One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition.

Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques.

Effects of non-local exchange on core level shifts for gas-phase and adsorbed molecules.

Density functional theory calculations are often used to interpret experimental shifts in core level binding energies. Calculations based on gradient-corrected (GC) exchange-correlation functionals are known to reproduce measured core level shifts (CLS) of isolated molecules and metal surfaces with reasonable accuracy. In the present study, we discuss a series of examples where the shifts calculated within a GC-functional significantly deviate from the experimental values, namely the CLS of C 1s in ethyl trifluoroacetate, Pd 3d in PdO and the O 1s shift for CO adsorbed on PdO(101). The deviations are traced to effects of the electronic self-interaction error with GC-functionals and substantially better agreements between calculated and measured CLS are obtained when a fraction of exact exchange is used in the exchange-correlation functional.

Direct imaging of atomic scale structure and electronic properties of GaAs wurtzite and zinc blende nanowire surfaces.

Using scanning tunneling microscopy and spectroscopy we study the atomic scale geometry and electronic structure of GaAs nanowires exhibiting controlled axial stacking of wurtzite (Wz) and zinc blende (Zb) crystal segments. We find that the nonpolar low-index surfaces {110}, {101[overline]0}, and {112[overline]0} are unreconstructed, unpinned, and without states in the band gap region. Direct comparison between Wz and Zb GaAs reveal a type-II band alignment and a Wz GaAs band gap of 1.52 eV.

In situ x-ray photoelectron spectroscopy of model catalysts: at the edge of the gap.

We present high-pressure x-ray photoelectron spectroscopy (HP-XPS) and first-principles kinetic Monte Carlo study addressing the nature of the active surface in CO oxidation over Pd(100). Simultaneously measuring the chemical composition at the surface and in the near-surface gas phase, we reveal both O-covered pristine Pd(100) and a surface oxide as stable, highly active phases in the near-ambient regime accessible to HP-XPS. Surprisingly, no adsorbed CO can be detected during high CO(2) production rates, which can be explained by a combination of a remarkably short residence time of the CO molecule on the surface and mass-transfer limitations in the present setup.

Formation and structure of graphene waves on Fe(110).

A very rich Fe-C phase diagram makes the formation of graphene on iron surfaces a challenging task. Here we demonstrate that the growth of graphene on epitaxial iron films can be realized by chemical vapor deposition at relatively low temperatures, and that the formation of carbides can be avoided in excess of the carbon-containing precursors. The resulting graphene monolayer creates a novel periodically corrugated pattern on Fe(110). Using low-energy electron microscopy and scanning tunneling microscopy, we show that it is modulated in one dimension forming long waves with a period of ∼4 nm parallel to the [001] direction of the substrate, with an additional height modulation along the wave crests. The observed topography of the graphene/Fe superstructure is well reproduced by density functional theory calculations, and found to result from a unique combination of the lattice mismatch and strong interfacial interaction, as probed by core-level photoemission and x-ray absorption spectroscopy.

One-dimensional corrugation of the h-BN monolayer on Fe(110).

We report on a new nanopatterned structure represented by a single atomic layer of hexagonal boron nitride (h-BN) forming long periodic waves on the Fe(110) surface. The growth process and the structure of this system are characterized by X-ray absorption (XAS), core-level photoemission spectroscopy (CL PES), low-energy electron microscopy (LEEM), microbeam low-energy electron diffraction (µLEED), and scanning tunneling microscopy (STM). The h-BN monolayer on Fe(110) is periodically corrugated in a wavy fashion with an astonishing degree of long-range order, periodicity of 2.6 nm, and the corrugation amplitude of ∼0.8 Å. The wavy pattern results from a strong chemical bonding between h-BN and Fe in combination with a lattice mismatch in either [111] or [111] direction of the Fe(110) surface. Two primary orientations of h-BN on Fe(110) can be observed corresponding to the possible directions of lattice match between h-BN and Fe(110), with approximately equal area of the boron nitride domains of each orientation.

Vitamin D receptor genotypes in primary hyperparathyroidism.

