Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum

Boromycin is a boron-containing macrolide antibiotic produced by Streptomyces antibioticus with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. In vitro antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against Plasmodium falciparum and the zoonotic Plasmodium knowlesi. In contrast to tetracyclines, boromycin rapidly killed asexual stages of both Plasmodium species already at low concentrations (~ 1 nM) including multidrug resistant P. falciparum strains (Dd2, K1, 7G8). In addition, boromycin was active against P. falciparum stage V gametocytes at a low nanomolar range (IC50: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.

Trypanin Disruption Affects the Motility and Infectivity of the Protozoan Trypanosoma cruzi

The flagellum of Trypanosomatids is an organelle that contributes to multiple functions, including motility, cell division, and host–pathogen interaction. Trypanin was first described in Trypanosoma brucei and is part of the dynein regulatory complex. TbTrypanin knockdown parasites showed motility defects in procyclic forms; however, silencing in bloodstream forms was lethal. Since TbTrypanin mutants show drastic phenotypic changes in mammalian stages, we decided to evaluate if the Trypanosoma cruzi ortholog plays a similar role by using the CRISPR-Cas9 system to generate null mutants. A ribonucleoprotein complex of SaCas9 and sgRNA plus donor oligonucleotide were used to edit both alleles of TcTrypanin without any selectable marker. TcTrypanin −/− epimastigotes showed a lower growth rate, partially detached flagella, normal numbers of nuclei and kinetoplasts, and motility defects such as reduced displacement and speed and increased tumbling propensity. The epimastigote mutant also showed decreased efficiency of in-vitro metacyclogenesis. Mutant parasites were able to complete the entire life cycle in vitro; however, they showed a reduction in their infection capacity compared with WT and addback cultures. Our data show that T. cruzi life cycle stages have differing sensitivities to TcTrypanin deletion. In conclusion, additional work is needed to dissect the motility components of T. cruzi and to identify essential molecules for mammalian stages.

Integration of Energy Oriented Manufacturing Simulation into the Life Cycle Evaluation of Lightweight Body Parts

Recent years introduced process and material innovations in the design and manufacturing of lightweight body parts for larger scale manufacturing. However, lightweight materials and new manufacturing technologies often carry a higher environmental burden in earlier life cycle stages. The prospective life cycle evaluation of lightweight body parts remains to this day a challenging task. Yet, a functioning evaluation approach in early design stages is the prerequisite for integrating assessment results in engineering processes and thus allowing for a life cycle oriented decision making. The current paper aims to contribute to the goal of a prospective life cycle evaluation of fiber-reinforced lightweight body parts by improving models that enable to predict energy and material flows in the manufacturing stage. To this end, a modeling and simulation approach has been developed that integrates bottom-up process models into a process chain model. The approach is exemplarily applied on a case study of a door concept. In particular, the energy intensity of compression molding of glass fiber and carbon fiber sheet molding compounds has been analyzed and compared over the life cycle with a steel reference part.

Lean Construction Concept Used to Develop Infrastructure Facilities for Tourism Clusters

The relevance of the article is conditioned on tourist infrastructure problems and underdevelopment when creating and developing territorial clusters, for which there is not enough research materials in the context of tourism cluster facilities construction, despite the fact that the issues of lean construction (LC) are widely covered. Based on the relevance, the main hypothesis of the study was determined. It consists of the fact that the use of lean construction can increase the efficiency of construction megaprojects in the field of tourism clusters. The objective of this study is to develop a mechanism for the development of tourism clusters based on the lean construction concept that will be aimed at increasing the efficiency of construction projects taking into account the accumulated world experience. Within the framework of the tasks set, the analysis of the lean construction methodological base was carried out, methodological recommendations aimed at increasing the efficiency of construction megaprojects of tourism clusters based on the lean construction concept were developed, a model for the implementation of lean construction in infrastructure projects of tourism clusters, as well as a checklist of the analysis technology were elaborated. The proposed methodological approach to the implementation of tourism cluster megaprojects based on the lean construction concept is the basis for organizing and planning development activities at the tactical and operational levels. To assess the effectiveness of lean construction tool introduction to implement infrastructure projects of tourism clusters, a comparative analysis was carried out and the construction time and lifecycle cost of a typical guest house were calculated without taking into account the lean construction methodology and after its introduction. The results obtained, namely, the duration of the project and costs at life cycle stages made it possible to conclude that the proposed methodological approach is effective.

Chương 5 Thương hiệu và sản phẩm, quy trình phát triển sản phẩm (developing new products and managing the product life cycle)

every product passes through several life-cycle stages, and each stage poses new challenges requiring different marketing strategies and tactics

Transcriptome-wide identification of coding and noncoding RNA-binding proteins defines the comprehensive RNA interactome of Leishmania mexicana

