Predictive multiphase evolution in Al-containing high-entropy alloys.

The ability to predict and understand phases in high-entropy alloys (HEAs) is still being debated, and primarily true predictive capabilities derive from the known thermodynamics of materials. The present work demonstrates that prior work using high-throughput first-principles calculations may be further utilized to provide direct insight into the temperature- and composition-dependent phase evolution in HEAs, particularly Al-containing HEAs with a strengthening multiphase microstructure. Using a simple model with parameters derived from first-principles calculations, we reproduce the major features associated with Al-containing phases, demonstrating a generalizable approach for exploring potential phase evolution where little experimental data exists. Neutron scattering, in situ microscopy, and calorimetry measurements suggest that our high-throughput Monte Carlo technique captures both qualitative and quantitative features for both intermetallic phase formation and microstructure evolution at lower temperatures. This study provides a simple approach to guide HEA development, including ordered multi-phase HEAs, which may prove valuable for structural applications.

High-velocity deformation of Al0.3CoCrFeNi high-entropy alloy: Remarkable resistance to shear failure.

The mechanical behavior of a single phase (fcc) Al0.3CoCrFeNi high-entropy alloy (HEA) was studied in the low and high strain-rate regimes. The combination of multiple strengthening mechanisms such as solid solution hardening, forest dislocation hardening, as well as mechanical twinning leads to a high work hardening rate, which is significantly larger than that for Al and is retained in the dynamic regime. The resistance to shear localization was studied by dynamically-loading hat-shaped specimens to induce forced shear localization. However, no adiabatic shear band could be observed. It is therefore proposed that the excellent strain hardening ability gives rise to remarkable resistance to shear localization, which makes this material an excellent candidate for penetration protection applications such as armors.

Histones link inflammation and thrombosis through the induction of Weibel-Palade body exocytosis.

Essentials Dysregulated DNA and histone release can promote pathological immunothrombosis. Weibel-Palade bodies (WPBs) are sentinel-like organelles that respond to proinflammatory stimuli. Histones induce WPB exocytosis in a caspase, calcium and charge-dependent mechanism. A targetable axis may exist between DNA/histones and WPBs in inflammation and immunothrombosis. SUMMARY: Background Damage-associated molecular patterns (DAMPs), including molecules such as DNA and histones, are released into the blood following cell death. DAMPs promote a procoagulant phenotype through enhancement of thrombin generation and platelet activation, thereby contributing to immunothrombosis. Weibel-Palade bodies (WPBs) are dynamic endothelial cell organelles that contain procoagulant and proinflammatory mediators, such as von Willebrand factor (VWF), and are released in response to cell stresses. VWF mediates platelet adhesion and aggregation, and has been implicated as a procoagulant component of the innate immune response. Objective To determine the influence of histones and DNA on WPB release, and characterize their association in models of inflammation. Methods We treated C57BL/6J mice and cultured endothelial cells with histones (unfractionated, lysine-rich or arginine-rich) and DNA, and measured WPB exocytosis. We used inhibitors to determine a mechanism of histone-induced WPB release in vitro. We characterized the release of DAMPs and WPBs in response to acute and chronic inflammation in human and murine models. Results and conclusions Histones, but not DNA, induced the release of VWF (1.46-fold) from WBPs and caused thrombocytopenia (0.74-fold), which impaired arterial thrombus formation in mice. Histones induced WPB release from endothelial cells in a caspase-dependent, calcium-dependent and charge-dependent manner, and promoted platelet capture in a flow chamber model of VWF-platelet string formation. The levels of DAMPs and WPB-released proteins were elevated during inflammation, and were positively correlated in chronic inflammation. These studies showed that DAMPs can regulate the function and level of VWF by inducing its release from endothelial WPBs. This DAMP-WPB axis may propagate immunothrombosis associated with inflammation.

Tensile deformation mechanisms of an in-situ Ti-based metallic glass matrix composite at cryogenic temperature.

Remarkable tensile ductility was first obtained in an in-situ Ti-based bulk metallic glass (BMG) composite at cryogenic temperature (77 K). The novel cryogenic tensile plasticity is related to the effective accommodation of ductile body-centered cubic dendrites at 77 K, characteristic of the prevailing slip bands and dislocations, as well as lattice disorder, which can effectively hinder the propagation of critical shear bands. The greatly increased yield strength of dendrites contributes to the high yield strength of composite at 77 K. A trend of stronger softening is observed at low temperature, and a criterion is proposed to understand the softening behavior. The current research could also provide a guidance to the promising cryogenic application of these new advanced BMG composites.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment.

