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

Project and Work Organization in Solidarity Economy: A first Approach According to Production Engineering

Part 1: Knowledge-Based SustainabilityInternational audienceThis article presents the possible contributions of Production Engineering to solidarity economy as regards projects and organization of work. The authors present logistics as the main channel of introduction to planning and organizing solidarity economy, seeking to show that the participation of Production Engineering leads to a breakage of some strains marked by neoliberalism, making evident the need of serious ecological concerns within the scope of the projects in that sector towards a cleaner production. The authors also point out the impossibility of development of solidarity economy programs without well mapped processes that include environmental impact evaluations and environmental education as pillars of sustainability in any development program

Is the deep Indian Ocean MOC sustained by breaking internal waves?

The Indian Ocean hosts a vigorous basin-scale overturning that constitutes one of the major deep upwelling branches of the global meridional overturning circulation (MOC). The extent to which the deep Indian Ocean MOC is sustained by breaking internal waves is assessed by quantifying and comparing the energetics of the overturning and those of the regional internal wave field. A range of published inverse estimates of the circulation across 32°S is used to assess the basin average buoyancy fluxes. The turbulent dissipation needed to sustain the MOC ranges between 0.17 ± 0.04 and 1.19 ± 0.17 TW, which is consistent with the estimated 0.35−0.26+1.04 TW dissipated by breaking internal waves, as inferred from observed fine structure. Both estimates of turbulent dissipation are consistent with the total energy input into the regional internal wave field (0.21−0.05+0.08 TW) based on published estimates of energy conversion from winds, tides and geostrophic bottom flows. However, a discrepancy arises when comparing the energetics at different density levels. At mid-ocean density levels (∼1000–3000 m) the dissipation of internal wave energy is found to be significantly smaller (factor 5–10) than the dissipation needed to sustain inverse estimates of the MOC. The uncertainty related to undersampling of internal wave breaking hot spots was analyzed and found to be small, which suggests that mixing processes other than wave breaking due to weak wave-wave interactions, may be significant in the deep Indian Ocean

Enhanced Mediterranean-Atlantic exchange during Atlantic freshening phases

The Atlantic-Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W–E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and ?18Owater condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the Gibraltar Exchange to be inversely related to North Atlantic surface salinity. Consequently, Mediterranean enhancement of the Atlantic Meridional Overturning Circulation will be greatest when the overturning itself is at its weakest, a potentially critical negative feedback to Atlantic buoyancy change during times of ice sheet collapse