Structure-based drug design (SBDD) aims to discover drug candidates by finding molecules (ligands) that bind tightly to a disease-related protein (targets), which is the primary approach to computer-aided drug discovery. Recently, applying deep generative models for three-dimensional (3D) molecular design conditioned on protein pockets to solve SBDD has attracted much attention, but their formulation as probabilistic modeling often leads to unsatisfactory optimization performance. On the other hand, traditional combinatorial optimization methods such as genetic algorithms (GA) have demonstrated state-of-the-art performance in various molecular optimization tasks. However, they do not utilize protein target structure to inform design steps but rely on a random-walk-like exploration, which leads to unstable performance and no knowledge transfer between different tasks despite the similar binding physics. To achieve a more stable and efficient SBDD, we propose Reinforced Genetic Algorithm (RGA) that uses neural models to prioritize the profitable design steps and suppress random-walk behavior. The neural models take the 3D structure of the targets and ligands as inputs and are pre-trained using native complex structures to utilize the knowledge of the shared binding physics from different targets and then fine-tuned during optimization. We conduct thorough empirical studies on optimizing binding affinity to various disease targets and show that RGA outperforms the baselines in terms of docking scores and is more robust to random initializations. The ablation study also indicates that the training on different targets helps improve performance by leveraging the shared underlying physics of the binding processes. The code is available at https://github.com/futianfan/reinforced-genetic-algorithm.

PROteolysis TArgeting Chimeras (PROTACs) are an emerging therapeutic modality for degrading a protein of interest (POI) by marking it for degradation by the proteasome. Recent developments in artificial intelligence (AI) suggest that deep generative models can assist with the de novo design of molecules with desired properties, and their application to PROTAC design remains largely unexplored. We show that a graph-based generative model can be used to propose novel PROTAC-like structures from empty graphs. Our model can be guided towards the generation of large molecules (30--140 heavy atoms) predicted to degrade a POI through policy-gradient reinforcement learning (RL). Rewards during RL are applied using a boosted tree surrogate model that predicts a molecule's degradation potential for each POI. Using this approach, we steer the generative model towards compounds with higher likelihoods of predicted degradation activity. Despite being trained on sparse public data, the generative model proposes molecules with substructures found in known degraders. After fine-tuning, predicted activity against a challenging POI increases from 50% to >80% with near-perfect chemical validity for sampled compounds, suggesting this is a promising approach for the optimization of large, PROTAC-like molecules for targeted protein degradation.

人工智能尚未彻底改变材料和分子的设计。在这种观点中，我们确定了四个障碍，阻碍了原子深度学习，分子科学和高性能计算的整合。我们概述了重点的研究努力，解决这些挑战所提供的机会。

分子和材料科学的深度学习受应用科学，人工智能和高性能计算之间缺乏融合的限制。关于培训数据量，模型架构的规模和复杂程度以及计算基础设施的规模的瓶颈是限制分子和材料深度学习缩放的关键因素。在这里，我们呈现$ \ texit {litmatter} $，轻量级框架用于缩放分子深度学习方法。我们在超过400个GPU上培训四个图形神经网络架构，并调查这些方法的缩放行为。根据模型架构，可以看到高达60美元的培训时间加速。经验神经缩放关系量化模型依赖性缩放，使能最优计算资源分配和可伸缩分子几何深度学习模型实现的识别。

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule.However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has

Making histopathology image classifiers robust to a wide range of real-world variability is a challenging task. Here, we describe a candidate deep learning solution for the Mitosis Domain Generalization Challenge 2022 (MIDOG) to address the problem of generalization for mitosis detection in images of hematoxylin-eosin-stained histology slides under high variability (scanner, tissue type and species variability). Our approach consists in training a rotation-invariant deep learning model using aggressive data augmentation with a training set enriched with hard negative examples and automatically selected negative examples from the unlabeled part of the challenge dataset. To optimize the performance of our models, we investigated a hard negative mining regime search procedure that lead us to train our best model using a subset of image patches representing 19.6% of our training partition of the challenge dataset. Our candidate model ensemble achieved a F1-score of .697 on the final test set after automated evaluation on the challenge platform, achieving the third best overall score in the MIDOG 2022 Challenge.

Supervised Question Answering systems (QA systems) rely on domain-specific human-labeled data for training. Unsupervised QA systems generate their own question-answer training pairs, typically using secondary knowledge sources to achieve this outcome. Our approach (called PIE-QG) uses Open Information Extraction (OpenIE) to generate synthetic training questions from paraphrased passages and uses the question-answer pairs as training data for a language model for a state-of-the-art QA system based on BERT. Triples in the form of <subject, predicate, object> are extracted from each passage, and questions are formed with subjects (or objects) and predicates while objects (or subjects) are considered as answers. Experimenting on five extractive QA datasets demonstrates that our technique achieves on-par performance with existing state-of-the-art QA systems with the benefit of being trained on an order of magnitude fewer documents and without any recourse to external reference data sources.

While the capabilities of autonomous systems have been steadily improving in recent years, these systems still struggle to rapidly explore previously unknown environments without the aid of GPS-assisted navigation. The DARPA Subterranean (SubT) Challenge aimed to fast track the development of autonomous exploration systems by evaluating their performance in real-world underground search-and-rescue scenarios. Subterranean environments present a plethora of challenges for robotic systems, such as limited communications, complex topology, visually-degraded sensing, and harsh terrain. The presented solution enables long-term autonomy with minimal human supervision by combining a powerful and independent single-agent autonomy stack, with higher level mission management operating over a flexible mesh network. The autonomy suite deployed on quadruped and wheeled robots was fully independent, freeing the human supervision to loosely supervise the mission and make high-impact strategic decisions. We also discuss lessons learned from fielding our system at the SubT Final Event, relating to vehicle versatility, system adaptability, and re-configurable communications.

While the brain connectivity network can inform the understanding and diagnosis of developmental dyslexia, its cause-effect relationships have not yet enough been examined. Employing electroencephalography signals and band-limited white noise stimulus at 4.8 Hz (prosodic-syllabic frequency), we measure the phase Granger causalities among channels to identify differences between dyslexic learners and controls, thereby proposing a method to calculate directional connectivity. As causal relationships run in both directions, we explore three scenarios, namely channels' activity as sources, as sinks, and in total. Our proposed method can be used for both classification and exploratory analysis. In all scenarios, we find confirmation of the established right-lateralized Theta sampling network anomaly, in line with the temporal sampling framework's assumption of oscillatory differences in the Theta and Gamma bands. Further, we show that this anomaly primarily occurs in the causal relationships of channels acting as sinks, where it is significantly more pronounced than when only total activity is observed. In the sink scenario, our classifier obtains 0.84 and 0.88 accuracy and 0.87 and 0.93 AUC for the Theta and Gamma bands, respectively.

Vocal Bursts -- short, non-speech vocalizations that convey emotions, such as laughter, cries, sighs, moans, and groans -- are an often-overlooked aspect of speech emotion recognition, but an important aspect of human vocal communication. One barrier to study of these interesting vocalizations is a lack of large datasets. I am pleased to introduce the EmoGator dataset, which consists of 32,040 samples from 365 speakers, 16.91 hours of audio; each sample classified into one of 30 distinct emotion categories by the speaker. Several different approaches to construct classifiers to identify emotion categories will be discussed, and directions for future research will be suggested. Data set is available for download from https://github.com/fredbuhl/EmoGator.