Fuzzy PSO: A Generalization of Particle Swarm Optimization

In standard particle swarm optimization (PSO), the best particle in each neighborhood exerts its influence over other particles in the neighborhood. In this paper, we propose fuzzy PSO, a generalization which differs from standard PSO in the following respect: charisma is defined to be a fuzzy variable, and more than one particle in each neighborhood can have a non-zero degree of charisma, and, consequently, is allowed to influence others to a degree that depends on its charisma. We evaluate our model on the weighted maximum satisfiability (maxsat) problem, comparing performance to standard PSO and to Walk-Sat

Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics

Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent

Gaussian versus Cauchy Membership Functions in Fuzzy PSO

In standard particle swarm optimization (PSO), the best particle in each neighborhood exerts its influence over other particles in the neighborhood. Fuzzy PSO is a generalization which differs from standard PSO in the following respect: charisma (influence over others) is defined to be a fuzzy variable, and more than one particle in each neighborhood can have a non-zero degree of charisma, and, consequently, is allowed to influence others to a degree that depends on its charisma. In this paper, we compare between the use of the Gaussian and Cauchy membership functions (MF) as the MF of the charisma fuzzy variable. We evaluate the performance of the two MFs using the weighted max-sat problem

Cell Reports

The stringent response enables metabolic adaptation of bacteria under stress conditions and is governed by RelA/SpoT Homolog (RSH)-type enzymes. Long RSH-type enzymes encompass an N-terminal domain (NTD) harboring the second messenger nucleotide (p)ppGpp hydrolase and synthetase activity and a stress-perceiving and regulatory C-terminal domain (CTD). CTD-mediated binding of Rel to stalled ribosomes boosts (p)ppGpp synthesis. However, how the opposing activities of the NTD are controlled in the absence of stress was poorly understood. Here, we demonstrate on the RSH-type protein Rel that the critical regulative elements reside within the TGS (ThrRS, GTPase, and SpoT) subdomain of the CTD, which associates to and represses the synthetase to concomitantly allow for activation of the hydrolase. Furthermore, we show that Rel forms homodimers, which appear to control the interaction with deacylated-tRNA, but not the enzymatic activity of Rel. Collectively, our study provides a detailed molecular view into the mechanism of stringent response repression in the absence of stress