Natural products from marine invertebrates against <Emphasis Type="Italic">Leishmania</Emphasis> parasites: a comprehensive review

Parasitic infections by Leishmania parasites remains a severe public health problem, especially in developing countries where it is highly endemic. Chemotherapy still remains a first option for the treatment of those diseases, despite the fact that available drugs exhibit a variety of shortcomings. Thus, innovative, less toxic more affordable and effective antileishmanial agents are urgently needed. The marine environment holds an immeasurable bio- and chemical diversity, being a valuable source of natural products with therapeutic potential. As invertebrates comprise about 60 % of all marine organisms, bioprospecting this class of organisms for antileishmanial properties may unravel unique and selective hit molecules. In this context, this review covers results on the literature of marine invertebrate extracts and pure compounds evaluated against Leishmania parasites mainly by in vitro methods. It comprises results obtained from the phyla Porifera, Cnidaria, Bryozoa (Ectoprota), Mollusca, Echinodermata, Annelida, Cetnophora, Platyhelminthes, sub phyla Crustacea (phylum Arthropoda) and Tunicata (phylum Chordata). Moreover, structure–activity relationships and possible mechanisms of action are mentioned, whenever available information is provided. About 70 species of marine invertebrates belonging to seven different phyla are included in this work. Besides a variety of crude extracts, a total of 140 pure compounds was tested against different Leishmania species. Although the research on the antileishmanial potential of marine invertebrates is in its early beginnings, promising results have been achieved that encourage further research. As more extracts and compounds are being screened, the possibility of finding active and selective antileishmanial molecules increases, rising new hope in the search for new treatments against leishmaniases.     

Rare Variants Association Analysis in Large-Scale Sequencing Studies at the Single Locus Level

Genetic association analyses of rare variants in next-generation sequencing (NGS) studies are fundamentally challenging due to the presence of a very large number of candidate variants at extremely low minor allele frequencies. Recent developments often focus on pooling multiple variants to provide association analysis at the gene instead of the locus level. Nonetheless, pinpointing individual variants is a critical goal for genomic researches as such information can facilitate the precise delineation of molecular mechanisms and functions of genetic factors on diseases. Due to the extreme rarity of mutations and high-dimensionality, significances of causal variants cannot easily stand out from those of noncausal ones. Consequently, standard false-positive control procedures, such as the Bonferroni and false discovery rate (FDR), are often impractical to apply, as a majority of the causal variants can only be identified along with a few but unknown number of noncausal variants. To provide informative analysis of individual variants in large-scale sequencing studies, we propose the Adaptive False-Negative Control (AFNC) procedure that can include a large proportion of causal variants with high confidence by introducing a novel statistical inquiry to determine those variants that can be confidently dispatched as noncausal. The AFNC provides a general framework that can accommodate for a variety of models and significance tests. The procedure is computationally efficient and can adapt to the underlying proportion of causal variants and quality of significance rankings. Extensive simulation studies across a plethora of scenarios demonstrate that the AFNC is advantageous for identifying individual rare variants, whereas the Bonferroni and FDR are exceedingly over-conservative for rare variants association studies. In the analyses of the CoLaus dataset, AFNC has identified individual variants most responsible for gene-level significances. Moreover, single-variant results using the AFNC have been successfully applied to infer related genes with annotation information.     

pH dependence of ligand-induced human epidermal growth factor receptor activation investigated by molecular dynamics simulations

The activation of human epidermal growth factor receptor (hEGFR) involves a large conformational change in its soluble extracellular domains (sECD, residues 1–620), from a tethered to an extended conformation upon binding of ligands, such as EGF. It has been reported that this dynamic process is pH-dependent, that is, hEGFR can be activated by EGF at high pH to form an extended dimer but remains as an inactive monomer at low pH. In this paper, we perform all-atom molecular dynamics (MD) simulations starting from the tethered conformation of sECD:EGF complex, at pH 5.0 and 8.5, respectively. Simulation results indicate that sECD:EGF shows different dynamic properties between the two pHs, and the complex may have a higher tendency of activation at pH 8.5. Twenty residues, including 13 histidines, in sECD:EGF have different protonation states between the two pHs (calculated by the H++ server). The charge distribution at pH 8.5 is more favorable for forming an extended conformation toward the active state of sECD than that at pH 5.0. Our study may shed light on the mechanism of pH dependence of hEGFR activation.

