Genetically Compromising Phospholipid Metabolism Limits Candida albicans’ Virulence

Mycopathologia - Perturbing ergosterol synthesis has been previously shown to reduce the virulence of Candida albicans. We tested the hypothesis that further altering cell membrane composition by...     

Aggregation of cyclodextrins as an important factor to determine their complexation behavior

Here, we report a study on the complexation behavior of carotenoids with cyclodextrins (CDs) using solubility experiments and molecular-modelling methods. Carotenoids are an important group of naturally occurring dyes found in vegetables and fruits. Their antioxidant property has initiated investigations on their possible use as drugs. However, carotenoids are lipophilic molecules with very little inherent aqueous solubility. Cyclodextrin complexation has been widely used in order to increase the potential applications of hydrophobic compounds. Thus, the aim of our investigation was to design carotenoids with enhanced water solubility by cyclodextrin complexation. Molecular modelling of carotenoid-cyclodextrin complexes with a 1 : 1 stoichiometry successfully explained the experimentally observed capability of beta-cyclodextrins (beta-CDs) to form complexes with carotenoids as opposed to alpha-cyclodextrins (alpha-CDs) and gamma-cyclodextrins (gamma-CDs). Furthermore, molecular-dynamics calculations revealed that the aggregation properties of CD derivatives significantly influence their complexation behavior. Our docking calculations showed that RAMEB (random methylated beta-CD) is the beta-CD derivative that possesses the lowest tendency to aggregate. Solubility experiments yielded the same results, namely, RAMEB complexes possess the best water solubility. Our results showed that complexation of a ligand not buried inside of the CD cavity is dependent on two factors: i) the geometry of the inclusion part of the complex; ii) the self-aggregation property of the CD itself. The lower affinity the CDs possess for self-aggregation, the more likely are they involved in interactions with carotenoids. These results suggest that self-aggregation of CDs should be considered as an important parameter determining complexation in general.     

Using Network Analysis to Explore if Professional Opinions on Japanese Encephalitis Risk Factors in Nepal Reflect a Socio-ecological System Perspective

Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia and a significant public health problem in Nepal. Its epidemiology is influenced by factors affecting its amplifying hosts (pigs), vectors (mosquitoes), and dead-end hosts (including people). While most control efforts target reduced susceptibility to infection either by vaccination of people or pigs or by reduced exposure to mosquitoes; the economic reality of Nepal makes it challenging to implement standard JE control measures. An ecohealth approach has been nominated as a way to assist in finding and prioritizing locally relevant strategies for JE control that may be viable, feasible, and acceptable. We sought to understand if Nepalese experts responsible for JE management conceived of its epidemiology in terms of a socio-ecological system to determine if they would consider ecohealth approaches. Network analysis suggested that they did not conceive JE risk as a product of a socio-ecological system. Traditional proximal risk factors of pigs, mosquitoes, and vaccination predominated experts’ conception of JE risk. People seeking to encourage an ecohealth approach or social change models to JE management in Nepal may benefit from adopting social marketing concepts to encourage and empower local experts to examine JE from a socio-ecological perspective.     

Antigenotoxic and anticytotoxic effect of camel milk in mice treated with cisplatin

Camel milk (CM) has good nutritive value, in addition to its antigenotoxic and anticytotoxic effects. Therefore the aim of this investigation was to evaluate the capacity of CM to inhibit the micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow and improve the mitotic activity produced by cisplatin. Cisplatin is one of the most widely used antineoplastic drugs in the treatment of cancer. The 70 adult male Swiss albino mice were divided into seven groups:

• Gr. I: treated with distilled water and considered as a control group.
• Gr. II: treated with camel milk (33 ml/kg, b.w).
• Gr. III: treated previously with cisplatin (0.5 mg/kg, b.w).
• Gr. IV: treated with camel milk and followed after 2 h. with cisplatin (33 ml/kg → 0.5 mg/kg, b.w).
• Gr. V: treated with camel milk and cisplatin at the same time (33 ml/kg + 0.5 mg/kg, b.w).
• Gr. VI: treated with an acute single dose of cisplatin (2.5 mg/kg, b.w).
• Gr. VII: treated with camel milk prior and followed with an acute single dose of cisplatin (33 ml/kg → 2.5 mg /kg, b.w). The animals were sacrificed 24 h after cisplatin injection. The pretreatment with CM dose caused a significant decrease (P < 0.001) in the frequency of MnPCEs and increase (P < 0.001) in the mitotic index (MI) induced by cisplatin when compared with the groups treated with cisplatin alone. The possible explanation for the antigenotoxic and anticytotoxic effects observed in the pretreatment with CM is ascribed to its contents. In conclusion, from the findings we suggest that this milk has some antioxidant effect, and the antigenotoxic mechanism of this milk needs to be explored further before their use during cisplatin chemotherapy.

     

In vivo analysis of the role of O-glycosylations of von Willebrand factor

The objective of this project was to study the function of O-glycosylations in von Willebrand factor (VWF) life cycle. In total, 14 different murine Vwf cDNAs mutated on one or several O-glycosylations sites were generated: 9 individual mutants, 2 doublets, 2 clusters and 1 mutant with all 9 murine glycosylation sites mutated (Del-O-Gly). We expressed each mutated cDNA in VWF deficient-mice by hydrodynamic injection. An immunosorbent assay with Peanut Agglutinin (PNA) was used to verify the O-glycosylation status. Wild-type (WT) VWF expressed by hepatocytes after hydrodynamic injection was able to bind PNA with slightly higher affinity than endothelial-derived VWF. In contrast, the Del-O-Gly VWF mutant did not bind PNA, demonstrating removal of O-linked glycans. All mutants displayed a normal multimeric pattern. Two mutants, Del-O-Gly and T1255A/T1256A, led to expression levels 50% lower than those induced by WT VWF and their half-life in vivo was significantly reduced. When testing the capacity of each mutant to correct the bleeding time of VWF-deficient mice, we found that S1486A, T1255A, T1256A and the doublet T1255A/T1256A were unable to do so. In conclusion we have shown that O-glycosylations are dispensable for normal VWF multimerization and biosynthesis. It also appears that some O-glycosylation sites, particularly the T1255 and T1256 residues, are involved in the maintenance of VWF plasma levels and are essential for normal haemostasis. As for the S1486 residue, it seems to be important for platelet binding as demonstrated in vitro using perfusion experiments.     

Isotope chirality in long‐armed multifunctional organosilicon (“Cephalopod”) molecules

Long‐armed multifunctional organosilicon molecules display self‐replicating and self‐perfecting behavior in asymmetric autocatalysis (Soai reaction). Two representatives of this class were studied by statistical methods aiming at determination of probabilities of natural abundance chiral isotopomers. The results, reported here, show an astonishing richness of possibilities of the formation of chiral isotopically substituted derivatives. This feature could serve as a model for the evolution of biological chirality in prebiotic and early biotic stereochemistry.