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Dusseldorf, Germany

Heinrich Heine University Düsseldorf was founded in 1965 as the successor organisation to Düsseldorf’s Medical Academy of 1907. Following several expansions throughout the decades, the university has been comprising five faculties since 1993. At present, more than 20,000 full-time students are pursuing studies at HHU. There is a total staff of approximately 2,900 persons at HHU . Wikipedia.

The impressive efficiency and selectivity of biological catalysts has engendered a long-standing effort to understand the details of enzyme action. It is widely accepted that enzymes accelerate reactions through their steric and electronic complementarity to the reactants in the rate-determining transition states. Thus, tight binding to the transition state of a reactant (rather than to the corresponding substrate) lowers the activation energy of the reaction, providing strong catalytic activity. Debates concerning the fundamentals of enzyme catalysis continue, however, and non-natural enzyme mimics offer important additional insight in this area. Molecular structures that mimic enzymes through the design of a predetermined binding site that stabilizes the transition state of a desired reaction are invaluable in this regard. Catalytic antibodies, which can be quite active when raised against stable transition state analogues of the corresponding reaction, represent particularly successful examples. Recently, synthetic chemistry has begun to match nature's ability to produce antibody-like binding sites with high affinities for the transition state. Thus, synthetic, molecularly imprinted polymers have been engineered to provide enzyme-like specificity and activity, and they now represent a powerful tool for creating highly efficient catalysts. In this Account, we review recent efforts to develop enzyme models through the concept of transition state stabilization. In particular, models for carboxypeptidase A were prepared through the molecular imprinting of synthetic polymers. On the basis of successful experiments with phosphonic esters as templates to arrange amidinium groups in the active site, the method was further improved by combining the concept of transition state stabilization with the introduction of special catalytic moieties, such as metal ions in a defined orientation in the active site. In this way, the imprinted polymers were able to provide both an electrostatic stabilization for the transition state through the amidinium group as well as a synergism of transition state recognition and metal ion catalysis. The result was an excellent catalyst for carbonate hydrolysis. These enzyme mimics represent the most active catalysts ever prepared through the molecular imprinting strategy. Their catalytic activity, catalytic efficiency, and catalytic proficiency clearly surpass those of the corresponding catalytic antibodies. The active structures in natural enzymes evolve within soluble proteins, typically by the refining of the folding of one polypeptide chain. To incorporate these characteristics into synthetic polymers, we used the concept of transition state stabilization to develop soluble, nanosized carboxypeptidase A models using a new polymerization method we term the "post-dilution polymerization method". With this methodology, we were able to prepare soluble, highly cross-linked, single-molecule nanoparticles. These particles have controlled molecular weights (39 kDa, for example) and, on average, one catalytically active site per particle. Our strategies have made it possible to obtain efficient new enzyme models and further advance the structural and functional analogy with natural enzymes. Moreover, this bioinspired design based on molecular imprinting in synthetic polymers offers further support for the concept of transition state stabilization in catalysis. Source

Sousa F.L.,Heinrich Heine University Dusseldorf
Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood-Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent-ocean interface via the ATP synthase, (iii) harnessing of Na(+) gradients generated by H(+)/Na(+) antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type 'reduced iron → reduced carbon' at the beginning of bioenergetic evolution. Source

Yuki N.,National University of Singapore | Hartung H.-P.,Heinrich Heine University Dusseldorf
New England Journal of Medicine

The Guillain-Barré syndrome, an acute immune-mediated neuropathy, still carries a grave prognosis. The syndrome is manifested as a spectrum of peripheral-nerve disorders with several clinical variants that are characterized by the distribution of weakness of the limbs or cranialnerve- innervated muscles, underlying pathological abnormalities, and associated autoantibodies. 5-7,34,35,37,85 The most frequent antecedent infection is C. jejuni infection, which is associated with 30% of cases of the Guillain-Barré syndrome and 20% of cases of the Miller Fisher syndrome.9,40 Molecular mimicry between the bacterial and peripheral-nerve components appears to elicit autoantibodies and induce the development of the axonal subtype of the Guillain-Barré syndrome or the Miller Fisher syndrome after enteritis with C. jejuni. 40,50,53,54 Eculizumab, erythropoietin, and fasudil, which have been used in the treatment of other, unrelated medical conditions, have shown promise in animal models of the Guillain- Barré syndrome, 57,58,60 but clinical studies are lacking. Copyright © 2012 Massachusetts Medical Society. Source

Meisel R.,Heinrich Heine University Dusseldorf
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K

Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials. Source

Menzel A.M.,Heinrich Heine University Dusseldorf
Physics Reports

One characteristic feature of soft matter systems is their strong response to external stimuli. As a consequence they are comparatively easily driven out of their ground state and out of equilibrium, which leads to many of their fascinating properties. Here, we review illustrative examples. This review is structured by an increasing distance from the equilibrium ground state. On each level, examples of increasing degree of complexity are considered. In detail, we first consider systems that are quasi-statically tuned or switched to a new state by applying external fields. These are common liquid crystals, liquid crystalline elastomers, or ferrogels and magnetic elastomers. Next, we concentrate on systems steadily driven from outside e.g.by an imposed flow field. In our case, we review the reaction of nematic liquid crystals, of bulk-filling periodically modulated structures such as block copolymers, and of localized vesicular objects to an imposed shear flow. Finally, we focus on systems that are "active" and "self-driven". Here our range spans from idealized self-propelled point particles, via sterically interacting particles like granular hoppers, via microswimmers such as self-phoretically driven artificial Janus particles or biological microorganisms, via deformable self-propelled particles like droplets, up to the collective behavior of insects, fish, and birds. As we emphasize, similarities emerge in the features and behavior of systems that at first glance may not necessarily appear related. We thus hope that our overview will further stimulate the search for basic unifying principles underlying the physics of these soft materials out of their equilibrium ground state. © 2014 Elsevier B.V. Source

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