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Graphical abstract pH dependence of ligand-induced human epidermal growth factor receptor activation

     

Theoretical study of the interaction between molecular oxygen and tetraaza macrocyclic manganese complexes

Theoretical chemistry calculations using the Density Functional Theory (DFT) were carried out to understand the interaction between oxygen (O₂) and MnN₄ type manganese-based complexes during the formation of MnN₄-O₂ adducts. In order to understand how this interaction is affected by different macrocyclic ligands, O₂ was bonded to manganese-porphyrin (MnP), manganese-octamethylporphyrin (MnOMP), manganese-tetraaza[14]annulene (MnTAA), manganese-dibenzo [b,i] [1, 4, 8, 11]-tetraaza [14] annulene (MnDBTAA), manganese-2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene ([(tim)Mn]²⁺), and manganese-2,3,9,10-tetraphenyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene ([(ph-tim)Mn]²⁺). The binding and activation of the oxygen molecule was facilitated by an increasing trend in the O-O bond lengths and a decreasing one in the O-O vibrational frequency, with preference for the O₂ side-on interaction among MnN₄ macrocycles. The catalytic activities of the MnN₄ complexes toward the O₂ binding process increased in the following order: [(ph-tim)Mn]²⁺?<?MnP?<?MnOMP?<?MnDBTAA?<?MnTAA?<?[(tim)Mn]²⁺. Therefore, it was concluded that the [(tim)Mn]²⁺complex was the most active for the binding and activation of molecular oxygen.     

Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual,non-competitive mechanism of action

CD73 (ecto-5′-nucleotidase) has recently been established as a promising immuno-oncology target. Given its role in activating purinergic signaling pathways to elicit immune suppression, antagonizing CD73 (i.e., releasing the brake) offers a complimentary pathway to inducing anti-tumor immune responses. Here, we describe the mechanistic activity of a new clinical therapeutic, MEDI9447, a human monoclonal antibody that non-competitively inhibits CD73 activity. Epitope mapping, structural, and mechanistic studies revealed that MEDI9447 antagonizes CD73 through dual mechanisms of inter-CD73 dimer crosslinking and/or steric blocking that prevent CD73 from adopting a catalytically active conformation. To our knowledge, this is the first report of an antibody that inhibits an enzyme's function through 2 distinct modes of action. These results provide a finely mapped epitope that can be targeted for selective, potent, and non-competitive inhibition of CD73, as well as establish a strategy for inhibiting enzymes that function in both membrane-bound and soluble states.     

Effects of Straw Return in Deep Soils with Urea Addition on the Soil Organic Carbon Fractions in a Semi-Arid Temperate Cornfield

Returning straw to deep soil layers by using a deep-ditching-ridge-ploughing method is an innovative management practice that improves soil quality by increasing the soil organic carbon (SOC) content. However, the optimum quantity of straw return has not been determined. To solve this practical production problem, the following treatments with different amounts of corn straw were investigated: no straw return, CK; 400 kg ha^-1 straw, S₄₀₀; 800 kg ha^-1 straw, S₈₀₀; 1200 kg ha^-1 straw, S₁₂₀₀; and 1600 kg ha^-1 straw, S₁₆₀₀. After straw was returned to the soil for two years, the microbial biomass C (MBC), easily oxidized organic C (EOC), dissolved organic C (DOC) and light fraction organic C (LFOC) content were measured at three soil depths (0–10, 10–20, and 20–40 cm). The results showed that the combined application of 800 kg ha^-1 straw significantly increased the EOC, MBC, and LFOC contents and was a suitable agricultural practice for this region. Moreover, our results demonstrated that returning straw to deep soil layers was effective for increasing the SOC content.