Synthesis and evaluation of potent yaku'amide A analogs

Two full-length analogs of the anticancer peptide yaku’amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three E- and...

Theories as Representations

The nature of scientific representation has been the subject of considerable discussion recently with frequent comparisons made between theories and depictive artworks. Here it is argued that the Semantic Approach can be understood as a useful means of capturing this representational relationship, in both the scientific and artistic domains. In particular, by deploying the device of partial structures it can capture the manner in which apparently inconsistent theories and pictures can represent, as well as that of certain abstract artworks. Nevertheless, care must be taken in drawing on examples from one domain to support or undermine arguments made about the nature of representation in the other. The comparisons involved highlight crucial differences between theories and artworks that will be drawn upon in subsequent chapters.

SOME MODEL-THEORETIC RESULTS ON THE 3-VALUED PARACONSISTENT FIRST-ORDER LOGIC QCIORE

The 3-valued paraconsistent logic Ciore was developed by Carnielli, Marcos and de Amo under the name LFI2, in the study of inconsistent databases from the point of view of logics of formal inconsistency (LFIs). They also considered a first-order version of Ciore called LFI2*. The logic Ciore enjoys extreme features concerning propagation and retropropagation of the consistency operator: a formula is consistent if and only if some of its subformulas is consistent. In addition, Ciore is algebraizable in the sense of Blok and Pigozzi. On the other hand, the logic LFI2* satisfies a somewhat counter-intuitive property: the universal and the existential quantifier are inter-definable by means of the paraconsistent negation, as it happens in classical first-order logic with respect to the classical negation. This feature seems to be unnatural, given that both quantifiers have the classical meaning in LFI2*, and that this logic does not satisfy the De Morgan laws with respect to its paraconsistent negation. The first goal of the present article is to introduce a first-order version of Ciore (which we call QCiore) preserving the spirit of Ciore, that is, without introducing unexpected relationships between the quantifiers. The second goal of the article is to adapt to QCiore the partial structures semantics for the first-order paraconsistent logic LPT1 introduced by Coniglio and Silvestrini, which generalizes the semantic notion of quasi-truth considered by Mikeberg, da Costa and Chuaqui. Finally, some important results of classical Model Theory are obtained for this logic, such as Robinson’s joint consistency theorem, amalgamation and interpolation. Although we focus on QCiore, this framework can be adapted to other 3-valued first-order LFIs.

An experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance

The treatment of hospital- and community-associated infections by methicillin-resistant Staphylococcus aureus (MRSA) is a perpetual challenge. This Gram-positive bacterium is resistant specifically to β-lactam antibiotics, and generally to many other antibacterial agents. Its resistance mechanisms to β-lactam antibiotics are activated only when the bacterium encounters a β-lactam. This activation is regulated by the transmembrane sensor/signal transducer proteins BlaR1 and MecR1. Neither the transmembrane/metalloprotease domain, nor the complete MecR1 and BlaR1 proteins, are isolatable for mechanistic study. Here we propose a model for full-length MecR1 based on homology modeling, residue coevolution data, a new extensive experimental mapping of transmembrane topology, partial structures, molecular simulations, and available NMR data. Our model defines the metalloprotease domain as a hydrophilic transmembrane chamber effectively sealed by the apo-sensor domain. It proposes that the amphipathic helices inserted into the gluzincin domain constitute the route for transmission of the β-lactam-binding event in the extracellular sensor domain, to the intracellular and membrane-embedded zinc-containing active site. From here, we discuss possible routes for subsequent activation of proteolytic action. This study provides the first coherent model of the structure of MecR1, opening routes for future functional investigations on how β-lactam binding culminates in the proteolytic degradation of MecI.

Deep Generative Models for 3D Compound Design

Rational compound design remains a challenging problem for both computational methods and medicinal chemists. Computational generative methods have begun to show promising results for the design problem. However, they have not yet used the power of 3D structural information. We have developed a novel graph-based deep generative model that combines state-of-the-art machine learning techniques with structural knowledge. Our method (“DeLinker”) takes two fragments or partial structures and designs a molecule incorporating both. The generation process is protein context dependent, utilising the relative distance and orientation between the partial structures. This 3D information is vital to successful compound design, and we demonstrate its impact on the generation process and the limitations of omitting such information. In a large scale evaluation, DeLinker designed 60% more molecules with high 3D similarity to the original molecule than a database baseline. When considering the more relevant problem of longer linkers with at least five atoms, the outperformance increased to 200%. We demonstrate the effectiveness and applicability of this approach on a diverse range of design problems: fragment linking, scaffold hopping, and proteolysis targeting chimera (PROTAC) design. As far as we are aware, this is the first molecular generative model to incorporate 3D structural information directly in the design process. Code is available at https://github.com/oxpig/DeLinker.

Hierarchical Clustering-Aligning Framework Based Fast Large-Scale 3D Reconstruction Using Aerial Imagery

With extensive applications of Unmanned Aircraft Vehicle (UAV) in the field of remotesensing, 3D reconstruction using aerial images has been a vibrant area of research. However,fast large-scale 3D reconstruction is a challenging task. For aerial image datasets, large scale meansthat the number and resolution of images are enormous, which brings significant computationalcost to the 3D reconstruction, especially in the process of Structure from Motion (SfM). In thispaper, for fast large-scale SfM, we propose a clustering-aligning framework that hierarchicallymerges partial structures to reconstruct the full scene. Through image clustering, an overlappingrelationship between image subsets is established. With the overlapping relationship, we proposea similarity transformation estimation method based on joint camera poses of common images.Finally, we introduce the closed-loop constraint and propose a similarity transformation-based hybridoptimization method to make the merged complete scene seamless. The advantage of the proposedmethod is a significant efficiency improvement without a marginal loss in accuracy. Experimentalresults on the Qinling dataset captured over Qinling mountain covering 57 square kilometersdemonstrate the efficiency and robustness of the proposed method.

Ligand geometry controlling Zn-MOF partial structures for their catalytic performance in Knoevenagel condensation

Novel 1D to 3D structures of Zn-MOFs and their morphologies were assembled and showed high catalytic performance for Knoevenagel condensation.

Humin as an External Electron Mediator for Microbial Pentachlorophenol Dechlorination: Exploration of Redox Active Structures Influenced by Isolation Methods

Humin (HM) has been reported to function as an external electron mediator (EEM) in various microbial reducing reactions. In this study, the effect of isolation methods on EEM functionality and the chemical/electrochemical structures of HM were examined based on the correlation between dechlorination rates in the anaerobic HM-dependent pentachlorophenol (PCP)-dechlorinating consortium and the chemical/electrochemical structures of HM. A lack of PCP dechlorination activity suggested no EEM function in the HM samples prepared as a soluble fraction in dimethyl sulfoxide and sulfuric acid (which did not contain any electric capacitance). Other HM samples exhibited EEM functionality as shown by the dechlorination activity ranging from 0.55 to 3.48 (µmol Cl−) L−1d−1. The comparison of dechlorination activity with chemical structural characteristics suggested that HM with EEM functionalities had predominantly aliphatic and carbohydrate carbons with the partial structures C=O, O=C–N, and O=C–O. EEM functionality positively correlated with the proportion of O=C–N and O=C–O, suggesting an association between peptidoglycan structure and EEM functionality. The lack of detection of a quinone structure in one HM sample with EEM functionality and a negative correlation with aromatic or C=C carbon suggested that the mechanism containing quinone structures is a minor component for the functionality of EEM.