Summary Background Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent antiinflammatory properties. Objectives The objective of this study is to investigate the antiinflammatory activity of wild-type AT (AT-WT) and a reactive center loop mutant of AT (AT-RCL) which is not capable of inhibiting thrombin. Methods Cardioprotective activities of AT-WT and AT-RCL were monitored in a mouse model of ischemia/reperfusion injury in which the left anterior descending coronary artery was occluded and then released. Results We demonstrate that AT markedly reduces myocardial infarct size by a mechanism that is independent of its anticoagulant activity. Thus, AT-RCL attenuated myocardial infarct size to the same extent as AT-WT in this acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide (fondaparinux) abrogating the cardioprotective activity of AT and a heparin-site mutant of AT exhibiting no cardioprotective property. We further demonstrate that AT up-regulates production of prostacyclin in myocardial tissues and inhibits expression of proinflammatory cytokines TNF-α and IL-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-κB signaling pathways. Conclusions Our results suggest that both AT and the non-anticoagulant AT-RCL, through their antiinflammatory signaling effects, elicit potent cardioprotective responses. Thus, AT may have therapeutic potential for treating cardiac ischemia/reperfusion injury.

Pioneer transcription factors initiate cell-fate changes by binding to silent target genes. They are among the first factors to bind key regulatory sites and facilitate chromatin opening. Here, we identify an additional role for pioneer factors. In early Caenorhabditis elegans foregut development, the pioneer factor PHA-4/FoxA binds promoters and recruits RNA polymerase II (Pol II), often in a poised configuration in which Pol II accumulates near transcription start sites. At a later developmental stage, PHA-4 promotes chromatin opening. We found many more genes with poised RNA polymerase than had been observed previously in unstaged embryos, revealing that early embryos accumulate poised Pol II and that poising is dynamic. Our results suggest that Pol II recruitment, in addition to chromatin opening, is an important feature of PHA-4 pioneer factor activity.

We develop a manifestly microscopic method to deal with strongly interacting nuclear systems that have different interactions in spin-singlet and spin-triplet states. In a first step we analyze variational wave functions that have been suggested to describe such systems, and demonstrate that the so-called commutator contributions can have important effects whenever the interactions in the spin-singlet and the spin-triplet states are very different. We then identify these contributions as terms that correspond, in the language of perturbation theory, to non-parquet diagrams. We include these diagrams in a way that is suggested by the Jastrow-Feenberg approach and show that the corrections from non-parquet contributions are, at short distances, larger than all other many-body effects.

We apply parquet-diagram summation methods for the calculation of the superfluid gap in S-wave pairing in neutron matter for realistic nucleon-nucleon interactions such as the Argonne v6 and the Reid v6 potentials. It is shown that diagrammatic contributions that are outside the parquet class play an important role. These are, in variational theories, identified as so-called "commutator contributions". Moreover, using a particle-hole propagator appropriate for a superfluid system results in the suppression of the spin-channel contribution to the induced interaction. Applying these corrections to the pairing interaction, our results agree quite well with Quantum Monte Carlo data.

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