BACKGROUND: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). OBJECTIVES: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. MATERIALS AND METHODS: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. RESULTS: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250µg/l at one month; 5.2% with D-dimer levels between 250 and 499µg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500µg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. CONCLUSIONS: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

Loading-rate-independent delay of catastrophic avalanches in a bulk metallic glass.

The plastic flow of bulk metallic glasses (BMGs) is characterized by intermittent bursts of avalanches, and this trend results in disastrous failures of BMGs. In the present work, a double-side-notched BMG specimen is designed, which exhibits chaotic plastic flows consisting of several catastrophic avalanches under the applied loading. The disastrous shear avalanches have, then, been delayed by forming a stable plastic-flow stage in the specimens with tailored distances between the bottoms of the notches, where the distribution of a complex stress field is acquired. Differing from the conventional compressive testing results, such a delaying process is independent of loading rate. The statistical analysis shows that in the specimens with delayed catastrophic failures, the plastic flow can evolve to a critical dynamics, making the catastrophic failure more predictable than the ones with chaotic plastic flows. The findings are of significance in understanding the plastic-flow mechanisms in BMGs and controlling the avalanches in relating solids.

Non-monotonic changes in critical solidification rates for stability of liquid-solid interfaces with static magnetic fields.

We report the magnetic field dependence of the critical solidification rate for the stability of liquid-solid interfaces. For a certain temperature gradient, the critical solidification rate first increases, then decreases, and subsequently increases with increasing magnetic field. The effect of the magnetic field on the critical solidification rate is more pronounced at low than at high temperature gradients. The numerical simulations show that the magnetic-field dependent changes of convection velocity and contour at the interface agree with the experimental results. The convection velocity first increases, then decreases, and finally increases again with increasing the magnetic field intensity. The variation of the convection contour at the interface first decreases, then increases slightly, and finally increases remarkably with increasing the magnetic field intensity. Thermoelectromagnetic convection (TEMC) plays the role of micro-stirring the melt and is responsible for the increase of interface stability within the initially increasing range of magnetic field intensity. The weak and significant extents of the magneto-hydrodynamic damping (MHD)-dependent solute build-up at the interface front result, respectively, in the gradual decrease and increase of interfacial stability with increasing the magnetic field intensity. The variation of the liquid-side concentration at the liquid-solid interface with the magnetic field supports the proposed mechanism.

Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells.

UNLABELLED: ESSENTIALS: It is unknown if thrombin activatable fibrinolysis inhibitor (TAFI) and protein C compete on cells. TAFI and protein C activation on endothelial cells was simultaneously quantified. TAFI and protein C do not compete for activation on endothelial cells. TAFI and protein C are independently recognized by the thrombin-thrombomodulin complex. BACKGROUND: When bound to thrombomodulin (TM), thrombin is a potent activator of protein C (PC) and thrombin activable fibrinolysis inhibitor (TAFI). By binding PC and presenting it to the thrombin-TM complex, endothelial cell PC receptor (EPCR) enhances PC activation. It is unknown whether PC and TAFI compete for the thrombin-TM complex on endothelial cells. OBJECTIVE: To compare PC and TAFI activation on the surface of cultured human endothelial cells in the absence or presence of JRK1535 and/or CTM1009, inhibitory antibodies directed against EPCR and TM, respectively, and to determine whether PC and TAFI compete with each other for activation. METHODS: PC and TAFI activation on endothelial cells were compared, and the effect of PC on TAFI activation and TAFI on PC activation was determined in the absence or presence of JRK1535 and/or CTM1009. RESULTS: In the absence of antibodies, activation of PC was four-fold faster than that of TAFI. Blocking EPCR with JRK1535 resulted in a 53-fold decrease in PC activation and no effect on TAFI activation. Blocking TM with CTM1009 inhibited both TAFI and PC activation. Neither TAFI nor PC competed with each other in the absence or presence of JRK1535. CONCLUSIONS: PC and TAFI are concurrently activated in a TM-dependent manner and do not compete for the thrombin-TM complex, raising the possibility that they interact with distinct activation complexes. EPCR selectively enhances PC activation so that PC and TAFI activation kinetics become comparable on endothelial cells.

Universal Quake Statistics: From Compressed Nanocrystals to Earthquakes.

