The recent solids-state structure [Janes et al. (1994), Nature Struct. Biol. 1, 311-319], in contrast, places the helix in the extreme C-terminal section of structure and the Lys9-Tyr13 segment is not helical. The X-ray structure does not predict the NOEs or chemical shifts observed for endothelins in aqueous media containing polar organic co-solvents. An analysis of the chemical shift data for reporter groups indicates that the helical conformational preference of endothelins is not significantly altered by the addition of acetonitrile, acetic acid, or ethylene glycol. The validity of the analytic strategy is supported by results for both more rigid and less helical analogs. We conclude that the structure observed in crystals obtained from purely aqueous media is influenced by intermolecular interactions in the solid state and is not a significant contributor to the conformational equilibrium observed for monomeric ET-1.

Conformation of endothelin in aqueous ethylene glycol determined by 1H-NMR and molecular dynamics simulations.

The solution conformation of a 21-residue vasoconstrictor peptide endothelin-1 (ET-1) in water-ethylene glycol has been determined by two-dimensional 1H-NMR spectroscopy and constrained molecular dynamics simulations. The N-terminus (residues 1-4) appears to undergo conformational averaging and no single structure consistent with the NMR constraints could be found for this region. Residues 5-8 form a turn, and residues 9-16 exist in a helical conformation. A flexible 'hinge' between residues 8-9 allows various orientations of the turn relative to the helix. Another 'hinge' at residue 17 connects the extended C-terminus to the bicyclic core region (residues 1-15). Residues important for binding and biological activity form a contiguous surface on one side of the helix, with the two disulfides extending from the other side of the helix.

Solution conformation of a cyclic pentapeptide endothelin antagonist. Comparison of structures obtained from constrained dynamics and conformational search.

The structure of a cyclic pentapeptide, cyclo-(D-Trp-D-Asp-L-Pro-D-Val-L-Leu), that has high selectively for the endothelin ETA receptor has been determined by NMR spectroscopy using constrained molecular dynamics and conformational search procedures. Structures obtained using two methods of refinement, namely (i) constrained molecular dynamics; and (ii) systematic searches of conformational space for optimal satisfaction of distance constraints, were compared to those obtained from systematic searches of conformational space without NMR data. The two different procedures of refinement produce similar conformations that are consistent with the NMR distance constraints. Conformational searches for optimal energy without any NMR distance constraints produced several low-energy structures, two of which have essentially the same backbone as those structures derived from distance-constrained procedures and one of these even reproduces several side-chain positions well. The pentapeptide backbone consists of a linked gamma- and beta-turn conformation, with the leucine and tryptophan as corner residues of the type II beta-turn. The side chains are highly ordered both in aqueous solvent and in dimethyl sulfoxide. In aqueous media the leucine side chain is directed towards the indole ring, presumably to reduce the non-polar surface exposure, producing unusual upfield shifts for the methyls (and particularly H gamma). This structural feature was reproduced in one of the structures obtained from conformational searches performed without NMR data. Exhaustive conformational searches appear to provide an alternative method for structure generation for cyclic peptides.

Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications.

OBJECTIVE: Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Plasma levels of OPG seem to be elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. The aim of the present study was to examine the association between plasma OPG levels and microvascular complications and glycemic control in patients with type 2 diabetes. DESIGN AND METHODS: Four groups of 20 subjects in each, individually matched for age and gender, were included in the study: (i) subjects with normal glucose tolerance (NGT); (ii) subjects with impaired glucose tolerance (IGT); (iii) type 2 diabetic patients without retinopathy; and (iv) type 2 diabetic patients with diabetic maculopathy (DMa). Plasma concentration of OPG was measured in duplicate by a sandwich ELISA method. Furthermore, fundus photography, flourescein angiography, and measurements of urinary albumin excretion rate (RIA) were performed. RESULTS: Plasma OPG was significantly higher in diabetic (iii+iv) than in NGT (i) subjects (3.04+/-0.15 vs 2.54+/-0.16 ng/ml, P<0.05). Plasma OPG was significantly higher in the DMa (iv) group than in the NGT (i) group (3.25+/-0.23 vs 2.54+/-0.16 ng/ml, P=0.01). Moreover, plasma OPG was significantly higher (3.61+/-0.36 ng/ml) in the group of diabetic subjects with both microalbuminuria and DMa (n=7) than in the NGT (i) (2.54+/-0.16 ng/ml, P<0.01), IGT (ii) (2.82+/-0.21 ng/ml, P<0.05), and no retinopathy (iii) groups (2.83+/-0.20 ng/ml, P<0.05). CONCLUSIONS: We found increased levels of OPG in plasma from diabetic patients with microvascular complications. This finding indicates that OPG may be involved in the development of vascular dysfunction in diabetes [corrected].

The single prostacyclin receptor of gel-filtered platelets provides a correlation with antiaggregatory potency of PGI2 mimics.

