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

Incriminating bluetongue virus vectors with climate envelope models

1 The spread of vector-borne diseases into new areas, commonly attributed to environmental change or increased trade and travel, could be exacerbated if novel vector species in newly invaded areas spread infection beyond the range of traditional vectors. 2 By analysing the differential degree of overlap between the environmental envelopes for bluetongue, a devastating livestock disease, and its traditional (Afro-Asian) and potential new (Palearctic) midge vectors, we have implicated the latter in the recent dramatic northward spread of this disease into Europe. 3 The traditional vector of bluetongue virus, the Afro-Asian midge Culicoides imicola, was found to occur in warm (annual mean 12–20 °C), thermally stable locations that were dry in summer (< 400 mm precipitation). The Palearctic C. obsoletus and C. pulicaris complexes were both found to occur in cooler (down to 7 °C annual mean), thermally more variable and wetter (up to 700 mm summer precipitation) locations. 4 Of 501 recorded outbreaks from the 1998–2004 bluetongue epidemic in southern Europe, 40% fall outside the climate envelope of C. imicola, but within the species’ envelopes of the C. obsoletus and C. pulicaris complexes. 5 The distribution in multivariate environmental space of bluetongue virus is closer to that of the Palaearctic vectors than it is to that of C. imicola. This suggests that Palearctic vectors now play a substantial role in transmission and have facilitated the spread of bluetongue into cooler, wetter regions of Europe. 6 Synthesis and applications. The risk to Northern Europe now depends on how much of the distributions of the widespread, abundant Palearctic midge vectors (the C. obsoletus and C. pulicaris complexes) bluetongue can occupy, perhaps determined by thermal constraints on viral replication. This was highlighted by the sudden appearance in summer 2006 of bluetongue virus at latitudes of more than 50° North – approximately 6° further North than previous outbreaks in southern Europe. Future surveillance for bluetongue and for related Culicoides-borne pathogens should include studies to record and explain the distributional patterns of all potential Palearctic vector species

Proposal of the Next Incarnation of Accelerator Test Facility at KEK for the International Linear Collider

The realization of the International Linear Collider (ILC) will require the ability to create and reliably maintain nanometer size beams. The ATF damping ring is the unique facility where ILC emittancies are possible. In this paper we present and evaluate the proposal to create a final focus facility at the ATF which, using compact final focus optics and an ILC-like bunch train, would be capable of achieving 35nm beam size. Such a facility would enable the development of beam diagnostics and tuning methods, as well as the training of young accelerator physicists

ATF2 Proposal: v.1

Since the ICFA decision on the choice of technology, a world-wide collaboration on the design of the ILC has rapidly progressed. The formation of the GDE will accelerate the work towards a final design. An important technical challenge is obviously the high gradient acceleration but what is similarly challenging is the collision of extremely small beams of a few nanometer size. The latter challenge has three distinct issues: creating small emittance beams, preserving the emittance during acceleration and transport, and focusing the beams to nanometers. Most studies have been done using computer simulations but many issues still remain that require experimental verification. KEK-ATF was built to create small emittance beams, and succeeded in obtaining an emittance that almost satisfies the ILC requirements. In this proposal we present a project, ATF2, which addresses the third issue, namely the focusing of the beam into nanometer spot.ybr> In the longer term, the ATF2 project would also provide invaluable input for the CLIC design of a future multi-TeV collider. The ATF2 project will extend the extraction beamline of the ATF with an ILC-type final focus system to create a tightly focused, stable beam by making use of the small emittance of the ATF.<br

Genome-wide and fine-resolution association analysis of malaria in West Africa

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations