Deep learning has been widely used for protein engineering. However, it is limited by the lack of sufficient experimental data to train an accurate model for predicting the functional fitness of high-order mutants. Here, we develop SESNet, a supervised deep-learning model to predict the fitness for protein mutants by leveraging both sequence and structure information, and exploiting attention mechanism. Our model integrates local evolutionary context from homologous sequences, the global evolutionary context encoding rich semantic from the universal protein sequence space and the structure information accounting for the microenvironment around each residue in a protein. We show that SESNet outperforms state-of-the-art models for predicting the sequence-function relationship on 26 deep mutational scanning datasets. More importantly, we propose a data augmentation strategy by leveraging the data from unsupervised models to pre-train our model. After that, our model can achieve strikingly high accuracy in prediction of the fitness of protein mutants, especially for the higher order variants (> 4 mutation sites), when finetuned by using only a small number of experimental mutation data (<50). The strategy proposed is of great practical value as the required experimental effort, i.e., producing a few tens of experimental mutation data on a given protein, is generally affordable by an ordinary biochemical group and can be applied on almost any protein.

This work addresses the problem of generating 3D holistic body motions from human speech. Given a speech recording, we synthesize sequences of 3D body poses, hand gestures, and facial expressions that are realistic and diverse. To achieve this, we first build a high-quality dataset of 3D holistic body meshes with synchronous speech. We then define a novel speech-to-motion generation framework in which the face, body, and hands are modeled separately. The separated modeling stems from the fact that face articulation strongly correlates with human speech, while body poses and hand gestures are less correlated. Specifically, we employ an autoencoder for face motions, and a compositional vector-quantized variational autoencoder (VQ-VAE) for the body and hand motions. The compositional VQ-VAE is key to generating diverse results. Additionally, we propose a cross-conditional autoregressive model that generates body poses and hand gestures, leading to coherent and realistic motions. Extensive experiments and user studies demonstrate that our proposed approach achieves state-of-the-art performance both qualitatively and quantitatively. Our novel dataset and code will be released for research purposes at https://talkshow.is.tue.mpg.de.

Referring image segmentation aims at localizing all pixels of the visual objects described by a natural language sentence. Previous works learn to straightforwardly align the sentence embedding and pixel-level embedding for highlighting the referred objects, but ignore the semantic consistency of pixels within the same object, leading to incomplete masks and localization errors in predictions. To tackle this problem, we propose CoupAlign, a simple yet effective multi-level visual-semantic alignment method, to couple sentence-mask alignment with word-pixel alignment to enforce object mask constraint for achieving more accurate localization and segmentation. Specifically, the Word-Pixel Alignment (WPA) module performs early fusion of linguistic and pixel-level features in intermediate layers of the vision and language encoders. Based on the word-pixel aligned embedding, a set of mask proposals are generated to hypothesize possible objects. Then in the Sentence-Mask Alignment (SMA) module, the masks are weighted by the sentence embedding to localize the referred object, and finally projected back to aggregate the pixels for the target. To further enhance the learning of the two alignment modules, an auxiliary loss is designed to contrast the foreground and background pixels. By hierarchically aligning pixels and masks with linguistic features, our CoupAlign captures the pixel coherence at both visual and semantic levels, thus generating more accurate predictions. Extensive experiments on popular datasets (e.g., RefCOCO and G-Ref) show that our method achieves consistent improvements over state-of-the-art methods, e.g., about 2% oIoU increase on the validation and testing set of RefCOCO. Especially, CoupAlign has remarkable ability in distinguishing the target from multiple objects of the same class.

