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

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

Loss of the mechanotransducer zyxin promotes a synthetic phenotype of vascular smooth muscle cells.

BACKGROUND: Exposure of vascular smooth muscle cells (VSMCs) to excessive cyclic stretch such as in hypertension causes a shift in their phenotype. The focal adhesion protein zyxin can transduce such biomechanical stimuli to the nucleus of both endothelial cells and VSMCs, albeit with different thresholds and kinetics. However, there is no distinct vascular phenotype in young zyxin-deficient mice, possibly due to functional redundancy among other gene products belonging to the zyxin family. Analyzing zyxin function in VSMCs at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin-dependent changes in gene expression in VSMCs exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype. METHODS AND RESULTS: DNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery-derived and mouse aortic VSMCs. Zyxin-null VSMCs showed a remarkable shift to a growth-promoting, less apoptotic, promigratory and poorly contractile phenotype with ≈90% of the stretch-responsive genes being zyxin dependent. Interestingly, zyxin-null cells already seemed primed for such a synthetic phenotype, with mechanical stretch further accentuating it. This could be accounted for by higher RhoA activity and myocardin-related transcription factor-A mainly localized to the nucleus of zyxin-null VSMCs, and a condensed and localized accumulation of F-actin upon stretch. CONCLUSIONS: At the cellular level, zyxin is a key regulator of stretch-induced gene expression. Loss of zyxin drives VSMCs toward a synthetic phenotype, a process further consolidated by exaggerated stretch

Disruption of the N-alpha-Acetyltransferase NatB Causes Sensitivity to Reductive Stress in Arabidopsis thaliana

In Arabidopsis thaliana, the evolutionary conserved N-terminal acetyltransferase (Nat) complexes NatA and NatB co-translationally acetylate 60% of the proteome. Both have recently been implicated in the regulation of plant stress responses. While NatA mediates drought tolerance, NatB is required for pathogen resistance and the adaptation to high salinity and high osmolarity. Salt and osmotic stress impair protein folding and result in the accumulation of misfolded proteins in the endoplasmic reticulum (ER). The ER-membrane resident E3 ubiquitin ligase DOA10 targets misfolded proteins for degradation during ER stress and is conserved among eukaryotes. In yeast, DOA10 recognizes conditional degradation signals (Ac/N-degrons) created by NatA and NatB. Assuming that this mechanism is preserved in plants, the lack of Ac/N-degrons required for efficient removal of misfolded proteins might explain the sensitivity of NatB mutants to protein harming conditions. In this study, we investigate the response of NatB mutants to dithiothreitol (DTT) and tunicamycin (TM)-induced ER stress. We report that NatB mutants are hypersensitive to DTT but not TM, suggesting that the DTT hypersensitivity is caused by an over-reduction of the cytosol rather than an accumulation of unfolded proteins in the ER. In line with this hypothesis, the cytosol of NatB depleted plants is constitutively over-reduced and a global transcriptome analysis reveals that their reductive stress response is permanently activated. Moreover, we demonstrate that doa10 mutants are susceptible to neither DTT nor TM, ruling out a substantial role of DOA10 in ER-associated protein degradation (ERAD) in plants. Contrary to previous findings in yeast, our data indicate that N-terminal acetylation (NTA) does not inhibit ER targeting of a substantial amount of proteins in plants. In summary, we provide further evidence that NatB-mediated imprinting of the proteome is vital for the response to protein harming stress and rule out DOA10 as the sole recognin for substrates in the plant ERAD pathway, leaving the role of DOA10 in plants ambiguous

Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

Molecular switches are essential modules in signaling networksand transcriptional reprogramming. Here, we describe a role forsmall ubiquitin-related modifier SUMO as a molecular switch inepidermal growth factor receptor (EGFR) signaling. Using quantita-tive mass spectrometry, we compare the endogenous SUMOproteomes of HeLa cells before and after EGF stimulation. Thereby,we identify a small group of transcriptional coregulators includingIRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling.Comparison of cells expressing wild type or SUMOylation-deficientIRF2BP1indicates that transient deSUMOylation of IRF2BP proteinsis important for appropriate expression of immediate early genesincludingdual specificity phosphatase1(DUSP1, MKP-1) and thetranscription factor ATF3. We find that IRF2BP1is a repressor,whose transient deSUMOylation on the DUSP1promoter allows—and whose timely reSUMOylation restricts—DUSP1transcription.Our work thus provides a paradigm how comparative SUMOproteome analyses serve to reveal novel regulators in signal trans-duction and transcription