New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness (“hubs”), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.
The chaperonin 60 (Cpn60) is present in all three kingdoms of life and is one of the most conserved proteins in living organisms. The Escherichia coli Cpn60 (GroEL) is the best studied representative of the huge Cpn60 family. It is an essential protein because in conjunction with the chaperonin 10 (Cpn10 or GroES) it forms a protein-folding machine required for correct folding of many proteins and for recycling of misfolded proteins. As many other chaperones, GroEL and GroES are also known as heat-shock proteins (HSPs), since heat stress leads to a strong induction of their expression, a measure to counteract the increase in misfolded proteins as a result of a high nonphysiological temperature. A large amount of literature is available which is dedicated to the elucidation of how protein folding is assisted by this molecular chaperone. However, apart from this primary task, additional so-called 'moonlighting' functions of GroEL proteins unrelated to their folding activity have emerged in the past years. In fact, it becomes apparent that GroEL proteins have diverse functions in particular in mutualistic and pathogenic microorganism-host interactions. In this brief review, we describe some of these recent findings focusing on the importance of GroEL for microorganism-insect interactions.
BackgroundDefence mechanisms of organisms are shaped by their lifestyle, environment and pathogen pressure. Carpenter ants are social insects which live in huge colonies comprising genetically closely related individuals in high densities within nests. This lifestyle potentially facilitates the rapid spread of pathogens between individuals. In concert with their innate immune system, social insects may apply external immune defences to manipulate the microbial community among individuals and within nests. Additionally, carpenter ants carry a mutualistic intracellular and obligate endosymbiotic bacterium, possibly maintained and regulated by the innate immune system. Thus, different selective forces could shape internal immune defences of Camponotus floridanus.ResultsThe immune gene repertoire of C. floridanus was investigated by re-evaluating its genome sequence combined with a full transcriptome analysis of immune challenged and control animals using Illumina sequencing. The genome was re-annotated by mapping transcriptome reads and masking repeats. A total of 978 protein sequences were characterised further by annotating functional domains, leading to a change in their original annotation regarding function and domain composition in about 8 % of all proteins. Based on homology analysis with key components of major immune pathways of insects, the C. floridanus immune-related genes were compared to those of Drosophila melanogaster, Apis mellifera, and other hymenoptera. This analysis revealed that overall the immune system of carpenter ants comprises many components found in these insects. In addition, several C. floridanus specific genes of yet unknown functions but which are strongly induced after immune challenge were discovered. In contrast to solitary insects like Drosophila or the hymenopteran Nasonia vitripennis, the number of genes encoding pattern recognition receptors specific for bacterial peptidoglycan (PGN) and a variety of known antimicrobial peptide (AMP) genes is lower in C. floridanus. The comparative analysis of gene expression post immune-challenge in different developmental stages of C. floridanus suggests a stronger induction of immune gene expression in larvae in comparison to adults.ConclusionsThe comparison of the immune system of C. floridanus with that of other insects revealed the presence of a broad immune repertoire. However, the relatively low number of PGN recognition proteins and AMPs, the identification of Camponotus specific putative immune genes, and stage specific differences in immune gene regulation reflects Camponotus specific evolution including adaptations to its lifestyle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1748-1) contains supplementary material, which is available to authorized users.
Clustering technique in wireless sensor networks incorporate proper utilization of the limited energy resources of the deployed sensor nodes with the highest residual energy that can be used to gather data and send the information. However, the problem of unbalanced energy consumption exists in a particular cluster node in the network. Some more powerful nodes act as cluster head to control sensor network operation when the network is organized into heterogeneous clusters. It is important to assume that energy consumption of these cluster head nodes is balanced. Often the network is organized into clusters of equal size where cluster head nodes bear unequal loads. Instead in this paper, we proposed a new protocol lowenergy adaptive unequal clustering protocol using Fuzzy c-means in wireless sensor networks (LAUCF), an unequal clustering size model for the organization of network based on Fuzzy c-means (FCM) clustering algorithm, which can lead to more uniform energy dissipation among the cluster head nodes, thus increasing network lifetime. A heuristic comparison between our proposed protocol LAUCF and other different energy-aware protocol including low energy adaptive clustering hierarchy (LEACH) has been carried out. Simulation result shows that our proposed heterogeneous clustering approach using FCM protocol is more effective in prolonging the network lifetime compared with LEACH and other protocol for long run.
The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.
The present paper discusses the dispersion equation for horizontally polarized shear waves (SH waves) in a non-homogeneous self-reinforced layer over a semi infinite self-reinforced medium with an irregularity. The dispersion equation has been obtained in closed form. In the isotropic case, when non homogeneity and irregularity are absent, the dispersion equation reduces to standard SH wave equation. The dispersion curves have been presented by means of graphs for different sizes of irregularity and different values of non-homogeneity parameters. The influence of depth of irregularity and non-homogeneity parameters on phase velocity has been studied.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.