AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Biodégradabilité de l'essence dans l'environnement : de l'évaluation globale au cas des hydrocarbures récalcitrants

Les produits pétroliers, du fait de leur utilisation massive, constituent des polluants importants des sols et des aquifères. Le devenir de ces polluants rejetés dans l'environnement est principalement gouverné par les processus de biodégradation. L'existence de ces phénomènes dépend de la biodégradabilité intrinsèque du polluant mais aussi de la présence de microflores dégradatrices compétentes dans les sols et les eaux souterraines. Au cours de ce travail, nous avons développé une méthodologie permettant d'évaluer la biodégradabilité de l'essence en conditions aérobies. Elle consiste à mesurer, par chromatographie en phase gazeuse, après incubation dans des conditions optimales, la consommation de chacun des hydrocarbures présents dans différentes fractions de l'essence (essence réelle, mélanges modèles). Les résultats indiquent que la biodégradabilité de l'essence est quasi totale (94 %). Les microflores de l'environnement ont des capacités élevées (85 % et plus de dégradation). Les performances des microflores de sols non pollués sont cependant limitées pour la dégradation des triméthylalcanes, comme le 2,2,4-triméthylpentane (isooctane) ou le 2,3,4-triméthylpentane, et des cycloalcanes. Les microflores provenant de sols pollués ont des capacités de dégradation plus larges puisque la dégradation est totale pour la moitié des échantillons étudiés. Le cyclohexane est toujours dégradé par mutualisme et/ou cométabolisme. Les triméthylalcanes avec un atome de carbone quaternaire, comme l'isooctane, et/ou des groupements méthyles sur des atomes de carbone consécutifs sont dégradés par cométabolisme mais peuvent aussi servir de substrat de croissance à des souches spécialisées. Une souche, Mycobacterium austroafricanum (IFP 2173), capable de croissance sur isooctane, a été isolée à partir d'un échantillon pollué par essence. Cette souche a la capacité de cométaboliser certains hydrocarbures (cyclo- et iso-alcanes, aromatiques) et en particulier le cyclohexane. M. austroafricanum IFP 2173 peut aussi utiliser pour sa croissance un large spectre d'hydrocarbures (n- et iso-alcanes, aromatiques)

Gasoline and Diesel Oil Biodegradation

Fuels are major organic pollutants of soils and ground waters. Persistency of pollutants in the environment depends on the intrinsic biodegradability of constituting hydrocarbons of fuels, on the presence of active microflorae at the polluted areas and on local environmental factors. The intrinsic biodegradability of fuels such as gasoline or diesel oil was determined by using a reference aerobic microflora taken from an urban waste water treatment plant. Gasoline exhibited a high intrinsic biodegradability (96%) but that of a commercial diesel oil was significantly lower (between 60 and 73%). The recalcitrant hydrocarbons of fuels were cycloalkanes and branched alkanes, in particular those having quaternary carbon atoms or consecutive substituting groups on the main carbon chain. In the case of various types of diesel oil, the composition in terms of hydrocarbon structural classes accounted for the diverse biodegradation rates observed. In particular, the biodegradation rate was close to 100% when linear alkanes were most abundant (Fischer-Tropsch diesel oil). The fuel degradation capability was widespread among the environment microflorae tested. Microflorae from polluted soils displayed in general a slightly higher degradation capacity than that of nonpolluted soils. Several mechanisms are involved in the efficiency of microflorae taken from polluted environments: - the presence of microorganisms with specialised metabolic capacities; - the occurrence of cometabolism; - some positive interactions between strains (cooperation). The mechanisms involved in the degradation of recalcitrant hydrocarbons were illustrated in the case of cyclohexane degradation by pure strains

Adiciones al tema de las citas cervantinas en Calderón: las citas sobre Lope de Vega

We have studied the meiotic segregation of a chromosome length polymorphism (CLP) in the yeast Saccharomyces cerevisiae. The neopolymorphism frequently observed within the smallest chromosomes (I, VI, III and IX) is not completely understood. We focused on the analysis of the structure of chromosome I in 88 segregants from a cross between YNN295 and FL100trp. Strain FL100trp is known to carry a reciprocal translocation between the left arm of chromosome III and the right arm of chromosome I. PCR and Southern hybridization analyses were performed and a method for the rapid detection of chromosome I rearrangements was developed. Seven chromosome I types were identified among the 88 segregants. We detected 22 recombination events between homologous chromosomes I and seven ectopic recombination events between FL100trp chromosome III and YNN295 chromosome I. These recombination events occurred in 20 of the 22 tetrads studied (91%). Nine tetrads (41%) showed two recombination events. This showed that homologous recombination involving polymorphic homologues or heterologous chromosomes is the main source of neopolymorphism. Only one of the seven chromosome I variants resulted from a transposition event rather than a recombination event. We demonstrated that a Tyl element had transposed within the translocated region of chromosome I, generating mutations in the 3&39; LTR, at the border between U5 and PBS

Involvement of reactive oxygen species in the bactericidal activity of activated carbon fibre supporting silver bactericidal activity of ACF(Ag) mediated by ROS.

absen