Craig Interpolation with Clausal First-Order Tableaux

We develop foundations for computing Craig-Lyndon interpolants of two given formulas with first-order theorem provers that construct clausal tableaux. Provers that can be understood in this way include efficient machine-oriented systems based on calculi of two families: goal-oriented such as model elimination and the connection method, and bottom-up such as the hypertableau calculus. We present the first interpolation method for first-order proofs represented by closed tableaux that proceeds in two stages, similar to known interpolation methods for resolution proofs. The first stage is an induction on the tableau structure, which is sufficient to compute propositional interpolants. We show that this can linearly simulate different prominent propositional interpolation methods that operate by an induction on a resolution deduction tree. In the second stage, interpolant lifting, quantified variables that replace certain terms (constants and compound terms) by variables are introduced. We justify the correctness of interpolant lifting (for the case without built-in equality) abstractly on the basis of Herbrand’s theorem and for a different characterization of the formulas to be lifted than in the literature. In addition, we discuss various subtle aspects that are relevant for the investigation and practical realization of first-order interpolation based on clausal tableaux.

     

Investigation of long term drift of an intraocular pressure sensor

Microsystem Technologies - “Zero drift” behavior of an optical intraocular pressure sensor is studied using an analytical model based on the deflection of a circular membrane. Results...     

Semantical investigations into nonmonotonic and probabilistic logics

Different forms of semantics have been proposed for conditionals of the form “Usually, if A then B”, ranging from quantitative probability distributions to qualitative approaches using plausibility orderings, possibility distributions, or conditional objects. Atomic-bound systems, also called big-stepped probabilities, allow qualitative reasoning with probabilities, aiming at bridging the gap between qualitative and quantitative argumentation and providing a model for the nonmonotonic reasoning system P. By using Goguen and Burstall’s notion of institutions for the formalization of logical systems, we elaborate precisely which formal connections exist among big-stepped probabilities, standard probabilities, and qualitative logics. Based on our investigations, we also develop two variants of conditional objects, one of them having a simpler semantics while still providing a model for system P.     

Analysis of time-dependent flow-sensitive PC-MRI data

Many flow visualization techniques, especially integration-based methods, are problematic when the measured data exhibit noise and discretization issues. Particularly, this is the case for flow-sensitive phase-contrast magnetic resonance imaging (PC-MRI) data sets which not only record anatomic information, but also time-varying flow information. We propose a novel approach for the visualization of such data sets using integration-based methods. Our ideas are based upon finite-time Lyapunov exponents (FTLE) and enable identification of vessel boundaries in the data as high regions of separation. This allows us to correctly restrict integration-based visualization to blood vessels. We validate our technique by comparing our approach to existing anatomy-based methods as well as addressing the benefits and limitations of using FTLE to restrict flow. We also discuss the importance of parameters, i.e., advection length and data resolution, in establishing a well-defined vessel boundary. We extract appropriate flow lines and surfaces that enable the visualization of blood flow within the vessels. We further enhance the visualization by analyzing flow behavior in the seeded region and generating simplified depictions.     

Rigid body dynamics with a scalable body,quaternions and perfect constraints

In this paper, we present a formulation of the quaternion constraint for rigid body rotations in the form of a standard perfect bilateral mechanical constraint, for which the associated Lagrangian multiplier has the meaning of a constraint force. First, the equations of motion of a scalable body are derived. A scalable body has three translational, three rotational, and one uniform scaling degree of freedom. As generalized coordinates, an unconstrained quaternion and a displacement vector are used. To the scalable body, a perfect bilateral constraint is added, restricting the quaternion to unit length and making the body rigid. This way a quaternion based differential algebraic equation (DAE) formulation for the dynamics of a rigid body is obtained, where the 7×7 mass matrix is regular and the unit length restriction of the quaternion is enforced by a mechanical constraint. Finally, the equations of motion in the form of a DAE are linked to the Newton–Euler equations of motion of a rigid body. The rigid body DAE formulation is useful for the construction of (energy) consistent integrators.     

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient’s immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL^pro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL^pro. Moreover, we report the discovery of isoindolines as a new class of potent PL^pro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL^pro are valuable starting points for the development of new pan-coronaviral inhibitors.     

Thermoplastic Starch Nanocomposites Reinforced with Cellulose Nanocrystal Suspensions Containing Residual Salt from Neutralization

Sulfuric acid-catalyzed hydrolysis of cellulose commonly isolates cellulose nanocrystals (CNCs). Neutralizing the reactant solution with sodium hydroxide facilitates efficient downstream processing, but residual salt remains in the product. This study examines the reinforcing effects of CNCs from suspensions that contain residual salt on the mechanical properties of thermoplastic starch nanocomposites. By reinforcing starch films with up to 5 wt% CNCs, stiffness and strength are improved by 118% and 79%, respectively, indicating a good dispersion of CNCs in the starch matrix. Compared to nanocomposites incorporating salt-free CNCs, the remaining salt has no significant impact on the material's mechanical performance. The results indicate great potential of CNCs containing residual salt as biobased, low-cost nanofiller in hydrophilic polymer matrices.     

(S)-Reutericyclin: Susceptibility Testing and In Vivo Effect on Murine Fecal Microbiome and Volatile Organic Compounds

We aimed to assess the in vitro antimicrobial activity and the in vivo effect on the murine fecal microbiome and volatile organic compound (VOC) profile of (S)-reutericyclin. The antimicrobial activity of (S)-reutericyclin was tested against Clostridium difficile, Listeria monocytogenes, Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Staphylococcus (S.) epidermidis, Streptococcus agalactiae, Pseudomonas aeruginosa and Propionibacterium acnes. Reutericyclin or water were gavage fed to male BALBc mice for 7 weeks. Thereafter stool samples underwent 16S based microbiome analysis and VOC analysis by gas chromatography mass spectrometry (GC-MS). (S)-reutericyclin inhibited growth of S. epidermidis only. Oral (S)-reutericyclin treatment caused a trend towards reduced alpha diversity. Beta diversity was significantly influenced by reutericyclin. Linear discriminant analysis Effect Size (LEfSe) analysis showed an increase of Streptococcus and Muribaculum as well as a decrease of butyrate producing Ruminoclostridium, Roseburia and Eubacterium in the reutericyclin group. VOC analysis revealed significant increases of pentane and heptane and decreases of 2,3-butanedione and 2-heptanone in reutericyclin animals. The antimicrobial activity of (S)-reutericyclin differs from reports of (R)-reutericyclin with inhibitory effects on a multitude of Gram-positive bacteria reported in the literature. In vivo (S)-reutericyclin treatment led to a microbiome shift towards dysbiosis and distinct alterations of the fecal VOC profile.