Slowly-compressed single crystals, bulk metallic glasses (BMGs), rocks, granular materials, and the earth all deform via intermittent slips or "quakes". We find that although these systems span 12 decades in length scale, they all show the same scaling behavior for their slip size distributions and other statistical properties. Remarkably, the size distributions follow the same power law multiplied with the same exponential cutoff. The cutoff grows with applied force for materials spanning length scales from nanometers to kilometers. The tuneability of the cutoff with stress reflects "tuned critical" behavior, rather than self-organized criticality (SOC), which would imply stress-independence. A simple mean field model for avalanches of slipping weak spots explains the agreement across scales. It predicts the observed slip-size distributions and the observed stress-dependent cutoff function. The results enable extrapolations from one scale to another, and from one force to another, across different materials and structures, from nanocrystals to earthquakes.

Extracellular DNA and histones: double-edged swords in immunothrombosis.

The existence of extracellular DNA in human plasma, also known as cell-free DNA (cfDNA), was first described in the 1940s. In recent years, there has been a resurgence of interest in the functional significance of cfDNA, particularly in the context of neutrophil extracellular traps (NETs). cfDNA and histones are key components of NETs that aid in the host response to infection and inflammation. However, cfDNA and histones may also exert harmful effects by triggering coagulation, inflammation, and cell death and by impairing fibrinolysis. In this article, we will review the pathologic nature of cfDNA and histones in macrovascular and microvascular thrombosis, including venous thromboembolism, cancer, sepsis, and trauma. We will also discuss the prognostic value of cfDNA and histones in these disease states. Understanding the molecular and cellular pathways regulated by cfDNA and histones may provide novel insights to prevent pathological thrombus formation and vascular occlusion.

A tensile deformation model for in-situ dendrite/metallic glass matrix composites.

In-situ dendrite/metallic glass matrix composites (MGMCs) with a composition of Ti46Zr20V12Cu5Be17 exhibit ultimate tensile strength of 1510 MPa and fracture strain of about 7.6%. A tensile deformation model is established, based on the five-stage classification: (1) elastic-elastic, (2) elastic-plastic, (3) plastic-plastic (yield platform), (4) plastic-plastic (work hardening), and (5) plastic-plastic (softening) stages, analogous to the tensile behavior of common carbon steels. The constitutive relations strongly elucidate the tensile deformation mechanism. In parallel, the simulation results by a finite-element method (FEM) are in good agreement with the experimental findings and theoretical calculations. The present study gives a mathematical model to clarify the work-hardening behavior of dendrites and softening of the amorphous matrix. Furthermore, the model can be employed to simulate the tensile behavior of in-situ dendrite/MGMCs.

Microwires fabricated by glass-coated melt spinning.

The glass-coated melt spinning method offers a route for the manufacture of metal filaments with a few micrometers in diameter in a single operation directly from the melt. Cobalt-based amorphous wires, Cu-15.0 atomic percent (at. %) Sn shape-memory wires, and Ni2MnGa (atomic percent) ferromagnetic wires were successfully produced by this method. The cobalt-based amorphous wire is flexible, and Cu-15.0 at. % Sn shape-memory wires have the tensile elongation of 14%. However, because of chemical reaction with glass and oxidation, it is hard to make Cu-Al-Ni shape-memory wires and Ni-Nb-Sn amorphous wires. Conditions for preparing these materials were summarized, and the differences of the solidification processes among glass-coated amorphous cobalt-based wires, Cu-15.0 at. % Sn shape-memory wires, and Ni2MnGa wires were analyzed and discussed.

Atomic-scale mechanisms of the glass-forming ability in metallic glasses.

The issue, composition dependence of glass-forming ability (GFA) in metallic glasses (MG), has been investigated by systematic experimental measurements coupled with theoretical calculations in Cu-Zr and Ni-Nb alloy systems. It is found that the atomic-level packing efficiency strongly relates to their GFA. The best GFA is located at the largest difference in the packing efficiency of the solute-centered clusters between the glassy and crystal alloys in both MG systems. This work provides an understanding of GFA from atomic level and will shed light on the development of new MGs with larger critical sizes.

Electronic structure inheritance and pressure-induced polyamorphism in lanthanide-based metallic glasses.

We report that a series of lanthanide-based bulk metallic glasses show a pressure-induced polyamorphic phase transition observed by in situ angle-dispersive x-ray diffraction under high pressures. The transition started from a low-density state at lower pressures, and went through continuous densification ending with a high-density state at higher pressures. We demonstrate that, under high pressure, this new type of polyamorphism in densely packed metallic glasses is inherited from its lanthanide-solvent constituent and related to the electronic structure of 4f electrons. The found electronic structure inheritance could provide the guidance for designing new metallic glasses with unique functional physical properties.