Vitamin D and parathyroid hormone (PTH) constitute the main regulators of systemic calcium homeostasis. As well as its calcaemic effects, active vitamin D3(1,25(OH)2D3) has a direct regulatory role on parathyroid cells. Active vitamin D3 acts via its receptor (VDR), and binding of the ligand-receptor complex to specific promoter regions of the PTH gene inhibits transcription. Active vitamin D3 constitutes a principal regulator of parathyroid cell growth, and polymorphism in the VDR gene has recently been related to bone mineral density and suggested as predisposing to osteoporosis. Impaired effects of active vitamin D3 may contribute to the relatively enhanced secretion and cell proliferation seen in hyperparathyroidism (HPT). Indeed, VDR dysfunction, of essentially unknown character, has been demonstrated in the pathological parathyroid tissue of primary HPT as well as HPT secondary to uraemia. Consistent with the essential role of active vitamin D3 in parathyroid regulation, the VDR gene polymorphism was studied in 90 postmenopausal women with primary hyperparathyroidism. The VDR genotype bb was found in 60.0% of HPT patients and in 33.3% of the postmenopausal female controls (P < 0.001). As the b allele has been linked to decreased transcriptional activity or messenger RNA stability, reduced VDR expression may impede regulatory actions of vitamin D and may contribute to parathyroid tumorigenesis in these patients.

Surface structure and reactivity of Pd(100) during CO oxidation near ambient pressures.

The surface structure of Pd(100) during CO oxidation was measured using a combination of a flow reactor and in situ surface X-ray diffraction coupled to a large-area 2-dimensional detector. The surface structure was measured for P(O(2))/P(CO) ratios between 0.6 and 10 at a fixed total gas pressure of 200 mbar and a fixed CO pressure of 10 ± 1 mbar. In conjunction with the surface structure the reactivity of the surface was also determined. For all P(O(2))/P(CO) ratios the surface was found to oxidize above a certain temperature. Three different types of oxides were observed: the surface oxide, an epitaxial layer of bulk-like PdO, and a non-epitaxial layer of bulk-like PdO. As soon as an oxide was present the reactivity of the surface was found to be mass transfer limited by the flux of CO molecules reaching the surface.

Impact of oxygen coadsorption on intercalation of cobalt under the h-BN nanomesh.

The process of penetration of cobalt atoms through the h-BN nanomesh on Rh(111) is investigated with both spectroscopic and microscopic techniques. It is discovered that oxygen coadsorption can drastically modify the physical properties and behavior of the deposited Co clusters upon postannealing. In the absence of oxygen, Co forms small nanoparticles in the pores (bonding parts) of the h-BN nanomesh, which start to agglomerate at elevated temperatures without any considerable intercalation. However, even a tiny amount of coadsorbed oxygen reduces cobalt agglomeration and greatly promotes its intercalation and trapping under h-BN. The oxygen exposure necessary for a complete intercalation of 1-2 monolayers of Co is very low, and the formation of oxidic species can be easily avoided. The nanomesh structure remains intact upon intercalating submonolayer amounts of Co, while further intercalation gradually distorts and finally destroys the periodic corrugation. Fortunately, this process is not accompanied by damaging the h-BN sheet itself, and the original structure can be restored by removing Co upon annealing at higher temperatures.

An electrochemical cell for 2-dimensional surface optical reflectance during anodization and cyclic voltammetry.

We have developed an electrochemical cell for in situ 2-Dimensional Surface Optical Reflectance (2D-SOR) studies during anodization and cyclic voltammetry. The 2D-SOR signal was recorded from electrodes made of polycrystalline Al, Au(111), and Pt(100) single crystals. The changes can be followed at a video rate acquisition frequency of 200 Hz and demonstrate a strong contrast between oxidizing and reducing conditions. Good correlation between the 2D-SOR signal and the anodization conditions or the cyclic voltammetry current is also observed. The power of this approach is discussed, with a focus on applications in various fields of electrochemistry. The combination of 2D-SOR with other techniques, as well as its spatial resolution and sensitivity, has also been discussed.

