1,721,104 research outputs found
Potassium transporters in plants--involvement in K+ acquisition, redistribution and homeostasis
No full textPotassium is a major plant nutrient which has to be accumulated in great quantity by roots and distributed throughout the plant and within plant cells. Membrane transport of potassium can be mediated by potassium channels and secondary potassium transporters. Plant potassium transporters are present in three families of membrane proteins: the K(+) uptake permeases (KT/HAK/KUP), the K(+) transporter (Trk/HKT) family and the cation proton antiporters (CPA). This review will discuss the contribution of members of each family to potassium acquisition, redistribution and homeostasis
The Clickable Guard Cell, Version II: Interactive Model of Guard Cell Signal Transduction Mechanisms and Pathways
No full textPhenotyping and genotyping of Haemonchus contortus isolates reveals a new putative candidate mutation for benzimidazole resistance in nematodes
No full textIn vitro selection of Haemonchus contortus for benzimidazole resistance reveals a mutation at amino acid 198 of beta-tubulin
No full textBenzimidazoles were the first broad-spectrum anthelmintics and are still in use today against gastro-intestinal nematodes of ruminants such as Haemonchus contortus. Benzimidazoles block the polymerization of nematode microtubules. However, their efficacy is jeopardized by the spread of drug-resistant parasites that carry point mutations in beta-tubulin. Here we use a novel in vitro selection-in vivo propagation protocol to breed drug-resistant H. contortus. After 8 generations of selection with thiabendazole an in vitro resistance factor of 1000 was reached that was also relevant in vivo in infected sheep. The same procedure carried out with ivermectin produced only a moderate resistance phenotype that was not apparent in sheep. Cloning and sequencing of the beta-tubulin genes from the thiabendazole-resistant H. contortus mutants revealed all of the isotype 1 alleles, and part of the isotype 2 alleles, to carry the mutation glutamate(198) to alanine (E198A). An allele-specific PCR was developed, which may be helpful in monitoring the prevalence of alanine(198) encoding alleles in the beta-tubulin isotype 1 gene pool of H. contortus in the field
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Membrane therapy for chagas' disease
Full text linkCurrently, benznidazole and nifurtimox are the only drugs available for the specific treatment of Chagas’ disease. Both are limited by low efficacy in the chronic stage of the disease and considerable toxicity, which is why there is an urgent need for drugs that provide safe and efficient treatment for Chagas’ disease. Trypanosoma cruzi, the causative agent of Chagas’ disease, requires specific endogenous sterols and is therefore very sensitive to sterol biosynthesis inhibitors (SBIs). SBIs are widely used as antifungals and lend themselves to drug repurposing. Sterols are an essential class of lipids in eukaryotes, where they serve as structural components of membranes and play important roles as signaling molecules. The most abundant sterol in vertebrates is cholesterol, whereas fungi synthesize ergosterol, which has a greater degree of unsaturation and an additional methyl group at C24. Like fungi, trypanosomes require the presence of ergosterol and other 24-alkylated sterols; their similar sterol content is the rationale for testing inhibitors of ergosterol synthesis against trypanosomes.
In the framework of this PhD thesis various aspects of sterol anabolism in eukaryotes and its potential exploitation as drug target in parasites were analysed. First, using genome profiling, I did a comparative genomics study of sterol biosynthesis (SB) focusing on eukaryotic parasites. In vitro testing of known SBIs and quantifying the expression levels of SB genes during the different life stages of T. cruzi and Trypanosoma brucei completed this part of the thesis. Then, I used genetically modified yeast strains as a tool to assess selectivity of SBIs to ergosterol-containing cells. Finally, integrating the results from my work led to a specific proposition how to advance drug development in Chagas’ disease.
For the genome profiling an in silico pipeline was developed to globally evaluate sterol metabolism and perform comparative genomics. Hidden Markov model-based profiles for 42 SB enzymes allowed to represent the genomic makeup of a given species as a numerical vector. Hierarchical clustering of these vectors functionally grouped eukaryote proteomes and revealed convergent evolution, in particular metabolic reduction in obligate endoparasites. The only obligate endoparasites found to possess SB genes were the trypanosomatids, Trypanosoma spp. and Leishmania spp. However, the origin of SB genes in trypanosomatids remains obscure, as there was no evidence for horizontal transfer.
SBIs are generally thought to act by inhibition of ergosterol anabolism. To investigate this more closely, I developed an assay using genetically modified yeast strains that either synthesize ergosterol or cholesterol. Different efficiencies of a given molecule in inhibiting ergosterol- or cholesterol-producing yeast can thus be attributed to sterol content. Nystatin concentrations required to inhibit growth in the cholesterol-producing yeast strain were 10-fold higher than in the ergosterol-producing strain, demonstrating the validity of the approach. Like amphotericin B, nystatin binds to ergosterol and forms pores in the membrane that lead to death of the target cell. This clear-cut result was only observed for molecules that bind to the finished end product of SB. Inhibitors of enzymes involved in SB did not exclusively inhibit growth of ergosterol-producing yeast strain, showing that the selectivity of SBIs for fungi is not based on differences between cholesterol and ergosterol anabolism. Two possible explanations why SBIs are selective inhibitors of fungal and trypanosomatid growth are brought forward: i) mammalian cells can salvage cholesterol from the environment and thus circumvent inhibition of sterol de novo synthesis whereas trypanosomatids and fungi require the presence of ergosterol and other 24-alkylated sterols, which cannot be replaced by the host’s sterols or ii) fungal and protozoan orthologs of SB enzymes are more susceptible to SBIs than the respective mammalian orthologs.
Even though azoles have been used as antifungals for decades, their use against trypanosomatids is still not implemented. Even worse, the most advanced candidate – posaconazole – could not confirm its initial potential in a recent phase II clinical trial for chronic Chagas’ disease. Based on my findings and integrating the work of others, posaconazole should not be abandoned but partnered with another drug for combination therapy. In the concluding chapter I elaborate on why a sphingolipid biosynthesis inhibitor is probably the best match
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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