Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?

This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice. The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic–pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed. Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.     

Aerial seed bank in a cold desert annual-ephemeral species: Role of anatomical structure of stem and delayed fruit dehiscence in timing of seed dispersal

Why the fruits are retained on dead upright herbaceous plants and how this relates to seed dispersal and timing of germination remain unclear. Stems of the annual Euclidium syriacum (Brassicaceae) with infructescences bearing indehiscent silicles remain upright after plants die in the spring. We investigated the effect of anatomical structures of stem and pedicle and delayed silicle dehiscence on seed dispersal phenology of this species. For comparison, sections were made of the stem of the annual Goldbachia laevigata (Brassicaceae), which has stems that fall over when plants die. Compared to G. laevigata, the stem of E. syriacum has vascular bundles that are closer together, a thicker xylem and phloem, more fibers, a thicker perimedullary zone and a smaller pith diameter:stem diameter ratio. The thickened pedicle did not form an abcission layer. By late October, 5–20% of seeds were dispersed, depending on the position of infructescences on the plant. Snow covered the plants in late autumn and when it melted in mid-April many of the plants had fallen over, with a high number of seeds germinating in attached silicles; seedlings became rooted in soil. After snowmelt, 14–15% of the silicles on the remaining upright plants contained seeds; all seeds were dispersed by early July. The anatomical structures of the stem and pedicle plus the delayed dehiscence of silicles explain the presence of an aerial seed bank in E. syriacum and delay of germination of many of seeds until spring. Further, pieces of upright plants are broken off and dispersed by wind, which helps to explain the wide distribution of E. syriacum in the cold desert.     

Effect of woody plant expansion on decomposition of fine root mixtures in a grass-dominated temperate wetland

Wetlands Ecology and Management - Little is known about the effect of woody plant expansion on decomposition of root mixtures in grass-dominant temperate wetlands. Here, we collected fine roots...     

PDZ/PDZ interaction between PSD‐95 and nNOS neuronal proteins

N‐Methyl‐D‐aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD‐95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein‐protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95‐PDZ2/nNOS‐PDZ. Two energetically relevant events are structurally linked to a “two‐faced” or two areas of recognition between both domains. First, the assembly of a four‐stranded antiparallel β‐sheet between the β hairpins of nNOS and of PSD95‐PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β‐hairpin with the side chains of α2‐helix at the binding site of PSD95‐PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction.     

Exploring the carbohydrate‐binding ability of Canavalia bonariensis lectin in inflammation models

Lectins are a group of proteins of non‐immune origin recognized for their ability to bind reversibly to carbohydrates. Researchers have been intrigued by oligosaccharides and glycoconjugates for their involvement as mediators of complex cellular events and then many biotechnological applications of lectins are based on glycocode decoding and their activities. Here, we report a structural and biological study of a ConA‐like mannose/glucose‐specific lectin from Canavalia bonariensis seeds, CaBo. More specifically, we evaluate the binding of CaBo with α‐methyl‐D‐mannoside (MMA) and mannose‐1,3‐α‐D‐mannose (M13) and the resultant in vivo effects on a rat model of acute inflammation. A virtual screening was also carried out to cover a larger number of possible bindings of CaBo. In silico analysis demonstrated the stability of CaBo interaction with mannose‐type ligands, and the lectin was able to induce acute inflammation in rats with the participation of the carbohydrate recognition domain (CRD) and histamine release. These results confirm the ability of CaBo to interact with hybrid and high‐mannose N‐glycans, supporting the hypothesis that CaBo's biological activity occurs primarily through its interaction with cell surface glycosylated receptors.