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We determined that daptomycin had the highest activity against B. burgdorferi persisters among all the active hits (Table 1, Figure 3D) but had a high MIC (12.5 25 µg/mL) against log-phase organisms (Table 2).
The most active hits on cellular assays were resynthesized and enzymatic activity was measured.
Although the recall performance of a query is highly dependent on the enrichment of similar active compounds in the test set, it is likely that the higher structural diversity of active compounds of an activity class makes it more difficult to efficiently retrieve active hits when the number of hits is limited.
From the rescreens and confirmation by microscopy, we were able to confirm the 27 top active hits that had a significant difference in anti-persister activity over the current Lyme disease antibiotic amoxicillin (P<0.05) (Table 1).
Moreover, the latter was only capable of retrieving one of those active hits at EF 1.0%.
Clearly, the ISS search approach has a much higher chance to retrieve active hits more than the CSS approach.
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Fig. 7 The visualization of Active hit-calls for Bisphenol A under the ToxCast subtab [98].
The default table display includes only Active hit calls, but Background and Inactive hit calls for other assays can be toggled on/off.
The assay data table below the graphic shows Active hit calls by default but the Inactive and Background data can be included in the table by selecting the toggle buttons above the table.
Probability that an exploratory effort will successfully (1) develop a multi-tiered evaluation system for compound screening against a validated biological target, and (2) identify active hit compounds (range 0 1).
The most active hit (compound 1, Figure 2) was independently synthesized and iteratively titrated in a 12-point assay to confirm a potency (GI50) of 120 nM against Dd2 intraerythrocytic parasites (GI50 values were obtained with Dd2 parasites unless otherwise specified).
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