Scanning probe microscopy imaging of metallic nanocontacts

We show scanning probe microscopy measurements of metallic nanocontacts between controlled electromigration cycles. The nanowires used for the thinning process are fabricated by shadow evaporation. The highest resolution obtained using scanning force microscopy is about 3 nm. During the first few electromigration cycles the overall slit structure of the nanocontact is formed. The slit first passes along grain boundaries and then at a later stage vertically splits grains in the course of consuming them. We find that first the whole wire is heated and later during the thinning process as the slit forms the current runs over several smaller contacts which needs less power.Comment: 4 pages, 4 figure

Electron-Lattice Interaction on α−Ga(010)

We have investigated the (010) surface of α−Ga by angle-resolved photoemission and low energy electron diffraction. We find a surface state around the ¯C point of the surface Brillouin zone. The electron-phonon coupling at this surface is very strong with an electron-phonon mass enhancement parameter of λ=1.4±0.10. Our spectra show high background intensity in a projected bulk band gap which cannot be accounted for by defect scattering and is therefore interpreted as indicating a nonquasiparticle behavior. Upon cooling the sample below 220 K we observe a phase transition accompanied by spectral changes near the Fermi level

The Effect of Photoinduced Surface Oxygen Vacancies on the Charge Carrier Dynamics in TiO₂ Films

Metal-oxide semiconductors (MOS) are widely utilized for catalytic and photocatalytic applications in which the dynamics of charged carriers (e.g., electrons, holes) play important roles. Under operation conditions, photoinduced surface oxygen vacancies (PI-SOV) can greatly impact the dynamics of charge carriers. However, current knowledge regarding the effect of PI-SOV on the dynamics of hole migration in MOS films, such as titanium dioxide, is solely based upon volume-averaged measurements and/or vacuum conditions. This limits the basic understanding of hole-vacancy interactions, as they are not capable of revealing time-resolved variations during operation. Here, we measured the effect of PI-SOV on the dynamics of hole migration using time-resolved atomic force microscopy. Our findings demonstrate that the time constant associated with hole migration is strongly affected by PI-SOV, in a reversible manner. These results will nucleate an insightful understanding of the physics of hole dynamics and thus enable emerging technologies, facilitated by engineering hole-vacancy interactions

A new structural class of serine protease inhibitors revealed by the structure of the hirustasin–kallikrein complex

AbstractBackground: Hirustasin belongs to a class of serine protease inhibitors characterized by a well conserved pattern of cysteine residues. Unlike the closely related inhibitors, antistasin/ghilanten and guamerin, which are selective for coagulation factor Xa or neutrophil elastase, hirustasin binds specifically to tissue kallikrein. The conservation of the pattern of cysteine residues and the significant sequence homology suggest that these related inhibitors possess a similar three-dimensional structure to hirustasin.Results: The crystal structure of the complex between tissue kallikrein and hirustasin was analyzed at 2.4 Å resolution. Hirustasin folds into a brick-like structure that is dominated by five disulfide bridges and is sparse in secondary structural elements. The cysteine residues are connected in an abab cdecde pattern that causes the polypeptide chain to fold into two similar motifs. As a hydrophobic core is absent from hirustasin the disulfide bridges maintain the tertiary structure and present the primary binding loop to the active site of the protease. The general structural topography and disulfide connectivity of hirustasin has not previously been described.Conclusions: The crystal structure of the kallikrein–hirustasin complex reveals that hirustasin differs from other serine protease inhibitors in its conformation and its disulfide bond connectivity, making it the prototype for a new class of inhibitor. The disulfide pattern shows that the structure consists of two domains, but only the C-terminal domain interacts with the protease. The disulfide pattern of the N-terminal domain is related to the pattern found in other proteins. Kallikrein recognizes hirustasin by the formation of an antiparallel β sheet between the protease and the inhibitor. The P1 arginine binds in a deep negatively charged pocket of the enzyme. An additional pocket at the periphery of the active site accommodates the sidechain of the P4 valine

A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general

Fluorophore Labeled Kinase Detects Ligands That Bind within the MAPK Insert of p38α Kinase

The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38α mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38α, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38α signaling pathway

A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo: Implication for Treating Hyperproliferative Disorders

Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases and aberrant angiogenesis. Here we report that S1P lyase from the prokaryote Symbiobacterium thermophilum (StSPL) degrades extracellular S1P in vitro and in blood. Moreover, we investigated its effect on cellular responses typical of fibrosis, cancer and aberrant angiogenesis using renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells as disease models. In all cell types, wild-type StSPL, but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptor signaling by S1P depletion inhibited proliferation and expression of connective tissue growth factor in mesangial cells, proliferation, migration and VEGF expression in carcinoma cells, and proliferation and migration of endothelial cells. Upon intravenous injection of StSPL in mice, plasma S1P levels rapidly declined by 70% within 1 h and then recovered to normal 6 h after injection. Using the chicken chorioallantoic membrane model we further demonstrate that also under in vivo conditions StSPL, but not the inactive mutant, inhibited tumor cell-induced angiogenesis as an S1P-dependent process. Our data demonstrate that recombinant StSPL is active under extracellular conditions and holds promise as a new enzyme therapeutic for diseases associated with increased levels of S1P and S1P receptor signaling

Análisis de programas de mejora continua. Un estudio longitudinal en una empresa industrial

Las empresas han utilizado diversas herramientas que permiten que los operarios contribuyan al proceso de mejora continua. Entre las herramientas más usadas podemos destacar los sistemas de sugerencias tanto individuales como en grupo. En esta comunicación haremos un repaso de las principales características de ambos sistemas y los modos habituales de implantación. Nuestra ponencia pretende intentar responder a estas preguntas de investigación. ¿Qué resultados se derivan de la implantación de sistemas de sugerencias individuales o en grupo? ¿Cuál de los dos sistemas es más beneficioso para la empresa? ¿Qué problemas surgen durante el funcionamiento de estos programas? Para ello, analizaremos los datos de un caso de empresa industrial donde hemos recogido los datos históricos de 5 años de aplicación de un programa de mejora continua. Ambos programas han demostrado ser provechosos para la empresa, aunque las posibilidades de los sistemas de grupo parecen ser significativamente mayores

Surface Relaxations, Current Enhancements, and Absolute Distances in High Resolution Scanning Tunneling Microscopy

We have performed the most realistic simulation to date of the operation of a scanning tunneling microscope. Probe-sample distances from beyond tunneling to actual surface contact are covered. We simultaneously calculate forces, atomic displacements, and tunneling currents, allowing quantitative comparison with experimental values. A distance regime below which the probe becomes unstable is identified. It is shown that the real distance differs substantially from previous estimates because of large atomic displacements on the surface and at the probe tip

Mechanical parametric amplification and thermomechanical noise squeezing

A mechanical degenerate parametric amplifier has been devised which greatly increases the motional response of a microcantilever for small harmonic force excitations. The amplifier can improve force detection sensitivity for measurements dominated by sensor noise or backaction effects and can also produce mechanical squeezed states. In an initial squeezing demonstration, the thermal noise (Brownian motion) of the cantilever was reduced in one phase by 4.9 dB