Explore the vast range of titles available.

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1 – 3 . Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology. A regional atlas of the ageing human brain—spanning six distinct anatomical regions from individuals with and without Alzheimer’s dementia—provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology

As the cost of pretraining large language models grows, there is continued interest in strategies to improve learning efficiency during this core training stage. Motivated by cognitive development, where humans gradually build knowledge as their brains mature, we propose Curriculum-Guided Layer Scaling (CGLS), a framework for compute-efficient pretraining that synchronizes increasing data difficulty with model growth through progressive layer stacking (i.e. gradually adding layers during training). At the 100M parameter scale, using a curriculum transitioning from synthetic short stories to general web data, CGLS outperforms baseline methods on the question-answering benchmarks PIQA and ARC. Pretraining at the 1.2B scale, we stratify the DataComp-LM corpus with a DistilBERT-based classifier and progress from general text to highly technical or specialized content. Our results show that progressively increasing model depth alongside sample difficulty leads to better generalization and zero-shot performance on various downstream benchmarks. Altogether, our findings demonstrate that CGLS unlocks the potential of progressive stacking, offering a simple yet effective strategy for improving generalization on knowledge-intensive and reasoning tasks.

Compute scaling for language model (LM) pretraining has outpaced the growth of human-written texts, leading to concerns that data will become the bottleneck to LM scaling. To continue scaling pretraining in this data-constrained regime, we propose that explicitly modeling and inferring the latent thoughts that underlie the text generation process can significantly improve pretraining data efficiency. Intuitively, our approach views web text as the compressed final outcome of a verbose human thought process and that the latent thoughts contain important contextual knowledge and reasoning steps that are critical to data-efficient learning. We empirically demonstrate the effectiveness of our approach through data-constrained continued pretraining for math. We first show that synthetic data approaches to inferring latent thoughts significantly improve data efficiency over training on the same amount of raw data. Furthermore, we demonstrate latent thought inference without a strong teacher, where an LM bootstraps its own performance by using an EM algorithm to iteratively improve the capability of the trained LM and the quality of thought-augmented pretraining data. We show that a 1B LM can bootstrap its performance across at least three iterations and significantly outperform baselines trained on raw data, with increasing gains from additional inference compute when performing the E-step. The gains from inference scaling and EM iterations suggest new opportunities for scaling data-constrained pretraining.

Pretraining on large-scale, unstructured internet text enables language models to acquire a significant amount of world knowledge. However, this knowledge acquisition is data-inefficient--to learn a given fact, models must be trained on hundreds to thousands of diverse representations of it. This poses a challenge when adapting a pretrained model to a small corpus of domain-specific documents, where each fact may appear rarely or only once. We propose to bridge this gap with synthetic continued pretraining: using the small domain-specific corpus to synthesize a large corpus more amenable to learning, and then performing continued pretraining on the synthesized corpus. We instantiate this proposal with EntiGraph, a synthetic data augmentation algorithm that extracts salient entities from the source documents and then generates diverse text by drawing connections between the sampled entities. Synthetic continued pretraining with EntiGraph enables a language model to answer questions and follow generic instructions related to the source documents without access to them. If, instead, the source documents are available at inference time, we show that the knowledge acquired through our approach compounds with retrieval-augmented generation. To better understand these results, we build a simple mathematical model of EntiGraph, and show how synthetic data augmentation can \"rearrange\" knowledge to enable more data-efficient learning.

Language models (LMs) may lead their users to make suboptimal downstream decisions when they confidently hallucinate. This issue can be mitigated by having the LM verbally convey the probability that its claims are correct, but existing models cannot produce long-form text with calibrated confidence statements. Through the lens of decision-making, we define linguistic calibration for long-form generations: an LM is linguistically calibrated if its generations enable its users to make calibrated probabilistic predictions. This definition enables a training framework where a supervised finetuning step bootstraps an LM to emit long-form generations with confidence statements such as \"I estimate a 30% chance of...\" or \"I am certain that...\", followed by a reinforcement learning step which rewards generations that enable a user to provide calibrated answers to related questions. We linguistically calibrate Llama 2 7B and find in automated and human evaluations of long-form generations that it is significantly more calibrated than strong finetuned factuality baselines with comparable accuracy. These findings generalize under significant domain shifts to scientific and biomedical questions and to an entirely held-out person biography generation task. Our results demonstrate that long-form generations may be calibrated end-to-end by constructing an objective in the space of the predictions that users make in downstream decision-making.

