Artificial intelligence for natural product drug discovery.

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

Metacognition in the audiovisual McGurk illusion: perceptual and causal confidence.

Almost all decisions in everyday life rely on multiple sensory inputs that can come from common or independent causes. These situations invoke perceptual uncertainty about environmental properties and the signals' causal structure. Using the audiovisual McGurk illusion, this study investigated how observers formed perceptual and causal confidence judgements in information integration tasks under causal uncertainty. Observers were presented with spoken syllables, their corresponding articulatory lip movements or their congruent and McGurk combinations (e.g. auditory B/P with visual G/K). Observers reported their perceived auditory syllable, the causal structure and confidence for each judgement. Observers were more accurate and confident on congruent than unisensory trials. Their perceptual and causal confidence were tightly related over trials as predicted by the interactive nature of perceptual and causal inference. Further, observers assigned comparable perceptual and causal confidence to veridical 'G/K' percepts on audiovisual congruent trials and their causal and perceptual metamers on McGurk trials (i.e. illusory 'G/K' percepts). Thus, observers metacognitively evaluate the integrated audiovisual percept with limited access to the conflicting unisensory stimulus components on McGurk trials. Collectively, our results suggest that observers form meaningful perceptual and causal confidence judgements about multisensory scenes that are qualitatively consistent with principles of Bayesian causal inference. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters.

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/.

Good practices and recommendations for using and benchmarking computational metabolomics metabolite annotation tools.

BACKGROUND: Untargeted metabolomics approaches based on mass spectrometry obtain comprehensive profiles of complex biological samples. However, on average only 10% of the molecules can be annotated. This low annotation rate hampers biochemical interpretation and effective comparison of metabolomics studies. Furthermore, de novo structural characterization of mass spectral data remains a complicated and time-intensive process. Recently, the field of computational metabolomics has gained traction and novel methods have started to enable large-scale and reliable metabolite annotation. Molecular networking and machine learning-based in-silico annotation tools have been shown to greatly assist metabolite characterization in diverse fields such as clinical metabolomics and natural product discovery. AIM OF REVIEW: We highlight recent advances in computational metabolite annotation workflows with a special focus on their evaluation and comparison with other tools. Whilst the progress is substantial and promising, we also argue that inconsistencies in benchmarking different tools hamper users from selecting the most appropriate and promising method for their research. We summarize benchmarking strategies of the different tools and outline several recommendations for benchmarking and comparing novel tools. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review focuses on recent advances in mass spectral library-based and machine learning-supported metabolite annotation workflows. We discuss large-scale library matching and analogue search, the current bloom of mass spectral similarity scores, and how molecular networking has changed the field. In addition, the potentials and challenges of machine learning-supported metabolite annotation workflows are highlighted. Overall, recent developments in computational metabolomics have started to fundamentally change metabolomics workflows, and we expect that as a community we will be able to overcome current method performance ambiguities and annotation bottlenecks.

Older adults sacrifice response speed to preserve multisensory integration performance.

Aging has been shown to impact multisensory perception, but the underlying computational mechanisms are unclear. For effective interactions with the environment, observers should integrate signals that share a common source, weighted by their reliabilities, and segregate those from separate sources. Observers are thought to accumulate evidence about the world's causal structure over time until a decisional threshold is reached. Combining psychophysics and Bayesian modeling, we investigated how aging affects audiovisual perception of spatial signals. Older and younger adults were comparable in their final localization and common-source judgment responses under both speeded and unspeeded conditions, but were disproportionately slower for audiovisually incongruent trials. Bayesian modeling showed that aging did not affect the ability to arbitrate between integration and segregation under either unspeeded or speeded conditions. However, modeling the within-trial dynamics of evidence accumulation under speeded conditions revealed that older observers accumulate noisier auditory representations for longer, set higher decisional thresholds, and have impaired motor speed. Older observers preserve audiovisual localization performance, despite noisier sensory representations, by sacrificing response speed.

Integration of audiovisual spatial signals is not consistent with maximum likelihood estimation.

Multisensory perception is regarded as one of the most prominent examples where human behaviour conforms to the computational principles of maximum likelihood estimation (MLE). In particular, observers are thought to integrate auditory and visual spatial cues weighted in proportion to their relative sensory reliabilities into the most reliable and unbiased percept consistent with MLE. Yet, evidence to date has been inconsistent. The current pre-registered, large-scale (N = 36) replication study investigated the extent to which human behaviour for audiovisual localization is in line with maximum likelihood estimation. The acquired psychophysics data show that while observers were able to reduce their multisensory variance relative to the unisensory variances in accordance with MLE, they weighed the visual signals significantly stronger than predicted by MLE. Simulations show that this dissociation can be explained by a greater sensitivity of standard estimation procedures to detect deviations from MLE predictions for sensory weights than for audiovisual variances. Our results therefore suggest that observers did not integrate audiovisual spatial signals weighted exactly in proportion to their relative reliabilities for localization. These small deviations from the predictions of maximum likelihood estimation may be explained by observers' uncertainty about the world's causal structure as accounted for by Bayesian causal inference.

Timing of beta oscillatory synchronization and temporal prediction of upcoming stimuli.

Modulations of beta oscillatory power serve a predictive role, in preparation of future actions. It is well known that beta amplitude decreases prior to voluntary movements and expected tactile stimuli. Paradoxically, recent studies have reported a beta amplitude increase prior to expected visual and auditory stimuli. Moreover, it has been suggested that, in isochronic stimulus series, the rising beta slope is adjusted to the duration of the interstimulus interval. We investigated the characteristics of such timing related pre-stimulus beta power increases using visual stimulus sequences that were presented at three regular rates (0.61, 0.74 and 0.95Hz). EEG was recorded from twenty participants while they attended the sequences by performing a clock reading task. Time-frequency analyses showed a consistent pattern of beta modulation: the post-stimulus beta power decrease was followed by a steep increase. Contrary to recent views, we found that the peaks of beta power, for the three presentation rates, were reached at a similar latency post-stimulus, instead of a fixed interval preceding the next stimulus. This demonstrates that, at interstimulus intervals between 1-2s, beta synchronization slopes are not modulated by timing mechanisms related to prediction of upcoming stimuli. We reconcile the discrepant results by proposing that when shorter interval durations are used, as in previous studies, beta resynchronization is interrupted by the presentation of a new stimulus, making it seem as if beta power peaks prior to upcoming stimuli. We emphasize caution with respect to the notion that the timing of beta synchronization is an expression of predictive timing.