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This choice may raise a concern especially when one is interested in a separation of the "nominal" active space from the inactive space.
While it is worth noting that it is possible to devise a set of PubChem assays that give definite clear separation of active and inactive space even with a single conformer per compound, as our previous study identified [10], the focus of the present study is on getting a big picture from very heterogeneous data in PubChem.
Moreover, an osmotically inactive space of 35.4% could be calculated from these measurements; this value is very similar to that obtained in the control experiments (see above).
When plotted as a function of 1/osmolality (which is equivalent to a 'Boyle-van't Hoff graph' [ 3, 14]), these data could readily be fitted by a straight line; its intercept with the y-axis yields the osmotically active versus inactive space of the cells, with the latter amounting to 30.6% of total cell volume (Fig. 1a, Insert).
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The SiPM arrays adopted here have been optimized to reduce the inactive spaces between SiPMs.
In addition, multiple-conformer effects upon the separation between the non-inactive and inactive spaces are inferred based on the results of this study.
These results suggest that the use of ten diverse conformers per compound in PubChem bioassay data analysis using 3-D molecular similarity is not expected to increase the separation of non-inactive from random and inactive spaces "on average", although some assays show a noticeable separation between the non-inactive and random spaces when multiple conformers are used for each compound.
For example, one may argue that a much clearer separation between the non-inactive and random spaces (or between "active" and "inactive" spaces) could have been observed if we considered assays with very well established pharmacology, using an increasing number of conformers per compound.
In addition, the results from this section, in conjunction with the analyses for the random compound pairs in the previous section, provide clues to the question: does one see (greater) separation of active and inactive spaces when employing multiple conformers per compound, as opposed to a single conformer per compound?
It is now clear that ECMs are not inactive space-filling materials but, in contrast, apart from their structural roles they interact with cells and generate signals to control a multitude of vital cellular functions.
Such algorithms would therefore require large scale undersampling of inactives data points to obtain acceptable performance, thus sacrificing the coverage of inactivity space.
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Justyna Jupowicz-Kozak
CEO of Professional Science Editing for Scientists @ prosciediting.com