When Masked Diffusion Models (MDMs) generate sequences through iterative refinement, the rich internal computation over masked positions is discarded, forcing every subsequent refinement step to recompute the valuable internal information stored as model representations. To avoid a hard reset between denoising rounds, we propose Learned Relay Representations (Relay), a method that allows MDMs to be forward-thinking when denoising by explicitly learning how to propagate latent information for the benefit of future denoising steps. Relay introduces a differentiable per-token channel that passes information between forward passes and is trained via truncated backpropagation through time (BPTT). We show that this framework can be scaled to state-of-the-art Diffusion Language Models (DLMs), and is seamlessly compatible with techniques like block diffusion and KV caching. We first provide a thorough justification of the design choices in Relay on a challenging Sudoku-based planning task. We then scale Relay to Fast-dLLM v2, a state-of-the-art DLM, outperforming standard supervised finetuning on coding tasks while reducing inference latency by up to 32%. Our empirical results demonstrate that state-of-the-art DLMs can be explicitly trained to relay latent information forward across decoding steps, advancing the performance-latency Pareto frontier. We provide code for all our experiments.

What are the limits of controlling language models via synthetic training data? We develop a reinforcement learning (RL) primitive, the Dataset Policy Gradient (DPG), which can precisely optimize synthetic data generators to produce a dataset of targeted examples. When used for supervised fine-tuning (SFT) of a target model, these examples cause the target model to do well on a differentiable metric of our choice. Our approach achieves this by taking exact data attribution via higher-order gradients and using those scores as policy gradient rewards. We prove that this procedure closely approximates the true, intractable gradient for the synthetic data generator. To illustrate the potential of DPG, we show that, using only SFT on generated examples, we can cause the target model's LM head weights to (1) embed a QR code, (2) embed the pattern \\(67\\), and (3) have lower \\(^2\\) norm. We additionally show that we can cause the generator to (4) rephrase inputs in a new language and (5) produce a specific UUID, even though neither of these objectives is conveyed in the generator's input prompts. These findings suggest that DPG is a powerful and flexible technique for shaping model properties using only synthetic training examples.

We challenge a common assumption underlying most supervised deep learning: that a model makes a prediction depending only on its parameters and the features of a single input. To this end, we introduce a general-purpose deep learning architecture that takes as input the entire dataset instead of processing one datapoint at a time. Our approach uses self-attention to reason about relationships between datapoints explicitly, which can be seen as realizing non-parametric models using parametric attention mechanisms. However, unlike conventional non-parametric models, we let the model learn end-to-end from the data how to make use of other datapoints for prediction. Empirically, our models solve cross-datapoint lookup and complex reasoning tasks unsolvable by traditional deep learning models. We show highly competitive results on tabular data, early results on CIFAR-10, and give insight into how the model makes use of the interactions between points.

Bayesian deep learning seeks to equip deep neural networks with the ability to precisely quantify their predictive uncertainty, and has promised to make deep learning more reliable for safety-critical real-world applications. Yet, existing Bayesian deep learning methods fall short of this promise; new methods continue to be evaluated on unrealistic test beds that do not reflect the complexities of downstream real-world tasks that would benefit most from reliable uncertainty quantification. We propose the RETINA Benchmark, a set of real-world tasks that accurately reflect such complexities and are designed to assess the reliability of predictive models in safety-critical scenarios. Specifically, we curate two publicly available datasets of high-resolution human retina images exhibiting varying degrees of diabetic retinopathy, a medical condition that can lead to blindness, and use them to design a suite of automated diagnosis tasks that require reliable predictive uncertainty quantification. We use these tasks to benchmark well-established and state-of-the-art Bayesian deep learning methods on task-specific evaluation metrics. We provide an easy-to-use codebase for fast and easy benchmarking following reproducibility and software design principles. We provide implementations of all methods included in the benchmark as well as results computed over 100 TPU days, 20 GPU days, 400 hyperparameter configurations, and evaluation on at least 6 random seeds each.

There has been significant research done on developing methods for improving robustness to distributional shift and uncertainty estimation. In contrast, only limited work has examined developing standard datasets and benchmarks for assessing these approaches. Additionally, most work on uncertainty estimation and robustness has developed new techniques based on small-scale regression or image classification tasks. However, many tasks of practical interest have different modalities, such as tabular data, audio, text, or sensor data, which offer significant challenges involving regression and discrete or continuous structured prediction. Thus, given the current state of the field, a standardized large-scale dataset of tasks across a range of modalities affected by distributional shifts is necessary. This will enable researchers to meaningfully evaluate the plethora of recently developed uncertainty quantification methods, as well as assessment criteria and state-of-the-art baselines. In this work, we propose the Shifts Dataset for evaluation of uncertainty estimates and robustness to distributional shift. The dataset, which has been collected from industrial sources and services, is composed of three tasks, with each corresponding to a particular data modality: tabular weather prediction, machine translation, and self-driving car (SDC) vehicle motion prediction. All of these data modalities and tasks are affected by real, \"in-the-wild\" distributional shifts and pose interesting challenges with respect to uncertainty estimation. In this work we provide a description of the dataset and baseline results for all tasks.