Ferromagnetism and temperature-dependent Electronic Structure of hcp Gadolinium

We use a combination of a many-body model analysis with an ab initio band structure calculation to derive the temperature dependent electronic quasiparticle structure of the rare-earth metal Gadolinium. As a local-moment system Gd is properly represented by the ferromagnetic (multiband) Kondo-lattice model (s-f (d-f) model). The single-particle part of the model-Hamiltonian is taken from an augmented spherical wave (ASW) band calculation. The proposed method avoids the double counting of relevant interactions by exploiting an exact limiting case of the model and takes into account the correct symmetry of atomic orbitals. The a priori only weakly correlated 5d conduction bands get via interband exchange coupling to the localized 4f levels a distinct temperature dependence which explains by a Rudermann-Kittel-Kasuya-Yosida (RKKY) -type mechanism the ferromagnetism of Gd. We get a self-consistently derived Curie temperature of 294.1 K and a T=0-moment of 7.71 $\mu_{\rm B}$, surprisingly close to the experimental values. The striking induced temperature-dependence of the 5d conduction bands explains respective photoemission data. The only parameter of the theory (interband exchange coupling J) is uniquely fixed by the band calculation.Comment: 12 pages, 9 figure

Evidence for multiband superconductivity in the heavy fermion compound UNi2Al3

Epitaxial thin films of the heavy fermion superconductor UNi2Al3 with Tc{max}=0.98K were investigated. The transition temperature Tc depends on the current direction which can be related to superconducting gaps opening at different temperatures. Also the influence of the magnetic ordering at TN=5K on R(T) is strongly anisotropic indicating different coupling between the magnetic moments and itinerant charge carriers on the multi-sheeted Fermi surface. The upper critical field Hc2(T) suggests an unconventional spin-singlet superconducting state.Comment: 4 pages, 6 figures revised version: inset of fig. 2 changed, fig. 3 added accepted for pub. in Phys. Rev. Lett. (estimated 9/04

Synthetic protein scaffolds based on peptide motifs and cognate adaptor domains for improving metabolic productivity

he efficiency of many cellular processes relies on the defined interaction among different proteins within the same metabolic or signaling pathway. Consequently, a spatial colocalization of functionally interacting proteins has frequently emerged during evolution. This concept has been adapted within the synthetic biology community for the purpose of creating artificial scaffolds. A recent advancement of this concept is the use of peptide motifs and their cognate adaptor domains. SH2, SH3, GBD, and PDZ domains have been used most often in research studies to date. The approach has been successfully applied to the synthesis of a variety of target molecules including catechin, D-glucaric acid, H2, hydrochinone, resveratrol, butyrate, gamma-aminobutyric acid, and mevalonate. Increased production levels of up to 77-fold have been observed compared to non-scaffolded systems. A recent extension of this concept is the creation of a covalent linkage between peptide motifs and adaptor domains, which leads to a more stable association of the scaffolded systems and thus bears the potential to further enhance metabolic productivity

Design and Development of a Dynamically Deforming Leading Edge Airfoil for Unsteady Flow Control

ICIASF '97 RECORD, IEEE Publication No. 97CH36121, pp. 132-140.A novel approach to unsteady flow separation and dynamic stall control using a dynamically deforming leading edge airfoil is described. The design details of a carbon-fiber composite skin airfoil having a thickness of 0.002 in. at the leading edge and capable of deforming at 20 Hz in unsteady flow at freestream Mach numbers of up to 0.45, are discussed. Implementation of the scheme at model scales places extraordinary demands on the design, material and fabrication of such an airfoil. Rate scaling further requires very-rapid-response instrumental ion, measurement techniques and data acquisition schemes. The special instrumentation control system developed for these experiments as well as the fluid dynamic results of successful flow control that was achieved using this method, are also discussed.U.S. Army Research Office ARO MIPR 133-94, ARO 32480.11-EGU.S. Army Research Office ARO MIPR 133-94, ARO 32480.11-E

Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies

Next generation sequencing (NGS) can detect carrier status for rare recessive disorders, informing couples about their reproductive risk. The recent ACMG recommendations support offering NGS-based carrier screening (NGS-CS) in an ethnic and population-neutral manner for all genes that have a carrier frequency >1/200 (based on GnomAD). To evaluate current challenges for NGS-CS, we focused on the ciliopathies, a well-studied group of rare recessive disorders. We analyzed 118 ciliopathy genes by whole exome sequencing in ~400 healthy local individuals and ~1000 individuals from the UK1958-birth cohort. We found 20% of healthy individuals (1% of couples) to be carriers of reportable variants in a ciliopathy gene, while 50% (4% of couples) carry variants of uncertain significance (VUS). This large proportion of VUS is partly explained by the limited utility of the ACMG/AMP variant-interpretation criteria in healthy individuals, where phenotypic match or segregation criteria cannot be used. Most missense variants are thus classified as VUS and not reported, which reduces the negative predictive value of the screening test. We show how gene-specific variation patterns and structural protein information can help prioritize variants most likely to be disease-causing, for (future) functional assays. Even when considering only strictly pathogenic variants, the observed carrier frequency is substantially higher than expected based on estimated disease prevalence, challenging the 1/200 carrier frequency cut-off proposed for choice of genes to screen. Given the challenges linked to variant interpretation in healthy individuals and the uncertainties about true carrier frequencies, genetic counseling must clearly disclose these limitations of NGS-CS

MHC class II complexes sample intermediate states along the peptide exchange pathway

The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR- detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII’s ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual’s MHC restricted immune response

A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes

G protein-coupled receptors (GPCRs) are a main drug target and therefore a hot topic in pharmaceutical research. One important prerequisite to understand how a certain ligand affects a GPCR is precise knowledge about its binding mode and the specific underlying interactions. If no crystal structure of the respective complex is available, computational methods can be used to deduce the binding site. One of them are metadynamics simulations which have the advantage of an enhanced sampling compared to conventional molecular dynamics simulations. However, the enhanced sampling of higher-energy states hampers identification of the preferred binding mode. Here, we present a novel protocol based on clustering of multiple walker metadynamics simulations which allows identifying the preferential binding mode from such conformational ensembles. We tested this strategy for three different model systems namely the histamine H1 receptor in combination with its physiological ligand histamine, as well as the β2 adrenoceptor with its agonist adrenaline and its antagonist alprenolol. For all three systems, the proposed protocol was able to reproduce the correct binding mode known from the literature suggesting that the approach can more generally be applied to the prediction of GPCR ligand binding in future

Cardiomyocyte-specific RXFP1 overexpression protects against pressure overload-induced cardiac dysfunction independently of Relaxin

Heart failure (HF) prevalence is rising due to reduced early mortality and demographic change. Relaxin (RLN) mediates protective effects in the cardiovascular system through Relaxin-receptor 1 (RXFP1). Cardiac overexpression of RXFP1 with additional RLN supplementation attenuated HF in the pressure-overload transverse aortic constriction (TAC) model. Here, we hypothesized that robust transgenic RXFP1 overexpression in cardiomyocytes (CM) protects from TAC-induced HF even in the absence of RLN. Hence, transgenic mice with a CM-specific overexpression of human RXFP1 (hRXFP1tg) were generated. Receptor functionality was demonstrated by in vivo hemodynamics, where the administration of RLN induced positive inotropy strictly in hRXFP1tg. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. hRXFP1tg were protected from TAC without additional RLN administration, presenting not only less decline in systolic left ventricular (LV) function but also abrogated LV dilation and pulmonary congestion compared to WT mice. Molecularly, transgenic hearts exhibited not only a significantly attenuated fetal and fibrotic gene activation but also demonstrated less fibrotic tissue and CM hypertrophy in histological sections. These protective effects were evident in both sexes. Similar cardioprotective effects of hRXFP1tg were detectable in a RLN-knockout model, suggesting an alternative mechanism of receptor activation through intrinsic activity, alternative endogenous ligands or crosstalk with other receptors. In summary, CM-specific RXFP1 overexpression provides protection against TAC even in the absence of endogenous RLN. This suggests RXFP1 overexpression as a potential therapeutic approach for HF, offering baseline protection with optional RLN supplementation for specific activation