Self-supervised pre-training recently demonstrates success on large-scale multimodal data, and state-of-the-art contrastive learning methods often enforce the feature consistency from cross-modality inputs, such as video/audio or video/text pairs. Despite its convenience to formulate and leverage in practice, such cross-modality alignment (CMA) is only a weak and noisy supervision, since two modalities can be semantically misaligned even they are temporally aligned. For example, even in the commonly adopted instructional videos, a speaker can sometimes refer to something that is not visually present in the current frame; and the semantic misalignment would only be more unpredictable for the raw videos from the internet. We conjecture that might cause conflicts and biases among modalities, and may hence prohibit CMA from scaling up to training with larger and more heterogeneous data. This paper first verifies our conjecture by observing that, even in the latest VATT pre-training using only instructional videos, there exist strong gradient conflicts between different CMA losses within the same video, audio, text triplet, indicating them as the noisy source of supervision. We then propose to harmonize such gradients, via two techniques: (i) cross-modality gradient realignment: modifying different CMA loss gradients for each sample triplet, so that their gradient directions are more aligned; and (ii) gradient-based curriculum learning: leveraging the gradient conflict information on an indicator of sample noisiness, to develop a curriculum learning strategy to prioritize training on less noisy sample triplets. Applying those techniques to pre-training VATT on the HowTo100M dataset, we consistently improve its performance on different downstream tasks. Moreover, we are able to scale VATT pre-training to more complicated non-narrative Youtube8M dataset to further improve the state-of-the-arts.

在混合完成的多任务，多域和多模式数据上进行预训练仍然是视力感知预训练的开放挑战。在本文中，我们提出了GPPF，这是一个普遍的感知预训练框架，预先培训任务级的动态网络，该网络是由在标签的多任务和多域数据集上的各层知识“乐高”组成的。通过检查人类在复杂环境中学习的先天能力，我们识别并将三个关键要素转移到深网上：（1）同时暴露于每个批次中的各种交叉任务和跨域信息。 （2）由知识共享驱动的单独的乐高单元中的分区知识存储。 （3）用于训练和下游任务的乐高单元子集的稀疏激活。值得注意的是，由于其在输入形状，损失功能，输出格式，数据分布等方面的差异，不同视觉任务的联合培训是不平凡的。因此，我们创新地开发了插件的多任务培训算法，该培训算法是支持单个迭代多个任务（SIMT）同时培训。 Simt用大型多任务多任务数据集为预训练的基础奠定了基础，并且被证明对于我们的GPPF实验中的稳定培训至关重要。令人兴奋的是，详尽的实验表明，我们的GPPF-R50型号在GPPF-15M中的8个预训练预培训任务的强大基线上取得了显着改善，并在22个下游任务中收获了一系列SOTA，并具有相似的计算预算。我们还验证了GPPF对SOTA视觉变压器的概括能力，并具有一致的改进。这些可靠的实验结果充分证明了我们新颖的GPPF框架提供的有效的知识学习，存储，共享和转移。

美国食品药品监督管理局（FDA）推荐的产品特定指南（PSG）对促进和指导通用药物产品开发有助于。为了评估PSG，FDA评估者需要花费大量时间和精力来手动从参考列出的药物标签中手动检索吸收，分布，代谢和排泄（ADME）的支持性药物信息。在这项工作中，我们利用最先进的预训练的语言模型自动将来自FDA批准的药物标签的药代动力学部分中的ADME段落标记，以促进PSG评估。我们通过微调从变形金刚（BERT）模型的预训练的双向编码器表示，采用了转移学习方法来开发新颖的ADME语义标签应用，可以自动从药物标签中自动检索ADME段落而不是手动工作。我们证明，对预训练的BERT模型进行微调可以胜过传统的机器学习技术，实现高达11.6％的绝对F1改进。据我们所知，我们是第一个成功应用BERT来解决ADME语义标签任务的人。我们进一步评估了使用一系列分析方法，例如注意力相似性和基于层的消融，进一步评估了预训练和微调对BERT模型整体性能的相对贡献。我们的分析表明，通过微调学到的信息集中在BERT的顶层中的特定于任务知识上，而预先训练的BERT模型的好处来自底层。

促性腺营养蛋白释放激素受体（GNRH1R）是治疗子宫疾病的有前途的治疗靶标。迄今为止，在临床研究中可以使用几个GNRH1R拮抗剂，而不满足多个财产约束。为了填补这一空白，我们旨在开发一个基于学习的框架，以促进有效，有效地发现具有理想特性的新的口服小型分子药物靶向GNRH1R。在目前的工作中，首先通过充分利用已知活性化合物和靶蛋白的结构的信息，首先提出了配体和结构组合模型，即LS-Molgen，首先提出了分子生成的方法，该信息通过其出色的性能证明了这一点。比分别基于配体或结构方法。然后，进行了A中的计算机筛选，包括活性预测，ADMET评估，分子对接和FEP计算，其中约30,000个生成的新型分子被缩小到8，以进行实验合成和验证。体外和体内实验表明，其中三个表现出有效的抑制活性（化合物5 IC50 = 0.856 nm，化合物6 IC50 = 0.901 nm，化合物7 IC50 = 2.54 nm对GNRH1R，并且化合物5在基本PK属性中表现良好例如半衰期，口服生物利用度和PPB等。我们认为，提议的配体和结构组合结合的分子生成模型和整个计算机辅助工作流程可能会扩展到从头开始的类似任务或铅优化的类似任务。

