NeuroPAL: A Multicolor Atlas for Whole-Brain Neuronal Identification in C. elegans.

Comprehensively resolving neuronal identities in whole-brain images is a major challenge. We achieve this in C. elegans by engineering a multicolor transgene called NeuroPAL (a neuronal polychromatic atlas of landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that resolves all neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. We showcase three applications that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding for these stimuli.

Electrical stimulus artifact cancellation and neural spike detection on large multi-electrode arrays.

Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is greatly complicated by electrical stimulation artifacts across the array, which can exhibit complex and nonlinear waveforms, and overlap temporarily with evoked spikes. Here we develop a scalable algorithm based on a structured Gaussian Process model to estimate the artifact and identify evoked spikes. The effectiveness of our methods is demonstrated in both real and simulated 512-electrode recordings in the peripheral primate retina with single-electrode and several types of multi-electrode stimulation. We establish small error rates in the identification of evoked spikes, with a computational complexity that is compatible with real-time data analysis. This technology may be helpful in the design of future high-resolution sensory prostheses based on tailored stimulation (e.g., retinal prostheses), and for closed-loop neural stimulation at a much larger scale than currently possible.

B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics.

Throughout an organism's life, a multitude of complex and interdependent biological systems transition through biophysical processes that serve as indicators of the underlying biological states. Inferring these latent, unobserved states is a goal of modern biology and neuroscience. However, in many experimental setups, we can at best obtain discrete snapshots of the system at different times and for different individuals. This challenge is particularly relevant in the study of Alzheimer's Disease (AD) progression, where we observe the aggregation of pathology in brain donors, but the underlying disease state is unknown. This paper proposes a biophysically motivated Bayesian framework (B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics), where the disease state is modeled and continuously inferred from observed quantifications of multiple AD pathological proteins. Inspired by biophysical models, we describe pathological burden as an exponential process. The progression of AD is modeled by assigning a latent score, termed pseudotime, to each pathological state, creating a pseudotemporal order of donors based on their pathological burden. We study the theoretical properties of the model using linearization to reveal convergence and identifiability properties. We provide Markov chain Monte Carlo estimation algorithms, illustrating the effectiveness of our approach with multiple simulation studies across various data conditions. Applying this methodology to data from the Seattle Alzheimer's Disease Brain Cell Atlas, we infer the pseudotime ordering of donors. Finally, we analyze the information within each pathological feature to refine the model, focusing on the most informative pathologies. This framework lays the groundwork for continuous pseudotime modeling in the analysis of neurodegenerative diseases.

Quantifying the impact of SARS-CoV-2 temporal vaccination trends and disparities on disease control.

SARS-CoV-2 vaccines have been distributed at unprecedented speed. Still, little is known about temporal vaccination trends, their association with socioeconomic inequality, and their consequences for disease control. Using data from 161 countries/territories and 58 states, we examined vaccination rates across high and low socioeconomic status (SES), showing that disparities in coverage exist at national and subnational levels. We also identified two distinct vaccination trends: a rapid initial rollout, quickly reaching a plateau, or sigmoidal and slow to begin. Informed by these patterns, we implemented an SES-stratified mechanistic model, finding profound differences in mortality and incidence across these two vaccination types. Timing of initial rollout affects disease outcomes more substantially than final coverage or degree of SES disparity. Unexpectedly, timing is not associated with wealth inequality or GDP per capita. While socioeconomic disparity should be addressed, accelerating initial rollout for all over focusing on increasing coverage is an accessible intervention that could minimize the burden of disease across socioeconomic groups.

Socioeconomic status determines COVID-19 incidence and related mortality in Santiago, Chile.

The COVID-19 pandemic has affected cities particularly hard. Here, we provide an in-depth characterization of disease incidence and mortality and their dependence on demographic and socioeconomic strata in Santiago, a highly segregated city and the capital of Chile. Our analyses show a strong association between socioeconomic status and both COVID-19 outcomes and public health capacity. People living in municipalities with low socioeconomic status did not reduce their mobility during lockdowns as much as those in more affluent municipalities. Testing volumes may have been insufficient early in the pandemic in those places, and both test positivity rates and testing delays were much higher. We find a strong association between socioeconomic status and mortality, measured by either COVID-19-attributed deaths or excess deaths. Finally, we show that infection fatality rates in young people are higher in low-income municipalities. Together, these results highlight the critical consequences of socioeconomic inequalities on health outcomes.