High-Resolution X-ray Photoelectron Spectroscopy of an IrO2(110) Film on Ir(100).

High-resolution X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) were used to characterize IrO2(110) films on Ir(100) with stoichiometric as well as OH-rich terminations. Core-level Ir 4f and O 1s peaks were identified for the undercoordinated Ir and O atoms and bridging and on-top OH groups at the IrO2(110) surfaces. Peak assignments were validated by comparison of the core-level shifts determined experimentally with those computed using DFT, quantitative analysis of the concentrations of surface species, and the measured variation of the Ir 4f peak intensities with photoelectron kinetic energy. We show that exposure of the IrO2(110) surface to O2 near room temperature produces a large quantity of on-top OH groups because of reaction of background H2 with the surface. The peak assignments made in this study can serve as a foundation for future experiments designed to utilize XPS to uncover atomic-level details of the surface chemistry of IrO2(110).

Direct observation of atomic scale surface relaxation in ortho twin structures in GaAs by XSTM.

We have studied the (110) GaAs surface of a structure containing ortho twins by cross-sectional scanning tunnelling microscopy and we have compared the experimental results with ab initio density functional theory calculations and STM simulations. Both experimentally and theoretically we find that the surface of different twin crystallites are significantly displaced with respect to each other, parallel to the twin boundary. This result is explained by a surface relaxation of the atoms in the (110) GaAs surface and the difference between the atomic configuration of the ortho twins.

Combining high-energy X-ray diffraction with Surface Optical Reflectance and Planar Laser Induced Fluorescence for operando catalyst surface characterization.

We have combined three techniques, High Energy Surface X-Ray Diffraction (HESXRD), Surface Optical Reflectance, and Planar Laser Induced Fluorescence in an operando study of CO oxidation over a Pd(100) catalyst. We show that these techniques provide useful new insights such as the ability to verify that the finite region being probed by techniques such as HESXRD is representative of the sample surface as a whole. The combination is also suitable to determine when changes in gas composition or surface structure and/or morphology occur and to subsequently correlate them with high temporal resolution. In the study, we confirm previous results which show that the Pd(100) surface reaches high activity before an oxide can be detected. Furthermore, we show that the single crystal catalyst surface does not behave homogeneously, which we attribute to the surface being exposed to inhomogeneous gas conditions in mass transfer limited scenarios.

Surface development of a brazing alloy during heat treatment-a comparison between UHV and APXPS.

In an attempt to bridge the pressure gap, APXPS was used to follow the surface development of an aluminum brazing sheet during heating in an ambient oxygen-pressure mimicking the environment of an industrial brazing furnace. The studied aluminum alloy brazing sheet is a composite material consisting of two aluminum alloy standards whose surface is covered with a native aluminum oxide film. To emphasize the necessity of studies of this system in ambient sample environments it is compared to measurements in UHV. Changes in thickness and composition of the surface oxide were followed after heating to 300 °C, 400 °C, and 500 °C. The two sets presented in this paper show that the surface development strongly depends on the environment the sample is heated in.

No support for a truncated interferon-alpha 17 allele as risk factor for MS.

Cytokines have a central role in multiple sclerosis (MS) pathogenesis and may contribute to the aetiology of MS. A polymorphism in the IFNA17 gene with an allele carrying a pre-mature stop codon has been suggested to convey a 26-fold increased risk for MS. We investigated the possible association between this polymorphism and MS using population-based samples from a genetically well-characterized population. The IFNA17 gene variant was found in 2.8% of 327 MS cases and 3.3% of 698 referents (P = 0.64). Thus, our study does not support an association between the IFNA17 allele and risk for MS.

Kinetics of the reduction of the Rh(111) surface oxide: linking spectroscopy and atomic-scale information.

