Susceptibility of Yeast-Like Fungi to a New Antifungal Agent, LY 121019

LY 121019, a new antifungal antibiotic agent, was tested for activity against 200 clinical isolates of Candida and other yeast-like fungi. LY 121019 had its greatest inhibitory effect on C. albicans , and C. tropicalis. C. glabrata and most other Candida species were not as sensitive. Cryptococcus and other yeast-like fungi, with the exception of a few strains, were not susceptible to LY 121019. Zusammenfassung :  LY 121019, ein neues Antimyzetikum, wurde auf seine AktivitÄt gegen 200 klinische Isolate von Candida und anderen, hefeÄhnlichen Pilzen untersucht. LY 121019 hat seine grÖßte Hemmwirkung gegen C. albicans und C. tropicalis. C. glabrata und die meisten anderen Candida -Arten waren nicht so empfindlich. Cryptococcus und andere, hefeÄhnliche Pilze waren, mit Ausnahme weniger StÄmme, nicht fÜr LY 121019 empfindlich.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73892/1/j.1439-0507.1988.tb04426.x.pd

Regulation of Bestrophins by Ca2+: A Theoretical and Experimental Study

Bestrophins are a recently discovered family of Cl− channels, for which no structural information is available. Some family members are activated by increased intracellular Ca2+ concentration. Bestrophins feature a well conserved Asp-rich tract in their COOH terminus (Asp-rich domain), which is homologous to Ca2+-binding motifs in human thrombospondins and in human big-conductance Ca2+- and voltage-gated K+ channels (BKCa). Consequently, the Asp-rich domain is also a candidate for Ca2+ binding in bestrophins. Based on these considerations, we constructed homology models of human bestrophin-1 (Best1) Asp-rich domain using human thrombospondin-1 X-ray structure as a template. Molecular dynamics simulations were used to identify Asp and Glu residues binding Ca2+ and to predict the effects of their mutations to alanine. We then proceeded to test selected mutations in the Asp-rich domain of the highly homologous mouse bestrophin-2. The mutants expressed in HEK-293 cells were investigated by electrophysiological experiments using the whole-cell voltage-clamp technique. Based on our molecular modeling results, we predicted that Asp-rich domain has two defined binding sites and that D301A and D304A mutations may impact the binding of the metal ions. The experiments confirmed that these mutations do actually affect the function of the protein causing a large decrease in the Ca2+-activated Cl− current, fully consistent with our predictions. In addition, other studied mutations (E306A, D312A) did not decrease Ca2+-activated Cl− current in agreement with modeling results

Regulation of Bestrophins by Ca2+: A Theoretical and Experimental Study

Bestrophins are a recently discovered family of Cl− channels, for which no structural information is available. Some family members are activated by increased intracellular Ca2+ concentration. Bestrophins feature a well conserved Asp-rich tract in their COOH terminus (Asp-rich domain), which is homologous to Ca2+-binding motifs in human thrombospondins and in human big-conductance Ca2+- and voltage-gated K+ channels (BKCa). Consequently, the Asp-rich domain is also a candidate for Ca2+ binding in bestrophins. Based on these considerations, we constructed homology models of human bestrophin-1 (Best1) Asp-rich domain using human thrombospondin-1 X-ray structure as a template. Molecular dynamics simulations were used to identify Asp and Glu residues binding Ca2+ and to predict the effects of their mutations to alanine. We then proceeded to test selected mutations in the Asp-rich domain of the highly homologous mouse bestrophin-2. The mutants expressed in HEK-293 cells were investigated by electrophysiological experiments using the whole-cell voltage-clamp technique. Based on our molecular modeling results, we predicted that Asp-rich domain has two defined binding sites and that D301A and D304A mutations may impact the binding of the metal ions. The experiments confirmed that these mutations do actually affect the function of the protein causing a large decrease in the Ca2+-activated Cl− current, fully consistent with our predictions. In addition, other studied mutations (E306A, D312A) did not decrease Ca2+-activated Cl− current in agreement with modeling results

Branched Phospha[7]triangulanes

A highly strained, thermally stable (up to 150 °C) branched phospha[7]triangulane was synthesized from the second-generation bicyclopropylidene and transient phosphinidene [Ph?P=W(CO