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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Épisodes d’inactivité et revenus criminels dans une trajectoire de délinquance

L’instabilité de l’activité criminelle dans le temps est déjà bien documentée. On connaît toutefois peu les circonstances qui expliquent ces variations à court terme. Une meilleure connaissance de ces facteurs est souhaitable puisqu’il est possible que les transitions et les changements à court terme précèdent les points tournants des carrières criminelles. Les conditions qui rendent compte d’une interruption temporaire des activités peuvent, par exemple, contribuer à expliquer un désistement définitif. L’étude se fonde sur les trajectoires de 172 délinquants impliqués dans des crimes à but lucratif et analyse les variations mensuelles de leurs revenus criminels ainsi que les épisodes d’inactivité criminelle à l’intérieur d’une période fenêtre de 36 mois. La méthode des calendriers d’histoire de vie combinée aux modèles hiérarchiques permet d’examiner conjointement le rôle de facteurs statiques (les caractéristiques individuelles des sujets) et dynamiques (les circonstances de vie). Les résultats mettent en évidence l’importance des événements qui marquent le style de vie des délinquants et des paramètres qui caractérisent l’engagement criminel dans la compréhension des variations dans les trajectoires à l’étude. Ils soulignent également l’importance de la finalité derrière les activités criminelles pour expliquer la décision des délinquants de cesser temporaire leurs activités illicites

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

From <i>Drosophila</i> to Human: Biological Function of E3 Ligase Godzilla and Its Role in Disease

The ubiquitin–proteasome system is of fundamental importance in all fields of biology due to its impact on proteostasis and in regulating cellular processes. Ubiquitination, a type of protein post-translational modification, involves complex enzymatic machinery, such as E3 ubiquitin ligases. The E3 ligases regulate the covalent attachment of ubiquitin to a target protein and are involved in various cellular mechanisms, including the cell cycle, cell division, endoplasmic reticulum stress, and neurotransmission. Because the E3 ligases regulate so many physiological events, they are also associated with pathologic conditions, such as cancer, neurological disorders, and immune-related diseases. This review focuses specifically on the protease-associated transmembrane-containing the Really Interesting New Gene (RING) subset of E3 ligases. We describe the structure, partners, and physiological functions of the Drosophila Godzilla E3 ligase and its human homologues, RNF13, RNF167, and ZNRF4. Also, we summarize the information that has emerged during the last decade regarding the association of these E3 ligases with pathophysiological conditions, such as cancer, asthma, and rare genetic disorders. We conclude by highlighting the limitations of the current knowledge and pinpointing the unresolved questions relevant to RNF13, RNF167, and ZNRF4 ubiquitin ligases