Retention of thrombin inhibitory activity by recombinant serpins expressed as integral membrane proteins tethered to the surface of mammalian cells.

BACKGROUND: Serpins form a widely distributed protein superfamily, but no integral membrane serpins have been described. OBJECTIVES: To anchor three serpins -α(1) -proteinase inhibitor (α(1) PI) (M358R), antithrombin (AT), and heparin cofactor II (HCII) - in the plasma membranes of transfected mammalian cells and assess their ability to inhibit thrombin. METHODS: Serpin cDNAs were altered to include N-terminal, non-cleavable plasma membrane-targeting sequences from the human transferrin receptor (TR) (TR-serpin) or the human asialoglycoprotein receptor (AR) (AR-serpin), and used to transfect COS-1 or HEK 293 cells. Cells were analyzed for serpin expression by immunoblotting of subcellular fractions, by immunofluorescence microscopy, or by flow cytometry, with or without exposure to exogenous thrombin; AR-serpins and TR-serpins were also compared with their soluble recombinant counterparts. RESULTS: Both TR-α(1) PI (M358R) and AR-α(1) PI (M358R) were enriched in the integral membrane fraction of transfected COS-1 or HEK 293 cells, and formed inhibitory complexes with thrombin, although less rapidly than soluble α(1) PI (M358R). Thrombin inhibition was abrogated by an additional T345R mutation in AR-α(1) PI (M358R). Surface-displayed AR-AT also formed serpin-enzyme complexes with thrombin, but to a lesser extent than AR-α(1) PI (M358R); AR-HCII inhibitory function was not detected. Immunofluorescence detection and flow cytometric quantification of bound thrombin also supported the status of AR-α(1) PI (M358R) and AR-AT as thrombin inhibitors. CONCLUSIONS: Two of three thrombin-inhibitory serpins retained functionality when expressed as integral membrane proteins. Our findings could be applied to create and screen hypervariable serpin libraries expressed in mammalian cells, or to confer protease resistance on engineered cells in vivo.

Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus.

BACKGROUND: Thrombosis is a common complication for breast cancer patients receiving chemotherapy. However, the mechanisms by which breast cancer chemotherapeutic agents increase this risk are largely uncharacterized. Nucleic acids released by injured cells may enhance coagulation via the activation of the contact pathway. OBJECTIVES: In this study, we examined the effects of breast cancer chemotherapy agents on the release of cell-free DNA (CFDNA) and its relationship to thrombin generation using in vitro and in vivo methods. METHODS: CFDNA release and thrombin-antithrombin (TAT) levels were measured in plasma of breast cancer patients and healthy mice receiving chemotherapy. Venous whole blood and cultured cells were exposed to chemotherapy and CFDNA release and levels of DNA-histone complexes were measured. The procoagulant activity of isolated CFDNA was measured with calibrated, automated thrombin generation. RESULTS: Breast cancer patients receiving chemotherapy had elevated levels of CFDNA 24 h post-chemotherapy, a time-point at which elevated thrombin-antithrombin levels have been previously reported. Treatment of healthy mice with doxorubicin, epirubicin and 5-fluorouracil increased CFDNA release, with a corresponding elevation in TAT complex formation. Venous whole blood and neutrophils incubated with chemotherapeutic agents had elevated CFDNA in plasma or cell supernatants. In addition, incubation of venous whole blood with chemotherapy decreased histone-DNA complex levels. CFDNA released from epirubicin-treated whole blood significantly elevated thrombin generation in a dose-dependent manner, and involved activation of the contact pathway. CONCLUSIONS: Release of CFDNA from chemotherapy-injured cells may represent a novel mechanism by which thrombosis is triggered in cancer patients.

The chemotherapy metabolite acrolein upregulates thrombin generation and impairs the protein C anticoagulant pathway in animal-based and cell-based models.

