The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-

Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum

The human malaria parasite Plasmodium falciparum is responsible for the deaths of more than a million people each year. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway, which is absent in humans. However, the structural details of DXR inhibition by fosmidomycin in P. falciparum are unknown. Here, we report the crystal structures of fosmidomycin-bound complete quaternary complexes of PfDXR. Our study revealed that (i) an intrinsic flexibility of the PfDXR molecule accounts for an induced-fit movement to accommodate the bound inhibitor in the active site and (ii) a cis arrangement of the oxygen atoms of the hydroxamate group of the bound inhibitor is essential for tight binding of the inhibitor to the active site metal. We expect the present structures to be useful guides for the design of more effective antimalarial compounds

Optimal assignment methods for ligand-based virtual screening

<p>Abstract</p> <p>Background</p> <p>Ligand-based virtual screening experiments are an important task in the early drug discovery stage. An ambitious aim in each experiment is to disclose active structures based on new scaffolds. To perform these "scaffold-hoppings" for individual problems and targets, a plethora of different similarity methods based on diverse techniques were published in the last years. The optimal assignment approach on molecular graphs, a successful method in the field of quantitative structure-activity relationships, has not been tested as a ligand-based virtual screening method so far.</p> <p>Results</p> <p>We evaluated two already published and two new optimal assignment methods on various data sets. To emphasize the "scaffold-hopping" ability, we used the information of chemotype clustering analyses in our evaluation metrics. Comparisons with literature results show an improved early recognition performance and comparable results over the complete data set. A new method based on two different assignment steps shows an increased "scaffold-hopping" behavior together with a good early recognition performance.</p> <p>Conclusion</p> <p>The presented methods show a good combination of chemotype discovery and enrichment of active structures. Additionally, the optimal assignment on molecular graphs has the advantage to investigate and interpret the mappings, allowing precise modifications of internal parameters of the similarity measure for specific targets. All methods have low computation times which make them applicable to screen large data sets.</p

Economic analysis including long-term risks and costs of alternative diagnostic strategies to evaluate patients with chest pain

Background: Diagnosis costs for cardiovascular disease waste a large amount of healthcare resources. The aim of the study is to evaluate the clinical and economic outcomes of alternative diagnostic strategies in low risk chest pain patients. Methods: We evaluated direct and indirect downstream costs of 6 strategies: coronary angiography (CA) after positive troponin I or T (cTn-I or cTnT) (strategy 1); after positive exercise electrocardiography (ex-ECG) (strategy 2); after positive exercise echocardiography (ex-Echo) (strategy 3); after positive pharmacologic stress echocardiography (PhSE) (strategy 4); after positive myocardial exercise stress single-photon emission computed tomography with technetium Tc 99m sestamibi (ex-SPECT-Tc) (strategy 5) and direct CA (strategy 6). Results: The predictive accuracy in correctly identifying the patients was 83,1% for cTn-I, 87% for cTn-T, 85,1% for ex-ECG, 93,4% for ex-Echo, 98,5% for PhSE, 89,4% for ex-SPECT-Tc and 18,7% for CA. The cost per patient correctly identified results $2.051 for cTn-I,$2.086 for cTn-T, $1.890 for ex-ECG,$803 for ex-Echo, $533 for PhSE,$1.521 for ex-SPECT-Tc ($1.634 including cost of extra risk of cancer) and$29.673 for CA ($29.999 including cost of extra risk of cancer). The average relative cost-effectiveness of cardiac imaging compared with the PhSE equal to 1 (as a cost comparator), the relative cost of ex-Echo is 1.5×, of a ex-SPECT-Tc is 3.1×, of a ex-ECG is 3.5×, of cTnI is ×3.8, of cTnT is ×3.9 and of a CA is 56.3×. Conclusion: Stress echocardiography based strategies are cost-effective versus alternative imaging strategies and the risk and cost of radiation exposure is void

Chemical and Physical Environmental Conditions Underneath Mat- and Canopy-Forming Macroalgae, and Their Effects on Understorey Corals

Disturbed coral reefs are often dominated by dense mat- or canopy-forming assemblages of macroalgae. This study investigated how such dense macroalgal assemblages change the chemical and physical microenvironment for understorey corals, and how the altered environmental conditions affect the physiological performance of corals. Field measurements were conducted on macroalgal-dominated inshore reefs in the Great Barrier Reef in quadrats with macroalgal biomass ranging from 235 to 1029 g DW m−2 dry weight. Underneath mat-forming assemblages, the mean concentration of dissolved oxygen was reduced by 26% and irradiance by 96% compared with conditions above the mat, while concentrations of dissolved organic carbon and soluble reactive phosphorous increased by 26% and 267%, respectively. The difference was significant but less pronounced under canopy-forming assemblages. Dissolved oxygen declined and dissolved inorganic carbon and alkalinity increased with increasing algal biomass underneath mat-forming but not under canopy-forming assemblages. The responses of corals to conditions similar to those found underneath algal assemblages were investigated in an aquarium experiment. Coral nubbins of the species Acropora millepora showed reduced photosynthetic yields and increased RNA/DNA ratios when exposed to conditions simulating those underneath assemblages (pre-incubating seawater with macroalgae, and shading). The magnitude of these stress responses increased with increasing proportion of pre-incubated algal water. Our study shows that mat-forming and, to a lesser extent, canopy-forming macroalgal assemblages alter the physical and chemical microenvironment sufficiently to directly and detrimentally affect the metabolism of corals, potentially impeding reef recovery from algal to coral-dominated states after disturbance. Macroalgal dominance on coral reefs therefore simultaneously represents a consequence and cause of coral reef degradation

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)