Proteomic profiling of RNA-binding proteins in Leishmania is currently limited to polyadenylated mRNA-binding proteins, leaving proteins that interact with nonadenylated RNAs, including noncoding RNAs and pre-mRNAs, unidentified. Using a combination of unbiased orthogonal organic phase separation methodology and tandem mass tag-labelling-based high resolution quantitative proteomic mass spectrometry, we robustly identified 2,417 RNA-binding proteins, including 1289 putative novel non-poly(A)-RNA-binding proteins across the two main Leishmania life cycle stages. Eight out of twenty Leishmania deubiquitinases including the recently characterised L. mexicana DUB2 with an elaborate RNA-binding protein interactome were exclusively identified in the non-poly(A)-RNA-interactome. Additionally, an increased representation of WD40 repeat domains were observed in the Leishmania non-poly(A)-RNA-interactome, thus uncovering potential involvement of this protein domain in RNA-protein interactions in Leishmania. We also characterise the protein-bound RNAs using RNA-sequencing and show that in addition to protein coding transcripts ncRNAs are also enriched in the protein-RNA interactome. Differential gene expression analysis revealed enrichment of 145 out of 195 total L. mexicana protein kinase genes in the protein-RNA-interactome, suggesting important role of protein-RNA interactions in the regulation of the Leishmania protein kinome. Additionally, we characterise the quantitative changes in RNA-protein interactions in hundreds of Leishmania proteins following inhibition of heat shock protein 90 (Hsp90). Our results show that the Hsp90 inhibition in Leishmania causes widespread disruption of RNA-protein interactions in ribosomal proteins, proteasomal proteins and translation factors in both life cycle stages, suggesting downstream effect of the inhibition on protein synthesis and degradation pathways in Leishmania. This study defines the comprehensive RNA interactome of Leishmania and provides in-depth insight into the widespread involvement of RNA-protein interactions in Leishmania biology.

How Does Destination Image Evolve? Introducing the Co-creation of the Destination Image Approach

Although destination image is one of the most studied topics in tourism literature, little is known about how it is formed in the minds of people and how destination image evolves through destination life cycle stages. Thus, the purpose of this paper is to present a theoretical approach to the destination image formation process. In this conceptual paper, the co-created destination image (CoDI) approach was introduced. Co-creation and tourism area life cycle (TALC) approaches were used as the theoretical frameworks. The main elements of CoDI are interaction value, self-regulated image, and the co-creation process. Twelve CoDIs were developed for the four main stages of the TALC model—namely, exploration, development, stagnation, and decline. The CoDI approach shows that destination image formation evolves throughout the destination life cycle. Co-creation of the destination image is first introduced in this paper, which is used to explain how the image of destinations evolves.

Prevalence and Histopathological Studies on Intestinal Cestode Parasite of Avian Host Gallus Domesticus (L) From Nashik Region, Maharashtra State, India

The lowest infection is recorded in rainy season and highest in summer season, may be due to life cycle stages and intermediate host availability increases in winter and became adult in definitive host in summer. No nematode and trematode parasite were considered and identified during the study period. Cysts were found deep in submucosa, although touches to serosa. The non-penetrative type of worms is Cotugnia sp. and Thaparea sp.; while the penetrative type of worm is Raillietina sp. and Paruterina sp. Free gravid segments mostly found in the posterior region of intestine while mature segments are freely suspended from scoleces in the lumen of intestine, only scoleces are attached, either superficially (non-penetrative type) or deep in submucosa (Penetrative type). Keywords: Cestode, histopathology, prevalence, hold-fast organs, Penetrative scolex

Analysis of pir gene expression across the Plasmodium life cycle

Background Plasmodium interspersed repeat (pir) is the largest multigene family in the genomes of most Plasmodium species. A variety of functions for the PIR proteins which they encode have been proposed, including antigenic variation, immune evasion, sequestration and rosetting. However, direct evidence for these is lacking. The repetitive nature of the family has made it difficult to determine function experimentally. However, there has been some success in using gene expression studies to suggest roles for some members in virulence and chronic infection. Methods Here pir gene expression was examined across the life cycle of Plasmodium berghei using publicly available RNAseq data-sets, and at high resolution in the intraerythrocytic development cycle using new data from Plasmodium chabaudi. Results Expression of pir genes is greatest in stages of the parasite which invade and reside in red blood cells. The marked exception is that liver merozoites and male gametocytes produce a very large number of pir gene transcripts, notably compared to female gametocytes, which produce relatively few. Within the asexual blood stages different subfamilies peak at different times, suggesting further functional distinctions. Representing a subfamily of its own, the highly conserved ancestral pir gene warrants further investigation due to its potential tractability for functional investigation. It is highly transcribed in multiple life cycle stages and across most studied Plasmodium species and thus is likely to play an important role in parasite biology. Conclusions The identification of distinct expression patterns for different pir genes and subfamilies is likely to provide a basis for the design of future experiments to uncover their function.

Logistics Chain and Cost Assessment of Pruning-to-Energy Value Chains: Application of Life Cycle Cost Analysis Approach

Biomass from agricultural residue has significant potential as renewable energy resource. Therefore, cost-efficient processing and supply of agricultural residues are important to strategically plan and utilize this energy resource. This chapter describes the agricultural pruning to energy (PtE) value chains and presents the life cycle cost analysis (LCCA)-based cost assessment results, focusing on almond and peach tree pruning data obtained from Spain during 2015–2016. Along the main life cycle stages of PtE system, costs of harvesting, off-farm storage, transport, biomass loss, and management of biomass supply chain were considered. In terms of functional unit cost, the life cycle cost (LCC) was calculated to be about 126 €/t for almond PtE and 115 €/t for peach PtE value chain. In both cases, the harvesting stage was found to be cost at hot stage followed by the storage stage. The cost at harvesting stage was about 83% (of 126 €/t) and 82% (of 115 €/t) in the case of almond and peach cases, respectively. Similarly, the share of operational cost was about 74% and 76% for almond and peach cases, respectively. Therefore, more efforts should be made to improve the performance of logistics operations and management of such PtE initiatives.