The reduction of the surface oxide on Rh(111) by H(2) was observed in situ by scanning tunneling microscopy (STM) and high-resolution core level spectroscopy (HRCLS). At room temperature, H(2) does not adsorb on the oxide, only in reduced areas. Reduction starts in very few sites, almost exclusively in stepped areas. One can also initiate the reduction process by deliberately creating defects with the STM tip allowing us to examine the reduction kinetics in detail. Depending on the size of the reduced area and the hydrogen pressure, two growth regimes were found. At low H(2) pressures or small reduced areas, the reduction rate is limited by hydrogen adsorption on the reduced area. For large reduced areas, the reduction rate is limited by the processes at the border of the reduced area. Since a near-random distribution of the reduction nuclei was found and the reduction process at defects starts at a random time, one can use Johnson-Mehl-Avrami-Kolmogoroff (JMAK) theory to describe the process of reduction. The microscopic data from STM agree well with spatially averaged data from HRCLS measurements.

Unusual process of water formation on RuO2(110) by hydrogen exposure at room temperature.

The reduction mechanism of the RuO(2)(110) surface by molecular hydrogen exposure is unraveled to an unprecedented level by a combination of temperature programmed reaction, scanning tunneling microscopy, high-resolution core level shift spectroscopy, and density functional theory calculations. We demonstrate that even at room temperature hydrogen exposure to the RuO(2)(110) surface leads to the formation of water. In a two-step process, hydrogen saturates first the bridging oxygen atoms to form (O(br)-H) species and subsequently part of these O(br)-H groups move to the undercoordinated Ru atoms where they form adsorbed water. This latter process is driven by thermodynamics leaving vacancies in the bridging O rows.

Cell surface changes in HeLa cells as an indication of cell cycle events.

A HeLa cell line synchronized by double thymidine block and mitotic shake off was shown to have a characteristic surface morphology for each of the different cell cycle stages. Inhibitors of cell multiplication were used to arrest cells in specific cell cycle phases, and these cells had a surface morphology similar to that of synchronized cells in the same phase. The results indicated a close association between the cell surface topography and the cycles of DNA synthesis in the cell nucleus of this HeLa line.

Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines.

The EBV-encoded latent membrane protein 1 (LMP1) suppresses apoptosis in B lymphocytes through up-regulation of Bcl-2. However, the maximum induction of Bcl-2 by LMP1 takes about 48-72 h. We show in this report that up-regulation of the Bcl-2 homologue Mcl-1 by LMP1 preceded the induction of Bcl-2 and that the up-regulation was transient; therefore, Mcl-1 levels decreased when Bcl-2 levels started to increase. This finding supports the hypothesis that Mcl-1 functions as a rapidly inducible, short-term effector of cell viability. LMP1 also blocked the decline in the Mcl-1 levels in response to apoptotic stimulation triggered by elevated cyclic AMP. This effect of LMP1 was associated with a delayed cell death in the EBV-negative Burkitt lymphoma cell line BL41. The maintenance of Mcl-1 expression by LMP1 is likely to be a crucial immediate-early response that enables cells to survive until Bcl-2 can be up-regulated.

Interferon-induced cell cycle changes in human hematopoietic cell lines and fresh leukemic cells.

A panel of 26 human hematopoietic cell lines was tested for sensitivity to growth inhibition towards interferon-alpha (IFN-alpha) by estimating the effects on cell cycle phase distribution using flow cytometry analysis. The proportion of proliferating cells was assessed by studying the fractional increase of cells in mitosis during a 24-hr vinblastine block. Of 26 cell lines tested, 17 were sensitive to IFN-alpha, and the main cell cycle effect was accumulation in the G0-G1 phase. One Burkitt's lymphoma line, Namalwa, showed a decreased rate of progress through S without any G0/G1 accumulation. Three of the cell lines were also tested with IFN-beta and with IFN-alpha 2 produced by recombinant DNA technology. The latter IFN did not affect one of the cell lines; otherwise, the results were similar to those of IFN-alpha. Six of 16 clinical specimens from patients with hematopoietic neoplasias were IFN-sensitive, all displaying a G0-G1 block. Our results indicate that IFN sensitivity is an individually linked property unrelated to cell origin.