An updated analysis of NN elastic scattering data to 1.6 GeV

An energy-dependent and set of single-energy partial-wave analyses of $NN$ elastic scattering data have been completed. The fit to 1.6~GeV has been supplemented with a low-energy analysis to 400 MeV. Using the low-energy fit, we study the sensitivity of our analysis to the choice of $\pi NN$ coupling constant. We also comment on the possibility of fitting $np$ data alone. These results are compared with those found in the recent Nijmegen analyses. (Figures may be obtained from the authors upon request.)Comment: 17 pages of text, VPI-CAPS-7/

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

Circulating Microparticles Alter Formation, Structure, and Properties of Fibrin Clots

Despite the importance of circulating microparticles in haemostasis and thrombosis, there is limited evidence for potential causative effects of naturally produced cell-derived microparticles on fibrin clot formation and its properties. We studied the significance of blood microparticles for fibrin formation, structure, and susceptibility to fibrinolysis by removing them from platelet-free plasma using filtration. Clots made in platelet-free and microparticle-depleted plasma samples from the same healthy donors were analyzed in parallel. Microparticles accelerate fibrin polymerisation and support formation of more compact clots that resist internal and external fibrinolysis. These variations correlate with faster thrombin generation, suggesting thrombin-mediated kinetic effects of microparticles on fibrin formation, structure, and properties. In addition, clots formed in the presence of microparticles, unlike clots from the microparticle-depleted plasma, contain 0.1-0.5-μm size granular and CD61-positive material on fibres, suggesting that platelet-derived microparticles attach to fibrin. Therefore, the blood of healthy individuals contains functional microparticles at the levels that have a procoagulant potential. They affect the structure and stability of fibrin clots indirectly through acceleration of thrombin generation and through direct physical incorporation into the fibrin network. Both mechanisms underlie a potential role of microparticles in haemostasis and thrombosis as modulators of fibrin formation, structure, and resistance to fibrinolysis

Single-Molecule Interactions of a Monoclonal Anti-DNA Antibody with DNA

© 2016, Springer Science+Business Media New York.Interactions of DNA with proteins are essential for key biological processes and have both a fundamental and practical significance. In particular, DNA binding to anti-DNA antibodies is a pathogenic mechanism in autoimmune pathology, such as systemic lupus erythematosus. Here we measured at the single-molecule level binding and forced unbinding of surface-attached DNA and a monoclonal anti-DNA antibody MRL4 from a lupus erythematosus mouse. In optical trap-based force spectroscopy, a microscopic antibody-coated latex bead is trapped by a focused laser beam and repeatedly brought into contact with a DNA-coated surface. After careful discrimination of non-specific interactions, we showed that the DNA-antibody rupture force spectra had two regimes, reflecting formation of weaker (20–40 pN) and stronger (>40 pN) immune complexes that implies the existence of at least two bound states with different mechanical stability. The two-dimensional force-free off-rate for the DNA-antibody complexes was ∼2.2 × 10−3 s−1, the transition state distance was ∼0.94 nm, the apparent on-rate was ∼5.26 s−1, and the stiffness of the DNA-antibody complex was characterized by a spring constant of 0.0021 pN/nm, suggesting that the DNA-antibody complex is a relatively stable, but soft and deformable macromolecular structure. The stretching elasticity of the DNA molecules was characteristic of single-stranded DNA, suggesting preferential binding of the MRL4 antibody to one strand of DNA. Collectively, the results provide fundamental characteristics of formation and forced dissociation of DNA-antibody complexes that help to understand principles of DNA-protein interactions and shed light on the molecular basis of autoimmune diseases accompanied by formation of anti-DNA antibodies

Conformational Flexibility and Self-Association of Fibrinogen in Concentrated Solutions

© 2017 American Chemical Society. We studied the hydrodynamic behavior of fibrinogen, a blood plasma protein involved in blood clotting, in a broad 0.3-60 mg/mL range of concentration and 5-42 °C temperature using pulsed-field gradient 1 H NMR-diffusometry. Arrhenius plots revealed the activation energy for fibrinogen diffusion E d = 21.3 kJ/mol at 1.4 mg/mL and 28.4 kJ/mol at 38 mg/mL. We found a dramatic slowdown in fibrinogen self-diffusion with concentration beginning at 1.7-3.4 mg/mL, which deviated from the standard hard-particle behavior, suggesting a remarkable intermolecular entanglement. This concentration dependence was observed regardless of the absence or presence of the GPRP peptide (inhibitor of fibrin polymerization), and also in samples free of fibrin oligomers. By contrast, diffusivity of fibrinogen variant I-9 with truncated C-terminal portions of the Aα chains was much less concentration-dependent, indicating the importance of intermolecular linkages formed by the αC regions. Theoretical models combined with all-atom molecular dynamics simulations revealed partially bent fibrinogen solution conformations that interpolate between a flexible chain and a rigid rod observed in the crystal. The results obtained illuminate the important role of the αC regions in modulating the fibrinogen molecular shape through formation of weak intermolecular linkages that control the bulk properties of fibrinogen solutions

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ?2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30-0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38-0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ?60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates

Reply to Nielsen et al.:Social mindfulness is associated with countries’ environmental performance and individual environmental concern

Nielsen et al. (1) argue that Van Doesum et al. (2) need to consider three points for their interpretation of a positive association between individual-level social mindfulness (SoMi) and environmental performance (EPI) at the country level (3). The association is weaker when 1) it is controlled for GDP and 2) when the data of three countries are removed; also, 3) the data do not address the association between SoMi and individual-level environmental concern. We discuss these points in turn

Wherefore art thou competitors? How situational affordances help differentiate among prosociality, individualism, and competition

The Triple Dominance Measure (choosing between prosocial, individualistic, and competitive options) and the Slider Measure ("sliding" between various orientations, for example, from individualistic to prosocial) are two widely used techniques to measure social value orientation, that is, the weight individuals assign to own and others' outcomes in interdependent situations. Surprisingly, there is only moderate correspondence between these measures, but it is unclear why and what the implications are for identifying individual differences in social value orientation. Using a dataset of 8021 participants from 31 countries and regions, this study revealed that the Slider Measure identified fewer competitors than the Triple Dominance Measure, accounting for approximately one-third of the non-correspondence between the two measures. This is (partially) because many of the Slider items do not afford a competitive option. In items where competition is combined with individualism, competitors tended to make the same choices as individualists. Futhermore, we demonstrated the uniqueness of competitors. Compared to prosocials and individualists, competitors exhibited lower levels of both social mindfulness and trust. Overall, the present work highlights the importance of situational affordances in measuring personality, the benefits of distinguishing between individualists and competitors, and the importance of utilizing a measure that distinguishes between these two proself orientations.info:eu-repo/semantics/publishedVersio