A 3′UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1

BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5′ and 3′UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3′UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3′untranslated region (3′UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors

AI-augmented business process management systems: a research manifesto

AI-augmented Business Process Management Systems (ABPMSs) are an emerging class of process-aware information systems, empowered by trustworthy AI technology. An ABPMS enhances the execution of business processes with the aim of making these processes more adaptable, proactive, explainable, and context-sensitive. This manifesto presents a vision for ABPMSs and discusses research challenges that need to be surmounted to realize this vision. To this end, we define the concept of ABPMS, we outline the lifecycle of processes within an ABPMS, we discuss core characteristics of an ABPMS, and we derive a set of challenges to realize systems with these characteristics

Augmented Business Process Management Systems: A Research Manifesto

Augmented Business Process Management Systems (ABPMSs) are an emerging class of process-aware information systems that draws upon trustworthy AI technology. An ABPMS enhances the execution of business processes with the aim of making these processes more adaptable, proactive, explainable, and context-sensitive. This manifesto presents a vision for ABPMSs and discusses research challenges that need to be surmounted to realize this vision. To this end, we define the concept of ABPMS, we outline the lifecycle of processes within an ABPMS, we discuss core characteristics of an ABPMS, and we derive a set of challenges to realize systems with these characteristics.Comment: 19 pages, 1 figur

Skeletal fluorosis from the point of view of an occupational exposure to fluorides in former Czechoslovakia

Electrolytic production of aluminium in former Czechoslovakia started in the year 1953 in the Žiar valley in the central Slovakia. However, till 1995 the hygienic conditions for health protection were not met in the factory. It underwent a reconstruction afterwards

Toward a Solution of the “Peruvian Puzzle”: Pelagic Food-Web Structure and Trophic Interactions in the Northern Humboldt Current Upwelling System Off Peru

The northern Humboldt Current upwelling system (HCS) belongs to the most productive marine ecosystems, providing five to eight times higher fisheries landings per unit area than other coastal upwelling systems. To solve this “Peruvian puzzle”, to elucidate the pelagic food-web structure and to better understand trophic interactions in the HCS, a combined stable isotope and fatty acid trophic biomarker approach was adopted for key zooplankton taxa and higher trophic positions with an extensive spatial coverage from 8.5 to 16°S and a vertical range down to 1,000 m depth. A pronounced regional shift by up to ∼5‰ in the δ15N baseline of the food web occurred from North to South. Besides regional shifts, δ15N ratios of particulate organic matter (POM) also tended to increase with depth, with differences of up to 3.8‰ between surface waters and the oxygen minimum zone. In consequence, suspension-feeding zooplankton permanently residing at depth had up to ∼6‰ higher δ15N signals than surface-living species or diel vertical migrants. The comprehensive data set covered over 20 zooplankton taxa and indicated that three crustacean species usually are key in the zooplankton community, i.e., the copepods Calanus chilensis at the surface and Eucalanus inermis in the pronounced OMZ and the krill Euphausia mucronata, resulting in an overall low number of major trophic pathways toward anchovies. In addition, the semi-pelagic squat lobster Pleuroncodes monodon appears to play a key role in the benthic-pelagic coupling, as indicated by highest δ13C’ ratios of −14.7‰. If feeding on benthic resources and by diel vertical migration, they provide a unique pathway for returning carbon and energy from the seafloor to the epipelagic layer, increasing the food supply for pelagic fish. Overall, these mechanisms result in a very efficient food chain, channeling energy toward higher trophic positions and partially explaining the “Peruvian puzzle” of enormous fish production in the HCS

Double gametocyte infections in apicomplexan parasites of birds and reptiles

The simultaneous occurrence of male and female gametocytes inside a single host blood cell has been suggested to enhance apicomplexan transmission [’’double gametocyte infection (DGI) hypothesis’’]. We did a bibliographic search and a direct screen of blood smears from wild birds and reptiles to answer, for the first time, how common are these infections in the wild. Taking these two approaches together, we report here cases of DGIs in Plasmodium, Haemoproteus, Leucocy- tozoon and Hepatozoon, and cases of male–female DGIs in Haemoproteus of birds and reptiles and in Leucocy- tozoon of birds. Thus, we suggest that DGIs and male–female DGIs are more widespread than previously thought, opening a new research avenue on apicom- plexan transmissionPeer reviewe

Taenia larvae possess distinct acetylcholinesterase profiles with implications for host cholinergic signalling

Larvae of the cestodes Taenia solium and Taenia crassiceps infect the central nervous system of humans. Taenia solium larvae in the brain cause neurocysticercosis, the leading cause of adult-acquired epilepsy worldwide. Relatively little is understood about how cestode-derived products modulate host neural and immune signalling. Acetylcholinesterases, a class of enzyme that breaks down acetylcholine, are produced by a host of parasitic worms to aid their survival in the host. Acetylcholine is an important signalling molecule in both the human nervous and immune systems, with powerful modulatory effects on the excitability of cortical networks. Therefore, it is important to establish whether cestode derived acetylcholinesterases may alter host neuronal cholinergic signalling. Here we make use of multiple techniques to profile acetylcholinesterase activity in different extracts of both Taenia crassiceps and Taenia solium larvae. We find that the larvae of both species contain substantial acetylcholinesterase activity. However, acetylcholinesterase activity is lower in Taenia solium as compared to Taenia crassiceps larvae. Further, whilst we observed acetylcholinesterase activity in all fractions of Taenia crassiceps larvae, including on the membrane surface and in the excreted/secreted extracts, we could not identify acetylcholinesterases on the membrane surface or in the excreted/secreted extracts of Taenia solium larvae. Bioinformatic analysis revealed conservation of the functional protein domains in the Taenia solium acetylcholinesterases, when compared to the homologous human sequence. Finally, using whole-cell patch clamp recordings in rat hippocampal brain slice cultures, we demonstrate that Taenia larval derived acetylcholinesterases can break down acetylcholine at a concentration which induces changes in neuronal signalling. Together, these findings highlight the possibility that Taenia larval acetylcholinesterases can interfere with cholinergic signalling in the host, potentially contributing to pathogenesis in neurocysticercosis

Modulation of the immune response by nematode secreted acetylcholinesterase revealed by heterologous expression in Trypanosoma musculi

Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host

Crystal structure of the ferritin from the hyperthermophilic archaeal anaerobe Pyrococcus furiosus

The crystal structure of the ferritin from the archaeon, hyperthermophile and anaerobe Pyrococcus furiosus (PfFtn) is presented. While many ferritin structures from bacteria to mammals have been reported, until now only one was available from archaea, the ferritin from Archaeoglobus fulgidus (AfFtn). The PfFtn 24-mer exhibits the 432 point-group symmetry that is characteristic of most ferritins, which suggests that the 23 symmetry found in the previously reported AfFtn is not a common feature of archaeal ferritins. Consequently, the four large pores that were found in AfFtn are not present in PfFtn. The structure has been solved by molecular replacement and refined at 2.75-Å resolution to R = 0.195 and Rfree = 0.247. The ferroxidase center of the aerobically crystallized ferritin contains one iron at site A and shows sites B and C only upon iron or zinc soaking. Electron paramagnetic resonance studies suggest this iron depletion of the native ferroxidase center to be a result of a complexation of iron by the crystallization salt. The extreme thermostability of PfFtn is compared with that of eight structurally similar ferritins and is proposed to originate mostly from the observed high number of intrasubunit hydrogen bonds. A preservation of the monomer fold, rather than the 24-mer assembly, appears to be the most important factor that protects the ferritin from inactivation by heat