Gel-filtered human platelets (GFP) display only a single binding site for [3H]-PGI2: KD = 61nM, 234 fmol/10(8) platelets (1410 sites/platelet). Platelet-rich plasma (PRP) displays the same receptor density but the KD value increases to 123 nM due to protein binding of PGI2 which lowers its effective concentration. The [3H]-PGI2/GFP binding assay has been used to evaluate the molecular basis of aggregation inhibition for prostacyclin analogs and mimics, three PGE type structures, and PGD2. Antiaggregatory IC50s and radioligand binding IC50s correlate for PGE2, E1, and six PGI2 analogs. PGD2, and to a lesser extent 6-oxo-PGE1, display greater antiaggregatory potency than expected based on PGI2-binding site affinity data.

1H-n.m.r. analysis of glycolipids possessing mono- and multi-meric X and Y haptens: characterization of two novel extended Y structures from human adenocarcinoma.

Analysis of glycolipids having repeating core-structures of type 2 chains ([Gal beta 1----4GlcNAc beta 1----3]nGal beta 1----4Glc beta 1----1Cer) by 1- and 2-dimensional high resolution 1H-n.m.r. spectroscopy shows that fucosylation alpha 1----3 to GlcNAc with or without fucosylation alpha 1----2 to Gal produces predictable chemical shifts of anomeric protons and systematic, glycosylation-induced shift changes. These effects were analyzed for a series of glycolipids of known structure bearing mono- and multimeric X [Gal beta 1----4(Fuc alpha 1----3)GlcNAc beta 1----3] and Y [Fuc alpha 1----2Gal beta 1----4-(Fuc alpha 1----3)GlcNAc beta 1----3] determinants, and were subsequently used to elucidate the primary saccharide structure of two novel glycolipids isolated from human liver adenocarcinoma. They are proposed to be Y determinants carried on a norhexaosylceramide core, with the following structures: (Formula: see text).

1H-n.m.r. analysis of type-2 chain lacto-gangliosides. Confirmation of structure of a novel cancer-associated fucoganglioside, alpha-NeuAc-(2----6)- beta-D-Galp-(1----4)-beta-D-GlcpNAc-(1----3)-beta-D-Galp-(1----4)-[alp ha-L- Fucp-(1----3)]-beta-D-GlcpNAc-(1----3)-beta-D-Galp-(1----4)-beta -D-Glc p- (1----1)-Cer (VI6NeuAcIII3FucnLc6Cer).

Neolacto-glycosphingolipids, substituted with alpha-NeuAc-(2----3)- and -(2----6)-linked D-Galp residues were analyzed by one- and two-dimensional 1H-n.m.r. spectroscopy at 500 MHz in 49:1 (v/v) di(2H3)methyl sulfoxide-deuterium oxide solution. For the simplest structures analyzed, nLc4Cer, IV3NeuAcnLc4Cer, and IV6NeuAcnLc4Cer, sialosylation-induced changes in shifts of terminal and subterminal core residues were interpretable in terms of existing conformational models. Chemical shifts for H-3e and H-3a of NeuAc characteristic for the type of linkage, were also determined. In addition, regularly reproducible shifts were seen for H-1 and other resonances of terminal and subterminal core residues of all structures tested. Chemical-shift correlations proved to be useful in elucidating the structure of a unique ganglioside bearing an internal beta-D-Galp-(1----4)-[alpha-L-Fucp-(1----3)]-beta-D-GlcpNAc-(1---- 3) residue ("X-trisaccharide") with an alpha-NeuAc-(2----6)-substituted terminal group.

Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. II. Structure elucidation.

Fermentation of Dactylosporangium sp. (ATCC 53693) produces a mixture of tetracycline derivatives from which several related tetracycline glycosides, the dactylocyclines, were isolated and their structures determined. The most abundant glycoside in initial fermentations was found to be dactylocycline A. Each glycoside proved to be acid sensitive and readily hydrolyzed to a common aglycone, dactylocyclinone. While the aglycone was cross resistant with tetracycline, the dactylocyclines proved active against certain tetracycline-resistant organisms.

Peritonsillar abscess: risk of disease in the remaining tonsil after unilateral tonsillectomy à chaud.

The occurrence of disease in the remaining tonsil after unilateral tonsillectomy à chaud in the treatment of peritonsillar abscess, was studied in 536 patients. No patient had a history of previous severe tonsillitis at the time of the unilateral tonsillectomy, 6.1 per cent of the patients were readmitted for surgery of the remaining tonsil during the follow-up period. Ninety-seven per cent of these patients were younger than 30 years of age. Previous investigations have shown increasing frequency by age of pharyngitis after bilateral tonsillectomy. We suggest bilateral tonsillectomy in all cases of patients younger than 30 years old who suffer from peritonsillar abscess irrespective of previous tonsillar disease. Patients older than 30 should be treated with unilateral ablation, unless there is a clear indication for bilateral tonsillectomy.