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Modulating the Molybdenum Coordination Sphere of Escherichia coli Trimethylamie N-Oxide Reductase
(2018)
The well-studied enterobacterium Escherichia coli present in the human gut can reduce trimethylamine N-oxide (TMAO) to trimethylamine during anaerobic respiration. The TMAO reductase TorA is a monomeric, bis-molybdopterin guanine dinucleotide (bis-MGD) cofactor-containing enzyme that belongs to the dimethyl sulfoxide reductase family of molybdoenzymes. We report on a system for the in vitro reconstitution of TorA with molybdenum cofactors (Moco) from different sources. Higher TMAO reductase activities for TorA were obtained when using Moco sources containing a sulfido ligand at the molybdenum atom. For the first time, we were able to isolate functional bis-MGD from Rhodobacter capsulatus formate dehydrogenase (FDH), which remained intact in its isolated state and after insertion into apo-TorA yielded a highly active enzyme. Combined characterizations of the reconstituted TorA enzymes by electron paramagnetic resonance spectroscopy and direct electrochemistry emphasize that TorA activity can be modified by changes in the Mo coordination sphere. The combination of these results together with studies of amino acid exchanges at the active site led us to propose a novel model for binding of the substrate to the molybdenum atom of TorA.
The Potsdam answer set solving collection, or Potassco for short, bundles various tools implementing and/or applying answer set programming. The article at hand succeeds an earlier description of the Potassco project published in Gebser et al. (AI Commun 24(2):107-124, 2011). Hence, we concentrate in what follows on the major features of the most recent, fifth generation of the ASP system clingo and highlight some recent resulting application systems.
The Mo/Cu-dependent CO dehydrogenase (CODH) from Oligotropha carboxidovorans is an enzyme that is able to catalyze both the oxidation of CO to CO2 and the oxidation of H-2 to protons and electrons. Despite the close to atomic resolution structure (1.1 angstrom), significant uncertainties have remained with regard to the reaction mechanism of substrate oxidation at the unique Mo/Cu center, as well as the nature of intermediates formed during the catalytic cycle. So far, the investigation of the role of amino acids at the active site was hampered by the lack of a suitable expression system that allowed for detailed site-directed mutagenesis studies at the active site. Here, we report on the establishment of a functional heterologous expression system of O. carboxidovorans CODH in Escherichia coli. We characterize the purified enzyme in detail by a combination of kinetic and spectroscopic studies and show that it was purified in a form with characteristics comparable to those of the native enzyme purified from O. carboxidovorans. With this expression system in hand, we were for the first time able to generate active-site variants of this enzyme. Our work presents the basis for more detailed studies of the reaction mechanism for CO and H-2 oxidation of Mo/Cu-dependent CODHs in the future.
We introduce a new flexible paradigm of grounding and solving in Answer Set Programming (ASP), which we refer to as multi-shot ASP solving, and present its implementation in the ASP system clingo. Multi-shot ASP solving features grounding and solving processes that deal with continuously changing logic programs. In doing so, they remain operative and accommodate changes in a seamless way. For instance, such processes allow for advanced forms of search, as in optimization or theory solving, or interaction with an environment, as in robotics or query answering. Common to them is that the problem specification evolves during the reasoning process, either because data or constraints are added, deleted, or replaced. This evolutionary aspect adds another dimension to ASP since it brings about state changing operations. We address this issue by providing an operational semantics that characterizes grounding and solving processes in multi-shot ASP solving. This characterization provides a semantic account of grounder and solver states along with the operations manipulating them. The operative nature of multi-shot solving avoids redundancies in relaunching grounder and solver programs and benefits from the solver's learning capacities. clingo accomplishes this by complementing ASP's declarative input language with control capacities. On the declarative side, a new directive allows for structuring logic programs into named and parameterizable subprograms. The grounding and integration of these subprograms into the solving process is completely modular and fully controllable from the procedural side. To this end, clingo offers a new application programming interface that is conveniently accessible via scripting languages. By strictly separating logic and control, clingo also abolishes the need for dedicated systems for incremental and reactive reasoning, like iclingo and oclingo, respectively, and its flexibility goes well beyond the advanced yet still rigid solving processes of the latter.
teaspoon
(2018)
Answer Set Programming (ASP) is an approach to declarative problem solving, combining a rich yet simple modeling language with high performance solving capacities. We here develop an ASP-based approach to curriculum-based course timetabling (CB-CTT), one of the most widely studied course timetabling problems. The resulting teaspoon system reads a CB-CTT instance of a standard input format and converts it into a set of ASP facts. In turn, these facts are combined with a first-order encoding for CB-CTT solving, which can subsequently be solved by any off-the-shelf ASP systems. We establish the competitiveness of our approach by empirically contrasting it to the best known bounds obtained so far via dedicated implementations. Furthermore, we extend the teaspoon system to multi-objective course timetabling and consider minimal perturbation problems.
We introduce an approach to computing answer sets of logic programs, based on concepts successfully applied in Satisfiability (SAT) checking. The idea is to view inferences in Answer Set Programming (ASP) as unit propagation on nogoods. This provides us with a uniform constraint-based framework capturing diverse inferences encountered in ASP solving. Moreover, our approach allows us to apply advanced solving techniques from the area of SAT. As a result, we present the first full-fledged algorithmic framework for native conflict-driven ASP solving. Our approach is implemented in the ASP solver clasp that has demonstrated its competitiveness and versatility by winning first places at various solver contests.
We present the new multi-threaded version of the state-of-the-art answer set solver clasp. We detail its component and communication architecture and illustrate how they support the principal functionalities of clasp. Also, we provide some insights into the data representation used for different constraint types handled by clasp. All this is accompanied by an extensive experimental analysis of the major features related to multi-threading in clasp.
Acyclicity constraints are prevalent in knowledge representation and applications where acyclic data structures such as DAGs and trees play a role. Recently, such constraints have been considered in the satisfiability modulo theories (SMT) framework, and in this paper we carry out an analogous extension to the answer set programming (ASP) paradigm. The resulting formalism, ASP modulo acyclicity, offers a rich set of primitives to express constraints related to recursive structures. In the technical results of the paper, we relate the new generalization with standard ASP by showing (i) how acyclicity extensions translate into normal rules, (ii) how weight constraint programs can be instrumented by acyclicity extensions to capture stability in analogy to unfounded set checking, and (iii) how the gap between supported and stable models is effectively closed in the presence of such an extension. Moreover, we present an efficient implementation of acyclicity constraints by incorporating a respective propagator into the state-of-the-art ASP solver CLASP. The implementation provides a unique combination of traditional unfounded set checking with acyclicity propagation. In the experimental part, we evaluate the interplay of these orthogonal checks by equipping logic programs with supplementary acyclicity constraints. The performance results show that native support for acyclicity constraints is a worthwhile addition, furnishing a complementary modeling construct in ASP itself as well as effective means for translation-based ASP solving.
Answer set programming is a declarative problem-solving paradigm that rests upon a work flow involving modeling, grounding, and solving. While the former is described by Gebser and Schaub (2016), we focus here on key issues in grounding, or how to systematically replace object variables by ground terms in an effective way, and solving, or how to compute the answer sets, of a propositional logic program obtained by grounding.
Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
We present the new multi-threaded version of the state-of-the-art answer set solver clasp. We detail its component and communication architecture and illustrate how they support the principal functionalities of clasp. Also, we provide some insights into the data representation used for different constraint types handled by clasp. All this is accompanied by an extensive experimental analysis of the major features related to multi-threading in clasp.