Therapy of uncomplicated falciparum malaria in Europe: MALTHER - a prospective observational multicentre study

ABSTRACT: BACKGROUND: Malaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe. METHODS: A prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine. RESULTS: Between December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported,, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p=0.005) and adverse events (p=0.001), parasite and fever clearance times (p<0.001), and hospitalization rates (p=0.0066) and durations (p=0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group. CONCLUSIONS: This study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria.     

Going forward: Increasing the accessibility of imaging mass spectrometry

The driving force behind the high and increasing popularity of imaging mass spectrometry is its demonstrated potential for the determination of new diagnostic/prognostic biomarkers and its ability to simultaneously trace the distributions of pharmaceuticals and their metabolites in tissues without the need to develop expensive radioactively-labeled analogues. Both of these applications would benefit from standardized methods, for the development of novel MS-based molecular histology tests and governmental-approved MS-based assays for pharmaceutical development. In addition, the broader scientific community would benefit from the increased accessibility of the technique. Currently imaging MS studies are individual endeavors, utilizing the individual expertise and infrastructure of a single laboratory and their immediate collaborators. A wide array of tissue preparation, data acquisition and data analysis techniques has been developed but lacks an international collaborative structure and data sharing capabilities. Such a collaborative framework would enable methodological exchange and detailed comparisons of analytical capabilities, to explore synergies between the different methods and result in the development of robust standardized methods. Here we describe the activities of a new European imaging MS network that will explicitly compare and contrast existing methods to provide best practice guidelines for the entire healthcare research community.     

Effects of solubilization on the structure and function of the sensory rhodopsin II/transducer complex

Lipid-protein interactions are known to play a crucial role in structure and physiological activity of integral membrane proteins. However, current technology for membrane protein purification necessitates extraction from the membrane into detergent micelles. Also, due to experimental protocols, most of the data available for membrane proteins is obtained using detergent-solubilized samples. Stable solubilization of membrane proteins is therefore an important issue in biotechnology as well as in biochemistry and structural biology. An understanding of solubilization effects on structural and functional properties of specific proteins is of utmost relevance for the evaluation and interpretation of experimental results. In this study, a comparison of structural and kinetic data obtained for the archaebacterial photoreceptor/transducer complex from Natronomonas pharaonis (NpSRII/NpHtrII) in detergent-solubilized and lipid-reconstituted states is presented. Laser flash photolysis, fluorescence spectroscopy, and electron paramagnetic resonance spectroscopy data reveal considerable influence of solubilization on the photocycle kinetics of the receptor protein and on the structure of the transducer protein. Especially the protein-membrane proximal region and the protein-protein interfacial domains are sensitive towards non-native conditions. These data demonstrate that relevance of biochemical and structural information obtained from solubilized membrane proteins or membrane protein complexes has to be evaluated carefully.     

Electron transfer in peptides and proteins

Proteins and peptides use their amino acids as medium for electron-transfer reactions that occur either in single-step superexchange or in multistep hopping processes. Whereas the rate of the single-step electron transfer dramatically decreases with the distance, a hopping process is less distance dependent. Electron hopping is possible if amino acids carry oxidizable side chains, like the phenol group in tyrosine. These side chains become intermediate charge carriers. Because of the weak distance dependency of hopping processes, fast electron transfer over very long distances occurs in multistep reactions, as in the enzyme ribonucleotide reductase.     

Different feeding strategies in Antarctic scavenging amphipods and their implications for colonisation success in times of retreating glaciers

Background

Scavenger guilds are composed of a variety of species, co-existing in the same habitat and sharing the same niche in the food web. Niche partitioning among them can manifest in different feeding strategies, e.g. during carcass feeding. In the bentho-pelagic realm of the Southern Ocean, scavenging amphipods (Lysianassoidea) are ubiquitous and occupy a central role in decomposition processes. Here we address the question whether scavenging lysianassoid amphipods employ different feeding strategies during carcass feeding, and whether synergistic feeding activities may influence carcass decomposition. To this end, we compared the relatively large species Waldeckia obesa with the small species Cheirimedon femoratus, Hippomedon kergueleni, and Orchomenella rotundifrons during fish carcass feeding (Notothenia spp.). The experimental approach combined ex situ feeding experiments, behavioural observations, and scanning electron microscopic analyses of mandibles. Furthermore, we aimed to detect ecological drivers for distribution patterns of scavenging amphipods in the Antarctic coastal ecosystems of Potter Cove. In Potter Cove, the climate-driven rapid retreat of the Fourcade Glacier is causing various environmental changes including the provision of new marine habitats to colonise. While in the newly ice-free areas fish are rare, macroalgae have already colonised hard substrates. Assuming that a temporal dietary switch may increase the colonisation success of the most abundant lysianassoids C. femoratus and H. kergueleni, we aimed to determine their consumption rates (g food x g amphipods^?1 x day^?1) and preferences of macroalgae and fish.