长尾分布式数据的分类是一个具有挑战性的问题，它遭受了严重的班级不平衡，因此只有几个样本的尾巴阶级表现不佳。由于样本的匮乏，在将预审计的模型转移到下游任务时，在尾部类中学习对于微调尤其具有挑战性。在这项工作中，我们简单地修改了标准微调，以应对这些挑战。具体而言，我们提出了一个两阶段的微调：我们首先用类平衡的重新释放损失微调了预审计模型的最后一层，然后我们执行标准的微调。我们的修改有几个好处：（1）仅通过微调模型参数的一小部分，同时保持其余部分未触及，从而利用了预告片； （2）它允许模型学习特定任务的初始表示；重要的是（3）它可以保护学习尾巴的学习免于模型更新期间处于不利地位。我们对文本分类的两类和多级任务的合成数据集进行了广泛的实验，以及用于ADME的现实世界应用（即吸收，分布，代谢和排泄）语义标记。实验结果表明，所提出的两阶段微调既优于传统损失，又超过了微调，并且在上述数据集上进行了重新调整损失。

尖峰神经网络（SNN）引起了脑启发的人工智能和计算神经科学的广泛关注。它们可用于在多个尺度上模拟大脑中的生物信息处理。更重要的是，SNN是适当的抽象水平，可以将大脑和认知的灵感带入人工智能。在本文中，我们介绍了脑启发的认知智力引擎（Braincog），用于创建脑启发的AI和脑模拟模型。 Braincog将不同类型的尖峰神经元模型，学习规则，大脑区域等作为平台提供的重要模块。基于这些易于使用的模块，BrainCog支持各种受脑启发的认知功能，包括感知和学习，决策，知识表示和推理，运动控制和社会认知。这些受脑启发的AI模型已在各种受监督，无监督和强化学习任务上有效验证，并且可以用来使AI模型具有多种受脑启发的认知功能。为了进行大脑模拟，Braincog实现了决策，工作记忆，神经回路的结构模拟以及小鼠大脑，猕猴大脑和人脑的整个大脑结构模拟的功能模拟。一个名为BORN的AI引擎是基于Braincog开发的，它演示了如何将Braincog的组件集成并用于构建AI模型和应用。为了使科学追求解码生物智能的性质并创建AI，Braincog旨在提供必要且易于使用的构件，并提供基础设施支持，以开发基于脑部的尖峰神经网络AI，并模拟认知大脑在多个尺度上。可以在https://github.com/braincog-x上找到Braincog的在线存储库。

最近，由于其广泛的商业价值，从视觉丰富的文档（例如门票和简历）中自动提取信息已成为一个热门而重要的研究主题。大多数现有方法将此任务分为两个小节：用于从原始文档图像中获取纯文本的文本阅读部分以及用于提取密钥内容的信息提取部分。这些方法主要集中于改进第二个方法，同时忽略了这两个部分高度相关。本文提出了一个统一的端到端信息提取框架，从视觉上富含文档中提出，文本阅读和信息提取可以通过精心设计的多模式上下文块相互加强。具体而言，文本阅读部分提供了多模式功能，例如视觉，文本和布局功能。开发了多模式上下文块，以融合生成的多模式特征，甚至是从预训练的语言模型中获得的先验知识，以提供更好的语义表示。信息提取部分负责使用融合上下文功能生成密钥内容。该框架可以以端到端的可训练方式进行培训，从而实现全球优化。更重要的是，我们将视觉丰富的文档定义为跨两个维度的四个类别，即布局和文本类型。对于每个文档类别，我们提供或推荐相应的基准，实验设置和强大的基准，以弥补该研究领域缺乏统一评估标准的问题。报告了对四种基准测试的广泛实验（从固定布局到可变布局，从完整的文本到半未结构化的文本），证明了所提出的方法的有效性。数据，源代码和模型可用。