Drugs based on natural compounds: recent achievements and future perspectives

Phytochemistry Reviews -     

Structural Characterization of Biomolecules through Atomistic Simulations Guided by DEER Measurements

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Predicting the success of an invader: Niche shift versus niche conservatism

Invasive species can encounter environments different from their source populations, which may trigger rapid adaptive changes after introduction (niche shift hypothesis). To test this hypothesis, we investigated whether postintroduction evolution is correlated with contrasting environmental conditions between the European invasive and source ranges in the Asian tiger mosquito Aedes albopictus. The comparison of environmental niches occupied in European and source population ranges revealed more than 96% overlap between invasive and source niches, supporting niche conservatism. However, we found evidence for postintroduction genetic evolution by reanalyzing a published ddRADseq genomic dataset from 90 European invasive populations using genotype–environment association (GEA) methods and generalized dissimilarity modeling (GDM). Three loci, among which a putative heat‐shock protein, exhibited significant allelic turnover along the gradient of winter precipitation that could be associated with ongoing range expansion. Wing morphometric traits weakly correlated with environmental gradients within Europe, but wing size differed between invasive and source populations located in different climatic areas. Niche similarities between source and invasive ranges might have facilitated the establishment of populations. Nonetheless, we found evidence for environmental‐induced adaptive changes after introduction. The ability to rapidly evolve observed in invasive populations (genetic shift) together with a large proportion of unfilled potential suitable areas (80%) pave the way to further spread of Ae. albopictus in Europe.     

The distribution of residues in a polypeptide sequence is a determinant of aggregation optimized by evolution

It has been shown that the propensity of a protein to form amyloid-like fibrils can be predicted with high accuracy from the knowledge of its amino acid sequence. It has also been suggested, however, that some regions of the sequences are more important than others in determining the aggregation process. Here, we have addressed this issue by constructing a set of “sequence scrambled” variants of the first 29 residues of horse heart apomyoglobin (apoMb_1-29), in which the sequence was modified while maintaining the same amino acid composition. The clustering of the most amyloidogenic residues in one region of the sequence was found to cause a marked increase of the elongation rate (k_agg) and a remarkable shortening of the lag phase (t_lag) of the fibril growth, as determined by far-UV circular dichroism and thioflavin T fluorescence. We also show that taking explicitly into consideration the presence of aggregation-promoting regions in the predictive methods results in a quantitative agreement between the theoretical and observed k_agg and t_lag values of the apoMb_1-29 variants. These results, together with a comparison between homologous segments from the family of globins, indicate the existence of a negative selection against the clustering of highly amyloidogenic residues in one or few regions of polypeptide sequences.     

Inflammation and pericarditis: Are neutrophils actors behind the scenes?

The morbidity of acute pericarditis is increasing over time impacting on patient quality of life. Recent clinical trials focused especially on clinical aspects, with a modest interest in pathophysiological mechanisms. This narrative review, based on papers in English language obtained via PubMed up to April 2018, aims at focusing on the role of the innate immunity in pericarditis and discussing future potential therapeutic strategies impacting on disease pathophysiology. In developed countries, most cases of pericarditis are referred to as idiopathic, although etiological causes have been described, with autoreactive/lymphocytic, malignant, and infectious ones as the most frequent causes. Apart the known impairment of the adaptive immunity, recently a large body evidence indicated the central role of the innate immune system in the pathogenesis of recurrent pericarditis, starting from similarities with autoinflammatory diseases. Accordingly, the “inflammasome” has been shown to behave as an important player in pericarditis development. Similarly, the beneficial effect of colchicine in recurrent pericarditis confirms that neutrophils are important effectors as colchicine, which can block neutrophil chemotaxis, interferes with neutrophil adhesion and recruitment to injured tissues and abrogate superoxide production. Anyway, the role of the adaptive immune system in pericarditis cannot be reduced to a black or white issue as mechanisms often overlap. Therefore, we believe that more efficient therapeutic strategies have to be investigated by targeting neutrophil-derived mediators (such as metalloproteinases) and disentangling the strict interplay between neutrophils and platelets. In this view, some progress has been done by using the recombinant human interleukin-1 receptor antagonist anakinra.     

Structure of an engineered intein reveals thiazoline ring and provides mechanistic insight

We have engineered an intein which spontaneously and reversibly forms a thiazoline ring at the native N-terminal Lys-Cys splice junction. We identified conditions to stablize the thiazoline ring and provided the first crystallographic evidence, at 1.54 Å resolution, for its existence at an intein active site. The finding bolsters evidence for a tetrahedral oxythiazolidine splicing intermediate. In addition, the pivotal mutation maps to a highly conserved B-block threonine, which is now seen to play a causative role not only in ground-state destabilization of the scissile N-terminal peptide bond, but also in steering the tetrahedral intermediate toward thioester formation, giving new insight into the splicing mechanism. We demonstrated the stability of the thiazoline ring at neutral pH as well as sensitivity to hydrolytic ring opening under acidic conditions. A pH cycling strategy to control N-terminal cleavage is proposed, which may be of interest for biotechnological applications requiring a splicing activity switch, such as for protein recovery in bioprocessing.     

The potential of quantitative models to improve microalgae photosynthetic efficiency

The massive increase in carbon dioxide concentration in the atmosphere driven by human activities is causing huge negative consequences and new sustainable sources of energy, food and materials are highly needed. Algae are unicellular photosynthetic microorganisms that can provide a highly strategic contribution to this challenge as alternative source of biomass to complement crops cultivation. Algae industrial cultures are commonly limited by light availability, and biomass accumulation is strongly dependent on their photon‐to‐biomass conversion efficiency. Investigation of algae photosynthetic metabolism is thus strategic for the generation of more efficient strains with higher productivity. Algae are cultivated at industrial scale in conditions highly different from the natural niches they adapted to and strains development efforts must fully consider the seminal influence on productivity of regulatory mechanism of photosynthesis as well as of cultivation parameters like cells concentration, light distribution in the culture, mixing, nutrients and carbon dioxide availability. In this review we will focus in particular on how mathematical models can account for the complex influence of all environmental parameters and can be exploited for development of improved algae strains.     

Construction and structure studies of DNA-bipyridine complexes as versatile scaffolds for site-specific incorporation of metal ions into DNA

The facile construction of metal–DNA complexes using ‘Click’ reactions is reported here. A series of 2′-propargyl-modified DNA oligonucleotides were initially synthesized as structure scaffolds and were then modified through ‘Click’ reaction to incorporate a bipyridine ligand equipped with an azido group. These metal chelating ligands can be placed in the DNA context in site-specific fashion to provide versatile templates for binding various metal ions, which are exchangeable using a simple EDTA washing-and-filtration step. The constructed metal–DNA complexes were found to be thermally stable. Their structures were explored by solving a crystal structure of a propargyl-modified DNA duplex and installing the bipyridine ligands by molecular modeling and simulation. These metal–DNA complexes could have wide applications as novel organometallic catalysts, artificial ribonucleases, and potential metal delivery systems.