Results

We detected two functional groups with different feeding strategies among scavenging amphipods during carcass feeding: carcass ‘opener’ and ‘squeezer’. Synergistic effects between these groups were not statistically verified under the conditions tested. C. femoratus switched its diet when fish was not available by consuming macroalgae (about 0.2 day^?1) but preferred fish by feeding up to 80% of its own mass daily. Contrary, H. kergueleni rejected macroalgae entirely and consumed fish with a maximal rate of 0.8 day^?1.

Conclusion

This study reveals functional groups in scavenging shallow-water amphipods and provides new information on coastal intraguild niche partitioning. We conclude that the dietary flexibility of C. femoratus is a potential ecological driver and central to its success in the colonisation of newly available ice-free Antarctic coastal habitats.

     

Senescent skeletal muscle fibroadipogenic progenitors recruit and promote M2 polarization of macrophages

Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age-associated accumulation of immune cells in skeletal muscle. In this study, through cell–cell communication analysis of skeletal muscle single-cell RNA-sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs in vitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation- and etoposide-induced senescence. Compared to non-senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an in vitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages.     

Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2

The N‐Myc Downstream‐Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4 ^−/−) CRC models and an indirect co‐culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4 ^−/− ENS cell secretome, which is enriched for Nidogen‐1 (Nid1) and Fibulin‐2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS‐derived Nidogen‐1 and Fibulin‐2 enhance colorectal carcinogenesis.     

Nullius in Verba1: Advancing Data Transparency in Industrial Ecology

With the growth of the field of industrial ecology (IE), research and results have increased significantly leading to a desire for better utilization of the accumulated data in more sophisticated analyses. This implies the need for greater transparency, accessibility, and reusability of IE data, paralleling the considerable momentum throughout the sciences. The Data Transparency Task Force (DTTF) was convened by the governing council of the International Society for Industrial Ecology in late 2016 to propose best‐practice guidelines and incentives for sharing data. In this article, the members of the DTTF present an overview of developments toward transparent and accessible data within the IE community and more broadly. We argue that increased transparency, accessibility, and reusability of IE data will enhance IE research by enabling more detailed and reproducible research, and also facilitate meta‐analyses. These benefits will make the results of IE work more timely. They will enable independent verification of results, thus increasing their credibility and quality. They will also make the uptake of IE research results easier within IE and in other fields as well as by decision makers and sustainability practitioners, thus increasing the overall relevance and impact of the field. Here, we present two initial actions intended to advance these goals: (1) a minimum publication requirement for IE research to be adopted by the Journal of Industrial Ecology; and (2) a system of optional data openness badges rewarding journal articles that contain transparent and accessible data. These actions will help the IE community to move toward data transparency and accessibility. We close with a discussion of potential future initiatives that could build on the minimum requirements and the data openness badge system.     

Purification and characterization of the methylene tetrahydromethanopterin dehydrogenase MtdB and the methylene tetrahydrofolate dehydrogenase FolD from Hyphomicrobium zavarzinii ZV580

Recently, it has been shown that heterotrophic methylotrophic Proteobacteria contain tetrahydrofolate (H(4)F)- and tetrahydromethanopterin (H(4)MPT)-dependent enzymes. Here we report on the purification of two methylene tetrahydropterin dehydrogenases from the methylotroph Hyphomicrobium zavarzinii ZV580. Both dehydrogenases are composed of one type of subunit of 31 kDa. One of the dehydrogenases is NAD(P)-dependent and specific for methylene H(4)MPT (specific activity: 680 U/mg). Its N-terminal amino acid sequence showed sequence identity to NAD(P)-dependent methylene H(4)MPT dehydrogenase MtdB from Methylobacterium extorquens AM1. The second dehydrogenase is specific for NADP and methylene H(4)F (specific activity: 180 U/mg) and also exhibits methenyl H(4)F cyclohydrolase activity. Via N-terminal amino acid sequencing this dehydrogenase was identified as belonging to the classical bifunctional methylene H(4)F dehydrogenases/cyclohydrolases (FolD) found in many bacteria and eukarya. Apparently, the occurrence of methylene tetrahydrofolate and methylene tetrahydromethanopterin dehydrogenases is not uniform among different methylotrophic alpha-Proteobacteria. For example, FolD was not found in M. extorquens AM1, and the NADP-dependent methylene H(4)MPT dehydrogenase MtdA was present in the bacterium that also shows H(4)F activity.