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

Improved reference genome of Aedes aegypti informs arbovirus vector control

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector

The Hidden Foundations of Critical Reading

What do we actually know about the reading experiences taking place within literary studies? And what can we know? Despite the growing academic interest in real readers, literary scholars are a category of readers whose reading experiences we know very little about. This is somewhat paradoxical both because of the importance and impact of scholarly writing on new generations of readers and teachers, and because of the massive documentation available in terms of articles containing interpretations, often called readings, of literary works. These ‘readings’ present implicit models of how the reading of literature should be exercised. Even though these models can look very different in terms of ideological and theoretical orientation, most of them are united by an ideal of critical reading. Furthermore, critical reading is often considered to be ‘owned’ by the academy (Warner 2004) and is explicitly or implicitly contrasted to ordinary readers’ reading. Guillory (2000) claims for example that, due to the theory boom, the relation between these two categories of readers can be described as a gap which has increasingly widened since the 1960’s. Professional critical reading is characterized by distance, requires hard work and rejects reading for pleasure. Lay reading, on the other hand, valorizes immersion, identification and pleasure. Another way to describe the gap is as a difference between studying and (just) reading literature. The question is, however, if such a dichotomy doesn’t obscure as much as it reveals (Persson 2011). In light of the ‘affective turn’, and the growing interest in the emotional, bodily and sensual aspects of reading, the doxa of critical reading has, in its turn, been subject to critique by several scholars (Gallop 2004; Sedgwick 2003). But the outcome of this critique should not be a simple inversion of the hierarchy between critical and pleasurable reading. Much more interesting is to try and get a grip on the underlying motives and assumptions of critical reading. This way of reading has indeed its own kinds of pleasure, as Felski (2011) suggests. In my paper I will try to identify some of the hidden foundations of critical reading. One hypothesis is that the first of these is the reading experience itself. In articles by literary scholars the reading experience is often invisible and taken for granted, despite the fact that it is the fundamental prerequisite for the written interpretation that is postulated to be the final result of the experience. The second hidden foundation concerns the doxa of distance. How is this distance constructed rhetorically and stylistically? The third hidden foundation is that critical reading is done voluntarily and has its own (not openly acknowledged) pleasures and rewards. Which desires motivate critical reading? Can traces of these be found in the works of the literary scholars, and, if so, how? I will try to describe and analyze these hidden foundations in a couple of texts by prominent theorists Fredric Jameson and bell hooks. Both scholars take their starting point in an agenda of radical political change, which ought to imply that the tensions between the critical and the (politically) passionate should be particularly interesting and revealing. The main purpose of my paper is, in short, to try and get somewhat nearer to what characterizes the critical reading experience

A Highly Stereoselective Diels–Alder Cycloaddition of Enones with Chiral Cyclic 2‑Amidodienes Derived from Allenamides

Lewis acid promoted Diels–Alder cycloadditions of a series of <i>de novo</i> chiral cyclic 2-amidodienes are described. These cyclic 2-amidodienes are derived from chiral α-allyl allenamides via a sequence of <i>E-</i>selective 1,3-H shift and 6π-electron pericyclic ring closure. With enones serving as effective dienophiles, these cycloadditions can be highly diastereoselective depending upon the chiral amide substituent, thereby representing a facile entry to optically enriched [2.2.2]bicyclic manifolds

A Highly Stereoselective Diels–Alder Cycloaddition of Enones with Chiral Cyclic 2‑Amidodienes Derived from Allenamides

Lewis acid promoted Diels–Alder cycloadditions of a series of <i>de novo</i> chiral cyclic 2-amidodienes are described. These cyclic 2-amidodienes are derived from chiral α-allyl allenamides via a sequence of <i>E-</i>selective 1,3-H shift and 6π-electron pericyclic ring closure. With enones serving as effective dienophiles, these cycloadditions can be highly diastereoselective depending upon the chiral amide substituent, thereby representing a facile entry to optically enriched [2.2.2]bicyclic manifolds

An Approach to Cyclohepta[<i>b</i>]indoles through an Allenamide (4 + 3) Cycloaddition–Grignard Cyclization–Chugaev Elimination Sequence

A strategy for synthesizing highly functionalized cyclohepta­[<i>b</i>]­indoles through a concise (4 + 3) cycloaddition–cyclization–elimination sequence is described. The cycloaddition features nitrogen-stabilized oxyallyl cations derived from epoxidations of <i>N-</i>aryl-<i>N-</i>sulfonyl-substituted allenamides, while the cyclization and elimination employed an intramolecular Grignard addition and a one-step Chugaev process, respectively

An Approach to Cyclohepta[<i>b</i>]indoles through an Allenamide (4 + 3) Cycloaddition–Grignard Cyclization–Chugaev Elimination Sequence

A strategy for synthesizing highly functionalized cyclohepta­[<i>b</i>]­indoles through a concise (4 + 3) cycloaddition–cyclization–elimination sequence is described. The cycloaddition features nitrogen-stabilized oxyallyl cations derived from epoxidations of <i>N-</i>aryl-<i>N-</i>sulfonyl-substituted allenamides, while the cyclization and elimination employed an intramolecular Grignard addition and a one-step Chugaev process, respectively