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Abstract Recent experimental studies in the awake brain have identified a rule for synaptic plasticity that is instrumental for the instantaneous creation of memory traces in area CA1 of the mammalian brain: Behavioral Time scale Synaptic Plasticity. This one-shot learning rule differs in five essential aspects from previously considered plasticity mechanisms. We introduce a transparent model for the core function of this learning rule and establish a theory that enables a principled understanding of the system of memory traces that it creates. Theoretical predictions and numerical simulations show that our model is able to create a functionally powerful content-addressable memory without the need for high-resolution synaptic weights. Furthermore, it reproduces the repulsion effect of human memory, whereby traces for similar memory items are pulled apart to enable differential downstream processing. Altogether, our results create a link between synaptic plasticity in area CA1 of the hippocampus and its network function. They also provide a promising approach for implementing content-addressable memory with on-chip learning capability in highly energy-efficient crossbar arrays of memristors. 

Abstract Hyperdimensional computing (HDC) addresses massively parallel implementations of symbolic computations that are both more transparent than ANNs and LLMs and more suitable for in-memory computing on highly energy-efficient analog hardware. It captures an essential aspects of brain computations: objects, concepts, and their attributes are encoded by very sparse distributed representations. But currently known methods for binding these tokens together entail deficits in flexible information retrieval.We show that a mechanism which the brain employs for binding, Behavioral Time Scale Synaptic Plasticity (BTSP), overcomes these deficiencies by adding attractor features to high-dimensional representations. They drastically improve the capability to recover from composed representations the tokens which have been bound together in them. One arrives in this way at a functionally more powerful HDC paradigm that provides new perspectives both for understanding how brains carry out symbolic computations, and for implementing them in novel energy-efficient and massively parallel neuromorphic hardware. 

The Alchemical Transfer Method (ATM) is herein validated against the relative binding free energies of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM software to compute the relative binding free energies (RBFE) of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical relative binding free energy methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and post-corrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 relative binding free energy calculations for eight protein targets and found that ATM achieves accuracy comparable to existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM is applicable as a production tool for relative binding free energy (RBFE) predictions across a wide range of perturbation types within a unified, open-source framework. 

Abstract Motivation In the training of predictive models using high-dimensional genomic data, multiple studies’ worth of data are often combined to increase sample size and improve generalizability. A drawback of this approach is that there may be different sets of features measured in each study due to variations in expression measurement platform or technology. It is often common practice to work only with the intersection of features measured in common across all studies, which results in the blind discarding of potentially useful feature information that is measured in individual or subsets of studies. Results We characterize the loss in predictive performance incurred by using only the intersection of feature information available across all studies when training predictors using gene expression data from microarray and sequencing datasets. We study the properties of linear and polynomial regression for imputing discarded features and demonstrate improvements in the external performance of prediction functions through simulation and in gene expression data collected on breast cancer patients. To improve this process, we propose a pairwise strategy that applies any imputation algorithm to two studies at a time and averages imputed features across pairs. We demonstrate that the pairwise strategy is preferable to first merging all datasets together and imputing any resulting missing features. Finally, we provide insights on which subsets of intersected and study-specific features should be used so that missing-feature imputation best promotes cross-study replicability. Availability and implementation The code is available at https://github.com/YujieWuu/Pairwise_imputation. Supplementary information Supplementary information is available at Bioinformatics online. 

Abstract Human reasoning depends on reusing pieces of information by binding them together in new ways, thereby “making infinite uses of finite means” (Alexander von Humboldt). Needed for that is a binding mechanism that enables fast composition and decomposition of tokens of information. Binding can easily be implemented in symbolic computations through parentheses and ordering of symbols. But it is a highly nontrivial operation for distributed representations, where the tokens are encoded by activity patterns in large neural networks or large language models, or more abstractly, by a high dimensional vector. Vector Symbolic Architectures (VSAs) provide partial solutions, but are lacking the flexibility of the brain in information retrieval, e.g. retrieving the tokens from a composed representation or retrieval of a composed representation by just providing some tokens as a cue. We show that a mechanism which the brain employs for binding distributed representations, Behavioral Time Scale Synaptic Plasticity (BTSP), overcomes these deficiencies. In particular, it combines binding with attractor features that make information retrieval substantially more flexible and robust. We evaluate its performance on various applications, including encoding and decoding complex visual scenes and hierarchical binding. We also show that it enhances models for natural language processing and abstract brain computation. BTSP-based binding only requires binary synaptic weights and simple local synaptic plasticity, and can therefore easily be implemented through in-memory computing or other innovative designs for energy-efficient AI implementations. 

Key Points A method to concoct non‐stationary data series is proposed Eddy covariance and wavelet analysis methods underestimate turbulent momentum flux under non‐stationary condition by about 50% Mexican hat wavelet method has the potential to accurately calculate flux of non‐stationary turbulence after correction