The plasmin-antiplasmin system: structural and functional aspects

The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α2-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α2-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α2-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α2-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamil

Role of FGFRL1 and other FGF signaling proteins in early kidney development

The mammalian kidney develops from the ureteric bud and the metanephric mesenchyme. In mice, the ureteric bud invades the metanephric mesenchyme at day E10.5 and begins to branch. The tips of the ureteric bud induce the metanephric mesenchyme to condense and form the cap mesenchyme. Some cells of this cap mesenchyme undergo a mesenchymal-to-epithelial transition and differentiate into renal vesicles, which further develop into nephrons. The developing kidney expresses Fibroblast growth factor (Fgf)1, 7, 8, 9, 10, 12 and 20 and Fgf receptors Fgfr1 and Fgfr2. Fgf7 and Fgf10, mainly secreted by the metanephric mesenchyme, bind to Fgfr2b of the ureteric bud and induce branching. Fgfr1 and Fgfr2c are required for formation of the metanephric mesenchyme, however the two receptors can substitute for one another. Fgf8, secreted by renal vesicles, binds to Fgfr1 and supports survival of cells in the nascent nephrons. Fgf9 and Fgf20, expressed in the metanephric mesenchyme, are necessary to maintain survival of progenitor cells in the cortical region of the kidney. FgfrL1 is a novel member of the Fgfr family that lacks the intracellular tyrosine kinase domain. It is expressed in the ureteric bud and all nephrogenic structures. Targeted deletion of FgfrL1 leads to severe kidney dysgenesis due to the lack of renal vesicles. FgfrL1 is known to interact mainly with Fgf8. It is therefore conceivable that FgfrL1 restricts signaling of Fgf8 to the precise location of the nascent nephrons. It might also promote tight adhesion of cells in the condensed metanephric mesenchyme as required for the mesenchymal-to-epithelial transitio

The human α2-plasmin inhibitor: functional characterization of the unique plasmin(ogen)-binding region

The human α2-plasmin inhibitor (A2PI) possesses unique N- and C-terminal extensions that significantly influence its biological activities. The C-terminal segment, A2PIC (Asn398-Lys452), contains six lysines thought to be involved in the binding to lysine-binding sites in the kringle domains of human plasminogen, of which four (Lys422, Lys429, Lys436, Lys452) are completely and two (Lys406, Lys415) are partially conserved. Multiple Lys to Ala mutants of A2PIC were expressed in Escherichia coli and used in intrinsic fluorescence titrations with kringle domains K1, K4, K4+5, and K1+2+3 of human plasminogen. We were able to identify the C-terminal Lys452 as the main binding partner in recombinant A2PIC (rA2PIC) constructs with isolated kringles. We could show a cooperative, zipper-like enhancement of the interaction between C-terminal Lys452 and internal Lys436 of rA2PIC and isolated K1+2+3, whereas the other internal lysine residues contribute only to a minor extent to the binding process. Sulfated Tyr445 in the unique C-terminal segment revealed no influence on the binding affinity to kringle domain

A scalable approach to the computation of invariant measures for high-dimensional Markovian systems

Abstract The Markovian invariant measure is a central concept in many disciplines. Conventional numerical techniques for data-driven computation of invariant measures rely on estimation and further numerical processing of a transition matrix. Here we show how the quality of data-driven estimation of a transition matrix crucially depends on the validity of the statistical independence assumption for transition probabilities. Moreover, the cost of the invariant measure computation in general scales cubically with the dimension - and is usually unfeasible for realistic high-dimensional systems. We introduce a method relaxing the independence assumption of transition probabilities that scales quadratically in situations with latent variables. Applications of the method are illustrated on the Lorenz-63 system and for the molecular dynamics (MD) simulation data of the α-synuclein protein. We demonstrate how the conventional methodologies do not provide good estimates of the invariant measure based upon the available α-synuclein MD data. Applying the introduced approach to these MD data we detect two robust meta-stable states of α-synuclein and a linear transition between them, involving transient formation of secondary structure, qualitatively consistent with previous purely experimental reports

Supermultiplets in N=1 SUSY SU(2) Yang-Mills Theory

We study $\mathcal{N}=1$ supersymmetric Yang-Mills theory (SYM) on the lattice. The non-perturbative nature of supersymmetric field theories is still largely unknown. Similarly to QCD, SYM is confining and contains strongly bound states. Applying the variational method together with different smearing techniques we extract masses of the lightest bound states such as gluino-glue, glueball and mesonic states. As these states should form supermultiplets, this study allows to check whether SYM remains supersymmetric also on the quantum level.Comment: Presented at Lattice 2017, the 35th International Symposium on Lattice Field Theory at Granada, Spain (18-24 June 2017

Improved results for the mass spectrum of N=1 supersymmetric SU(3) Yang-Mills theory

This talk summarizes the results of the DESY-M\"unster collaboration for $\mathcal{N}=1$ supersymmetric Yang-Mills theory with the gauge group SU(3). It is an updated status report with respect to our preliminary data presented at the last conference. In order to control the lattice artefacts we have now considered a clover improved fermion action and different values of the gauge coupling.Comment: Presented at Lattice 2017, the 35th International Symposium on Lattice Field Theory at Granada, Spain (18-24 June 2017

Convenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular SNAr reactions

Benzodiazepinones are an important family of heterocycles with very attractive pharmacological properties and peptidomimetic abilities. We report herein a rapid and efficient two-step synthesis of polysubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones using a multicomponent condensation/cyclization strategy. The approach uses an Ugi four-component reaction to condense readily available Nα -Fmoc-amino acids, amines and isocyanides with a 2- fluorobenzaldehyde derivative followed by a one-pot Fmoc-group removal, intramolecular aromatic nucleophilic substitution for ring closure and side chain deprotection. The described method gives access to benzo-fused 7- and 8-membered rings bearing a wide variety of functionalized substituents and was applied to efficiently prepare tri- and tetrasubstituted 1,4- benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones in high yields in two straightforward steps

On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment – a review

Off-label intravitreal use of the vascular endothelial growth factor (VEGF) antibody bevacizumab for retinopathy of prematurity (ROP) increases despite lack of studies on safety, pharmacokinetics and dosage in developing individuals. Systemic absorption has been considered negligible. A literature search was performed with emphasis on potential adverse systemic effects in developing individuals

Contribution of nanoclays to the barrier properties of a model proton exchange membrane for fuel cell application

peer reviewedaudience: researcherDirect methanol fuel cells (DMFCs) that use a proton exchange membrane (PEM) as electrolyte, is a promising alternative source of energy for the future. However, methanol crossover from the anodic side to the cathodic one is a major problem in DMFC. Proper dispersion of layered silicates within the fuel cell membrane has been proposed as a strategy for improving the barrier properties of the membrane. The validity of this approach has been tested in case of a model membrane consisting of phosphotungstic acid doped poly(vinyl alcohol). A solvent casting technique has been used, which allows the nanofiller to be delaminated by an ultrasonic pre-treatment, as confirmed by TEM and XRD analysis. The layered silicates have a favourable impact on the methanol permeability, whose the decrease overcompensates some loss in ionic conductivity