Impact of Erg11 amino acid substitutions identified in Candida auris clade III isolates on triazole drug susceptibility

ERG11 sequencing of 28 Candida auris clade III isolates revealed the presence of concomitant V125A and F126L substitutions. Heterologous expression of Erg11-V125A/F126L in Saccharomyces cerevisiae led to reduced fluconazole and voriconazole susceptibilities. Generation of single substitution gene variants through site-directed mutagenesis uncovered that F126L primarily contributes to the elevated triazole MICs. A similar, yet diminished pattern of reduced susceptibility was observed with long-tailed triazoles posaconazole and itraconazole for V125A/F126L, F126L, Y132F, and K143R alleles.

Impact of Erg11 amino acid substitutions identified in Candida auris clade III isolates on triazole drug susceptibility

ERG11 sequencing of 28 Candida auris clade III isolates revealed the presence of concomitant V125A and F126L substitutions. Heterologous expression of Erg11-V125A/F126L in Saccharomyces cerevisiae led to reduced fluconazole and voriconazole susceptibilities. Generation of single substitution gene variants through site-directed mutagenesis uncovered that F126L primarily contributes to the elevated triazole MICs. A similar, yet diminished pattern of reduced susceptibility was observed with long-tailed triazoles posaconazole and itraconazole for V125A/F126L, F126L, Y132F, and K143R alleles.

A single de novo substitution in SARS-CoV-2 spike informs enhanced adherence to human ACE2.

SARS-CoV-2 initiates colonization of host cells by binding to cell membrane ACE2 receptor. This binding is mediated by the viral spike receptor binding domain (RBD). The COVID-19 pandemic has brought devastating consequences at a clinical, social and economical levels. Therefore, anticipation of potential novel SARS-causing species or SARS-CoV-2 variants with enhanced binding to ACE2 is key in the prevention of future threats to come. We have characterized a de novo single substitution, Q498Y, in SARS-CoV-2 RBD that confers stronger adherence to ACE2. While the SARS-CoV-2 beta variant, which includes three simultaneous amino acid replacements, induces a 4-fold stronger affinity, a single Q498Y substitution results in 2.5-fold tighter binding, compared to the Wuhan-Hu-1 SARS-CoV-2 2019 strain. Additionally, we crystallized RBDQ498Y complexed with ACE2 and provide here the structural basis for this enhanced affinity. These studies inform a rationale for prevention of potential SARS-causing viruses to come.

Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-β Monomers and Fibrils: Relevance to Alzheimer’s Disease

Background: The most important hallmark in the neuropathology of Alzheimer’s disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. Objective: To computationally assess the interaction between Aβ peptide and a set of curcumin derivatives previously explored in experimental assays. Methods: The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in-silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms. Results: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation. Conclusion: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.

Acquisition of the Tap-Trill Contrast by L1 Mandarin–L2 English–L3 Spanish Speakers

The goals of this study were to investigate the developmental patterns of acquisition of the Spanish tap and trill by L1 Mandarin–L2 English–L3 Spanish speakers, and to examine the extent to which the L1 and the L2 influenced the L3 productions. Twenty L1 Mandarin–L2 English–L3 Spanish speakers performed a reading task that elicited production of rhotics from the speakers’ L3 Spanish, L2 English, and L1 Mandarin, as well as the L2 English flap. The least proficient speakers produced a single substitution initially, generally [l]. The same non-target segment was produced for both rhotics, mirroring the results of previous studies investigating L1 English–L2 Spanish speakers, indicating that this may be a universal simplification strategy. In contrast to previous work on L1 English speakers, the L1 Mandarin–L2 English–L3 Spanish speakers who had acquired the tap did not tend to use it as the primary substitute for the trill. Overall, the L1 was a stronger source of cross-linguistic influence. Nonetheless, evidence of positive and negative L2 transfer was also found. The L2 flap allophone facilitated acquisition of the L3 tap, whereas non-target productions of the L2 /ɹ/ were also observed, revealing that both previously learned languages were possible sources of cross-linguistic influence.