Multiphoton absorption in amyloid protein fibres

Fibrillization of peptides leads to the formation of amyloid fibres, which, when in large aggregates, are responsible for diseases such as Alzheimer's and Parkinson's. Here, we show that amyloids have strong nonlinear optical absorption, which is not present in native non-fibrillized protein. Z-scan and pump-probe experiments indicate that insulin and lysozyme β-amyloids, as well as α-synuclein fibres, exhibit either two-photon, three-photon or higher multiphoton absorption processes, depending on the wavelength of light. We propose that the enhanced multiphoton absorption is due to a cooperative mechanism involving through-space dipolar coupling between excited states of aromatic amino acids densely packed in the fibrous structures. This finding will provide the opportunity to develop nonlinear optical techniques to detect and study amyloid structures and also suggests that new protein-based materials with sizable multiphoton absorption could be designed for specific applications in nanotechnology, photonics and optoelectronics

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the prometastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy

Characterization of the precipitation behavior and resulting mechanical properties of copper-alloyed ferritic steel : On the occasion of his 70th birthday, this work is dedicated to our mentor, colleague and friend Prof. Dr.-Ing. habil. Dietmar Eifler

From literature, it is well known that Cu precipitates in steels lead to an increase of hardness and quasi-static strength. However, the relation between Cu precipitates and cyclic mechanical properties has been investigated rather limited. Consequently, in the present work the evolution of Cu precipitates in a copper-alloyed low carbon, ferritic steel, aged at 550 °C, 600 °C and 650 °C for various times, and their influence on the resulting static and cyclic material properties were analyzed. Three-dimensional atom probe tomography (3DAPT) provided evidence that the ageing treatment led to the formation of Cu precipitates with different sizes and distribution. The existence of copper precipitates resulted in an increase of the ultimate tensile strength and yield strength of the investigated ferritic steel. Moreover, cyclic indentation tests were performed to investigate the influence of the ageing treatment and, hence, Cu precipitates, on hardness and especially cyclic properties of the material. The present results show a maximum of hardness and cyclic hardening potential at sizes of the precipitates of around 2.2 nm. Additionally, synchrotron X-ray diffraction (SYXRD) measurements were in a first approach proved to be viable for investigating the crystallographic structure of Cu precipitates within ferritic steels. Considering the evolution of Cu precipitates, determined with synchrotron as well as atom probe, a high dependency of quasi-static and cyclic properties on Cu precipitates could be demonstrated

Materials modelling in industrial bulk metal forming processes and process chains

Bulk metal forming processes range from processes with a single deformation step such as certain closed-die forging operations to processes with many subsequent stages such as hot rolling, ring rolling or open die forging. Modelling of these manufacturing processes requires both precise process models as well as adequate material models. Microstructure evolution by recrystallization is decisive in all of these processes since the microstructure determines the flow stress and hence the forming forces but it also influences the product properties. In this context, the propagation of variations in the processing conditions and in the material behavior are of special importance and methods for the quantification of uncertainties and their effect on model predictions are required. Such questions can be approached using models of different complexity on various scales as shown in the following examples: In closed die forging of a gear wheel from 25MoCr4 alloy the complex geometry requires a Finite Element process model which in this case is combined with a JMAK type material model. In plate rolling a simplified process model can be applied successfully. Based on the slab theory, which is enhanced for spatial resolution of shear strain using a meta model derived by FEM, this model can simulate even longer roll pass schedules within seconds and offers the possibility to combine it with numerical optimization techniques. Recrystallization of a high-manganese steel in interpass times between hot rolling passes is an example where models with spatial resolution (CP-FEM and phase field) are combined on the micro-scale to predict the recrystallization kinetics based on physically meaningful variables such as grain boundary mobility. In ring rolling the process model must include the closed-loop control system of the rolling machine to achieve a realistic prediction of the process kinematics. Feedback control loops for up to eight kinematic degrees of freedom (velocities and positions of all radial, axial and guiding rolls) have been defined using virtual sensors integrated in the simulation. Offline coupling with microstructure simulation is used to predict the final grain size and determine under which conditions static recrystallization occurs during the rolling sequence

Mixed-metal cluster chemistry. 37. Syntheses, structural, spectroscopic, electrochemical, and optical power limiting studies of tetranuclear molybdenum-iridium clusters