BACKGROUND: Thrombosis is a common complication in cancer patients receiving chemotherapy regimens that include cyclophosphamide. However, the mechanisms by which these agents increase this risk are largely uncharacterized. OBJECTIVES: To examine the effects of cyclophosphamide and its metabolite acrolein on procoagulant and anticoagulant pathways in both cell-based and animal-based models. METHODS: Thrombin and activated protein C (APC) generation were measured in defibrinated plasma exposed to acrolein-treated endothelial and smooth muscle cells. Tissue factor (TF) activity was measured on acrolein-treated cells. Cell surface levels of phosphatidylserine, TF, endothelial protein C receptor and thrombomodulin were measured. Healthy BALB/c mice received injections of saline (control), acrolein, or cyclophosphamide; blood was collected, and plasma thrombin-antithrombin (TAT) complex, protein C and APC levels were analyzed. RESULTS: Exposure of acrolein-treated endothelial and smooth muscle cells to defibrinated plasma increased thrombin generation in the plasma. This was associated with enhanced phosphatidylserine exposure and/or increased TF activity on acrolein-treated cells. Despite elevated levels of thrombin generation, plasma APC levels were not elevated. In vivo, treatment of mice with cyclophosphamide and acrolein resulted in elevations of plasma TAT complex levels, whereas APC levels remained low. CONCLUSIONS: This is the first study to examine thrombin generation and the APC pathway in chemotherapy-treated mice. Cyclophosphamide and acrolein appear to upregulate procoagulant pathways, while impairing endogenous anticoagulant pathways. This may explain, in part, the increased risk of thrombosis observed in cancer patients receiving cyclophosphamide-containing chemotherapy.

Responses of bone-forming cells on pre-immersed Zr-based bulk metallic glasses: Effects of composition and roughness.

Bulk metallic glasses (BMGs) demonstrate attractive properties for potential biomedical applications, owing to their amorphous structure. The present work has investigated the biocompatibility of Zr-based BMGs by studying the cellular behavior of bone-forming mouse MC3T3-E1 pre-osteoblast cells. A Ti-6Al-4V alloy was used as a reference material. Pre-immersion treatment was performed on BMG samples in phosphate-buffered saline prior to cell experiments. The effects of 1at.% yttrium alloying and surface roughness on cellular behavior were examined. The general biosafety of Zr-based BMGs for MC3T3-E1 cells was revealed as normal cell responses. Pre-immersion treatment was found to effectively reduce the surface concentrations of alloying elements. Micro-alloying with 1 at.% yttrium did not significantly affect cell adhesion and proliferation, but slightly decreased alkaline phosphatase (ALP) activity on rough surfaces. Lower cell adhesion and proliferation were found on smooth surfaces of Zr-based BMGs compared to their rougher counterparts. Higher ALP activity was detected on rougher surfaces. To obtain a mechanistic understanding surface free energy was correlated with cell adhesion.

Activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes.

BACKGROUND: The endoplasmic reticulum (ER) is responsible for the synthesis and folding of secretory, transmembrane and ER-resident proteins. Conditions that impair protein folding or overwhelm its protein folding capacity disrupt ER homeostasis, thereby causing ER stress. ER stress-induced apoptosis and inflammation are involved in the pathogenesis of inflammatory diseases. Activated protein C (APC) inhibits inflammation and apoptosis in monocytes, and this may partly explain the protective effects of APC treatment in severe sepsis. However, the precise molecular pathways by which APC modulates these effects remain unknown. OBJECTIVES: To investigate whether APC modulates the ER stress response in human monocytes. METHODS: We treated monocytes with ER stress-inducing agents in the presence or absence of APC to determine the effect on this response. Protein and mRNA levels were determined by immunoblotting and real-time PCR, respectively. Enzyme assays and flow cytometry were used to determine the role of APC in this model. RESULTS: In thapsigargin (Tg)-treated cells, APC dampened unfolded protein response activation, as indicated by reduced levels of the 78-kDa glucose-regulated protein (GRP78), in an endothelial protein C receptor-independent and protease-activated receptor-1-independent manner. Consistent with this, APC decreased phosphorylated eukaryotic translational initiation factor 2α and C/EBP homologous protein levels induced by Tg. APC inhibited Tg-induced ER Ca(2+) flux and reactive oxygen species generation. Functionally, APC diminished Tg-induced caspase-3 activity and degradation of the nuclear factor kappaB inhibitor IκBα. Furthermore, APC dampened the induction of tissue factor procoagulant activity facilitated by Tg. CONCLUSIONS: These studies suggest that APC modulates the adverse effects of ER Ca(2+) depletion in human monocytes.

Deformation crossover: from nano- to mesoscale.

In situ synchrotron and neutron diffraction were used to study deformation mechanisms in Ni over a broad range of grain sizes. The experimental data show that unlike in coarse-grained metals, where the deformation is dominated by dislocation slip, plastic deformation in nanocrystalline Ni is mediated by grain-boundary activities, as evidenced by the lack of intergranular strain and texture development. For ultrafine-grained Ni, although dislocation slip is an active deformation mechanism, deformation twinning also plays an important role, whose propensity increases with the grain size.