Publications

Non-Adversarial Inverse Reinforcement Learning via Successor Feature Matching

Arnav Kumar Jain

Harley Wiltzer

Jesse Farebrother

Irina Rish

Glen Berseth

Sanjiban Choudhury

In inverse reinforcement learning (IRL), an agent seeks to replicate expert demonstrations through interactions with the environment. Tradit… (see more)ionally, IRL is treated as an adversarial game, where an adversary searches over reward models, and a learner optimizes the reward through repeated RL procedures. This game-solving approach is both computationally expensive and difficult to stabilize. In this work, we propose a novel approach to IRL by direct policy optimization: exploiting a linear factorization of the return as the inner product of successor features and a reward vector, we design an IRL algorithm by policy gradient descent on the gap between the learner and expert features. Our non-adversarial method does not require learning a reward function and can be solved seamlessly with existing actor-critic RL algorithms. Remarkably, our approach works in state-only settings without expert action labels, a setting which behavior cloning (BC) cannot solve. Empirical results demonstrate that our method learns from as few as a single expert demonstration and achieves improved performance on various control tasks.

2024-11-11

ArXiv (preprint)

Specific inhibition and disinhibition in the higher-order structure of a cortical connectome

Michael W. Reimann

Daniela Egas Santander

András Ecker

Eilif Benjamin Muller

Neuronal network activity is thought to be structured around the activation of assemblies, or low-dimensional manifolds describing states of… (see more) activity. Both views describe neurons acting not independently, but in concert, likely facilitated by strong recurrent excitation between them. The role of inhibition in these frameworks – if considered at all – is often reduced to blanket inhibition with no specificity with respect to which excitatory neurons are targeted. We analyzed the structure of excitation and inhibition in the MICrONS 1mm3 dataset, an electron microscopic reconstruction of a piece of cortical tissue. We found that excitation was structured around a feed-forward flow in non-random motifs of seven or more neurons. This revealed a structure of information flow from a small number of sources to a larger number of potential targets that became only visible when larger motifs were considered instead of individual pairs. Inhibitory neurons targeted and were targeted by neurons in specific sequential positions of these motifs. Additionally, disynaptic inhibition was strongest between target motifs excited by the same group of source neurons, implying competition between them. The structure of this inhibition was also highly specific and symmetrical, contradicting the idea of non-specific blanket inhibition. None of these trends are detectable in only pairwise connectivity, demonstrating that inhibition is specifically structured by these large motifs. Further, we found that these motifs represent higher order connectivity patterns which are present, but to a lesser extent in a recently released, detailed computational model, and not at all in a distance-dependent control. These findings have important implications for how synaptic plasticity reorganizes neocortical connectivity to implement learning and for the specific role of inhibition in this process.

2024-11-11

Cerebral Cortex (New York, NY) (published)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Reaction-conditioned De Novo Enzyme Design with GENzyme

Chenqing Hua

Jiarui Lu

Yong Liu

Odin Zhang

Rex Ying

Wengong Jin

Shuangjia Zheng

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interact… (see more)ion prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

2024-11-10

ArXiv (preprint)

Towards Enhancing the Reproducibility of Deep Learning Bugs: An Empirical Study

Mehil B. Shah

Mohammad Masudur Rahman

Foutse Khomh

2024-11-09

Empirical Software Engineering (published)

Deep Learning Unlocks the True Potential of Organ Donation after Circulatory Death with Accurate Prediction of Time-to-Death

Xingzhi Sun

Edward De Brouwer

Chen Liu

Smita Krishnaswamy

Ramesh Batra

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Increasing the number of organ donations after circulatory death (DCD) has been identified as one of the most important ways of addressing t… (see more)he ongoing organ shortage. While recent technological advances in organ transplantation have increased their success rate, a substantial challenge in increasing the number of DCD donations resides in the uncertainty regarding the timing of cardiac death after terminal extubation, impacting the risk of prolonged ischemic organ injury, and negatively affecting post-transplant outcomes. In this study, we trained and externally validated an ODE-RNN model, which combines recurrent neural network with neural ordinary equations and excels in processing irregularly-sampled time series data. The model is designed to predict time-to-death following terminal extubation in the intensive care unit (ICU) using the last 24 hours of clinical observations. Our model was trained on a cohort of 3,238 patients from Yale New Haven Hospital, and validated on an external cohort of 1,908 patients from six hospitals across Connecticut. The model achieved accuracies of 95.3 {+/-} 1.0% and 95.4 {+/-} 0.7% for predicting whether death would occur in the first 30 and 60 minutes, respectively, with a calibration error of 0.024 {+/-} 0.009. Heart rate, respiratory rate, mean arterial blood pressure (MAP), oxygen saturation (SpO2), and Glasgow Coma Scale (GCS) scores were identified as the most important predictors. Surpassing existing clinical scores, our model sets the stage for reduced organ acquisition costs and improved post-transplant outcomes.

2024-11-08

medRxiv (preprint)