Tetrahedral Mo2Ir2(μ3-CO)(μ-CO)5(CO)4(η5-C5H5)2 (1) reacted with P(C6H4Me-4)3, P(C6H2Me2-3,5-OMe-4)3, and AsPh3 to afford the substitution products Mo2Ir2(μ-CO)3(CO)6(L)(η5-C5H5)2 [L = P(C6H4Me-4)3 (3), P(C6H2Me2-3,5-OMe-4)3 (4), AsPh3 (5)] in fair to good yields, while reaction of 1 with HC≡CSiPri3 proceeded by insertion into the Mo–Mo bond to give the pseudo-octahedral Mo2Ir2(μ4-η2-HC2SiPri3)(μ-CO)4(CO)4(η5-C5H5)2 (6) in fair yield. While MoIr3(μ-CO)3(CO)7(η5-C5H5) reacted with HC≡CSiMe3 to give a complex mixture of thus-far-uncharacterized products, its phosphine substitution product MoIr3(μ-CO)3(CO)5(PPh3)2(η5-C5H5) reacted with the same alkyne via insertion into a Mo–Ir bond to afford the pseudo-octahedral MoIr3(μ4-η2-HC2SiMe3)(μ-CO)3(CO)4(PPh3)2(η5-C5H5) (8) in good yield. Clusters 4, 5 (two isomers), 6 and 8 have been characterized by single-crystal X-ray diffraction studies. Cyclic voltammetric studies of Mo2Ir2(μ-CO)3(CO)6(PPh3)(η5-C5H5)2 (2), 3–6 and 8 confirmed the tuning of redox potentials upon phosphines/arsine introduction and alkyne modification. IR spectroelectrochemical studies of 2, 6, and 8 suggest decreasing proclivity for bridging carbonyl ligands following oxidation. Variable temperature 31P NMR studies of 3 and 4 revealed interconverting isomers in solution, the structures of which are assigned as analogues of the X-ray diffraction-confirmed isomers of 5. Studies of 2–5 using ns pulses and the open-aperture Z-scan technique revealed that all are optical limiters at wavelengths in the visible region

Phosphine, isocyanide, and alkyne reactivity at pentanuclear molybdenum/tungsten-iridium clusters

The trigonal bipyramidal clusters M2Ir3(μ-CO)3(CO)6(η5-C5H5)2(η5-C5Me4R) (M = Mo, R = Me 1a, R = H; M = W, R = Me, H) reacted with isocyanides to give ligand substitution products M2Ir3(μ-CO)3(CO)5(CNR′)(η5-C5H5)2(η5-C5Me4R) (M = Mo, R = Me, R′ = C6H3Me2-2,6 3a; M = Mo, R = Me, R′ = tBu 3b), in which core geometry and metal atom locations are maintained, whereas reactions with PPh3 afforded M2Ir3(μ-CO)4(CO)4(PPh3)(η5-C5H5)2(η5-C5Me4R) (M = Mo, R = Me 4a, H 4c; M = W, R = Me 4b, H), with retention of core geometry but with effective site-exchange of the precursors’ apical Mo/W with an equatorial Ir. Similar treatment of trigonal bipyramidal MIr4(μ-CO)3(CO)7(η5-C5H5)(η5-C5Me5) (M = Mo 2a, W 2b) with PPh3 afforded the mono-substitution products MIr4(μ-CO)3(CO)6(PPh3)(η5-C5H5)(η5-C5Me5) (M = Mo 5a; M = W 5b), and further reaction of the molybdenum example 5a with excess PPh3 afforded the bis-substituted cluster MoIr4(μ3-CO)2(μ-CO)2(CO)4(PPh3)2(η5-C5H5)(η5-C5Me5) (6). Reaction of 1a with diphenylacetylene proceeded with alkyne coordination and C C cleavage, affording Mo2Ir3(μ4–η2-PhC2Ph)(μ3-CPh)2(CO)4(η5-C5H5)2(η5-C5Me5) (7a) together with an isomer. Reactions of 2a and 2b with PhC CR afforded MIr4(μ3–η2-PhC2R)(μ3-CO)2(CO)6(η5-C5H5)(η5-C5Me5) (M = Mo, R = Ph 8a; M = W, R = Ph 8b, H; M = W, R = C6H4(C2Ph)-3 9a, C6H4(C2Ph)-4), while addition of 0.5 equivalents of the diynes 1,3-C6H4(C2Ph)2 and 1,4-C6H4(C2Ph)2 to WIr4(μ-CO)3(CO)7(η5-C5H5)(η5-C5Me5) gave the linked clusters [WIr4(CO)8(η5-C5H5)(η5-C5Me5)]2(μ6–η4-PhC2C6H4(C2Ph)-X) (X = 3, 4).The structures of 3a, 4a–4c, 5b, 6, 7a, 8a, 8b and 9a were determined by single-crystal X-ray diffraction studies, establishing the core isomerization of 4, the site selectivity for ligand substitution in 3–6, the alkyne C C dismutation in 7, and the site of alkyne coordination in 7–9. For clusters 3–6, ease of oxidation increases on increasing donor strength of ligand, increasing extent of ligand substitution, replacing Mo by W, and decreasing core Ir content, the Ir-rich clusters 5 and 6 being the most reversible. For clusters 7–9, ease of oxidation diminishes on replacing Mo by W, increasing the Ir content, and proceeding from mono-yne to diyne, although the latter two changes are small. In situ UV-vis-near-IR spectroelectrochemical studies of the (electrochemically reversible) reduction process of 8b were undertaken, the spectra becoming increasingly broad and featureless following reduction. The incorporation of isocyanides, phosphines, or alkyne residues in these pentanuclear clusters all result in an increased ease of oxidation and decreased ease of reduction, and thereby tune the electron richness of the clusters

SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.

Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends