Intracortical brain-machine interfaces (iBMIs) have enabled movement and speech in people living with paralysis by using neural data to decode behaviors in real-time. However, intracortical neural recordings exhibit significant instabilities over time, which poses problems for iBMIs, neuroscience, and machine learning. For iBMIs, neural instabilities require frequent decoder recalibration to maintain high performance, a critical bottleneck for real-world translation. Several approaches have been developed to address this issue, and the field has recognized the need for standardized datasets on which to compare them, but no standard dataset exists for evaluation over year-long timescales. In neuroscience, a growing body of research attempts to elucidate the latent computations performed by populations of neurons. Nonstationarity in neural recordings imposes significant challenges to the design of these studies, so a dataset containing recordings over large time spans would improve methods to account for instabilities. In machine learning, continuous domain adaptation of temporal data is an area of active research, and a dataset containing shift distributions on long time scales would be beneficial to researchers. To address these gaps, we present the LINK Dataset (Long-term Intracortical Neural activity and Kinematics), which contains intracortical spiking activity and kinematic data from 312 sessions of a non-human primate performing a dexterous, 2 degree-of-freedom finger movement task, spanning 1,242 days. We also present longitudinal analyses of the dataset's neural spiking activity and its relationship to kinematics, as well as overall decoding performance using linear and neural network models. The LINK dataset and code are freely available to the public through the dataset website (https://chesteklab.github.io/LINK_dataset/).
As spatially resolved transcriptomics (SRT) datasets increasingly span multiple adjacent or replicated slices, effective joint analysis across slices is needed to reconstruct tissue structures and identify consistent spatial gene expression patterns. This requires resolving spatial correspondences between slices while capturing shared transcriptomic features, two tasks that are typically addressed in isolation. Multi-slice analysis remains challenging due to physical distortions, technical variability, and batch effects. To address these challenges, we introduce Joint Alignment and Deep Embedding for multi-slice SRT (JADE), a unified computational framework that simultaneously learns spatial location-wise alignments and shared low-dimensional embeddings across tissue slices. Unlike existing methods, JADE adopts a roundtrip framework in which each iteration alternates between alignment and embedding refinement. To infer alignment, we employ attention mechanisms that dynamically assess and weight the importance of different embedding dimensions, allowing the model to focus on the most alignment-relevant features while suppressing noise. To the best of our knowledge, JADE is the first method that jointly optimizes alignment and representation learning in a shared latent space, enabling robust multi-slice integration. We demonstrate that JADE outperforms existing alignment and embedding methods across multiple evaluation metrics in the 10x Visium human dorsolateral prefrontal cortex (DLPFC) and Stereo-seq axolotl brain datasets. By bridging spatial alignment and feature integration, JADE provides a scalable and accurate solution for cross-slice analysis of SRT data.
The function of biomolecules such as proteins depends on their ability to interconvert between a wide range of structures or conformations. Researchers have endeavored for decades to develop computational methods to predict the distribution of conformations, which is far harder to determine experimentally than a static folded structure. We present ConforMix, an inference-time algorithm that enhances sampling of conformational distributions using a combination of classifier guidance, filtering, and free energy estimation. Our approach upgrades diffusion models---whether trained for static structure prediction or conformational generation---to enable more efficient discovery of conformational variability without requiring prior knowledge of major degrees of freedom. ConforMix is orthogonal to improvements in model pretraining and would benefit even a hypothetical model that perfectly reproduced the Boltzmann distribution. Remarkably, when applied to a diffusion model trained for static structure prediction, ConforMix captures structural changes including domain motion, cryptic pocket flexibility, and transporter cycling, while avoiding unphysical states. Case studies of biologically critical proteins demonstrate the scalability, accuracy, and utility of this method.
Previous studies have compared neural activities in the visual cortex to representations in deep neural networks trained on image classification. Interestingly, while some suggest that their representations are highly similar, others argued the opposite. Here, we propose a new approach to characterize the similarity of the decision strategies of two observers (models or brains) using decision variable correlation (DVC). DVC quantifies the image-by-image correlation between the decoded decisions based on the internal neural representations in a classification task. Thus, it can capture task-relevant information rather than general representational alignment. We evaluate DVC using monkey V4/IT recordings and network models trained on image classification tasks. We find that model–model similarity is comparable to monkey-monkey similarity, whereas model–monkey similarity is consistently lower. Strikingly, DVC decreases with increasing network performance on ImageNet-1k. Adversarial training does not improve model–monkey similarity in task-relevant dimensions assessed using DVC, although it markedly increases the model–model similarity. Similarly, pre-training on larger datasets does not improve model–monkey similarity. These results suggest a divergence between the task-relevant representations in monkey V4/IT and those learned by models trained on image classification tasks.
Multi-class tissue-type classification of colorectal cancer (CRC) histopathologic images is a significant step in the development of downstream machine learning models for diagnosis and treatment planning. However, publicly available CRC datasets used to build tissue classifiers often suffer from insufficient morphologic diversity, class imbalance, and low-quality image tiles, limiting downstream model performance and generalizability. To address this research gap, we introduce STARC-9 (STAnford coloRectal Cancer), a large-scale dataset for multi-class tissue classification. STARC-9 comprises 630,000 histopathologic image tiles uniformly sampled across nine clinically relevant tissue classes (each represented by 70,000 tiles), systematically extracted from hematoxylin & eosin-stained whole-slide images (WSI) from 200 CRC patients at the Stanford University School of Medicine. To construct STARC-9, we propose a novel framework, DeepCluster++, consisting of two primary steps to ensure diversity within each tissue class, followed by pathologist verification. First, an encoder from an autoencoder trained specifically on histopathologic images is used to extract feature vectors from all tiles within a given input WSI. Next, K-means clustering groups morphologically similar tiles, followed by an equal-frequency binning method to sample diverse patterns within each tissue class. Finally, the selected tiles are verified by expert gastrointestinal pathologists to ensure classification accuracy. This semi-automated approach significantly reduces the manual effort required for dataset curation while producing high-quality training examples. To validate the utility of STARC-9, we benchmarked baseline convolutional neural networks, transformers, and pathology-specific foundation models on downstream multi-class CRC tissue classification and segmentation tasks when trained on STARC-9 versus publicly available datasets, demonstrating superior generalizability of models trained on STARC-9. Although we demonstrate the utility of DeepCluster++ on CRC as a pilot use-case, it is a flexible framework that can be used for constructing high-quality datasets from large WSI repositories across a wide range of cancer and non-cancer applications. https://huggingface.co/datasets/Path2AI/STARC-9/tree/main https://github.com/Path2AI/STARC-9/.
