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Empirical investigation of the quintillion-scale, functionally diverse antibody repertoires that can be generated synthetically or naturally is critical for identifying potential biotherapeutic leads, yet remains burdensome. We present high-throughput nanophotonics- and bioprinter-enabled screening (HT-NaBS), a multiplexed assay for large-scale, sample-efficient, and rapid characterization of antibody libraries. Our platform is built upon independently addressable pixelated nanoantennas exhibiting wavelength-scale mode volumes, high-quality factors (high-Q) exceeding 5000, and pattern densities exceeding one million sensors per square centimeter. Our custom-built acoustic bioprinter enables individual sensor functionalization via the deposition of picoliter droplets from a library of capture antigens at rates up to 25,000 droplets per second. We detect subtle differentiation in the target binding signature through spatially-resolved spectral imaging of hundreds of resonators simultaneously, elucidating antigen-antibody binding kinetic rates, affinity constant, and specificity. We demonstrate HT-NaBS on a panel of antibodies targeting SARS-CoV-2, Influenza A, and Influenza B antigens, with a sub-picomolar limit of detection within 30 minutes. Furthermore, through epitope binning analysis, we demonstrate the competence and diversity of a library of native antibodies targeting functional epitopes on a priority pathogen (H5N1 bird flu) and on glycosylated therapeutic Cetuximab antibodies against epidermal growth factor receptor. With a roadmap to image tens of thousands of sensors simultaneously, this high-throughput, resource-efficient, and label-free platform can rapidly screen for high-affinity and broad epitope coverage, accelerating biotherapeutic discovery and de novo protein design.

User engagement, cognitive participation, and motivation during task execution in physical human-robot interaction are crucial for motor learning. These factors are especially important in contexts like robotic rehabilitation, where neuroplasticity is targeted. However, traditional robotic rehabilitation systems often face challenges in maintaining user engagement, leading to unpredictable therapeutic outcomes. To address this issue, various techniques, such as assist-as-needed controllers, have been developed to prevent user slacking and encourage active participation. In this paper, we introduce a new direction through a novel multi-modal robotic interaction designed to enhance user engagement by synergistically integrating visual, motor, cognitive, and auditory (speech recognition) tasks into a single, comprehensive activity. To assess engagement quantitatively, we compared multiple electroencephalography (EEG) biomarkers between this multi-modal protocol and a traditional motor-only protocol. Fifteen healthy adult participants completed 100 trials of each task type. Our findings revealed that EEG biomarkers, particularly relative alpha power, showed statistically significant improvements in engagement during the multi-modal task compared to the motor-only task. Moreover, while engagement decreased over time in the motor-only task, the multi-modal protocol maintained consistent engagement, suggesting that users could remain engaged for longer therapy sessions. Our observations on neural responses during interaction indicate that the proposed multi-modal approach can effectively enhance user engagement, which is critical for improving outcomes. This is the first time that objective neural response highlights the benefit of a comprehensive robotic intervention combining motor, cognitive, and auditory functions in healthy subjects.

Networks of excitatory and inhibitory (EI) neurons form a canonical circuit in the brain. Seminal theoretical results on dynamics of such networks are based on the assumption that synaptic strengths depend on the type of neurons they connect, but are otherwise statistically independent. Recent synaptic physiology datasets however highlight the prominence of specific connectivity patterns that go well beyond what is expected from independent connections. While decades of influential research have demonstrated the strong role of the basic EI cell type structure, to which extent additional connectivity features influence dynamics remains to be fully determined. Here we examine the effects of pair-wise connectivity motifs on the linear dynamics in excitatory-inhibitory networks using an analytical framework that approximates the connectivity in terms of low-rank structures. This low-rank approximation is based on a mathematical derivation of the dominant eigenvalues of the connectivity matrix, and predicts the impact on responses to external inputs of connectivity motifs and their interactions with cell-type structure. Our results reveal that a particular pattern of connectivity, chain motifs, have a much stronger impact on dominant eigenmodes than other pair-wise motifs. In particular, an over-representation of chain motifs induces a strong positive eigenvalue in inhibition-dominated networks and generates a potential instability that requires revisiting the classical excitation-inhibition balance criteria. Examining effects of external inputs, we show that chain motifs can on their own induce paradoxical responses, where an increased input to inhibitory neurons leads to a decrease in their activity due to the recurrent feedback. These findings have direct implications for the interpretation of experiments in which responses to optogenetic perturbations are measured and used to infer the dynamical regime of cortical circuits.

The seasonal human influenza virus undergoes rapid evolution, leading to significant changes in circulating viral strains from year to year. These changes are typically driven by adaptive mutations, particularly in the antigenic epitopes, the regions of the viral surface protein haemagglutinin targeted by human antibodies. Here we describe a consistent set of methods for data-driven predictive analysis of viral evolution. Our pipeline integrates four types of data: (1) sequence data of viral isolates collected on a worldwide scale, (2) epidemiological data on incidences, (3) antigenic characterization of circulating viruses, and (4) intrinsic viral phenotypes. From the combined analysis of these data, we obtain estimates of relative fitness for circulating strains and predictions of clade frequencies for periods of up to one year. Furthermore, we obtain comparative estimates of protection against future viral populations for candidate vaccine strains, providing a basis for pre-emptive vaccine strain selection. Continuously updated predictions obtained from the prediction pipeline for influenza and SARS-CoV-2 are available on the website previr.app.

Understanding biological functions requires identifying the physical limits and system-specific constraints that have shaped them. In Escherichia coli chemotaxis, gradient-climbing speed is information-limited, bounded by the sensory information they acquire from real-time measurements of their environment. However, it remains unclear what limits this information. Past work conjectured that E. coli's chemosensing is limited by the physics of molecule arrivals at their sensors. Here, we derive the physical limit on behaviorally-relevant information, and then perform single-cell experiments to quantify how much information E. coli's signaling pathway encodes. We find that E. coli encode two orders of magnitude less information than the physical limit due to their stochastic signal processing. Thus, system-specific constraints, rather than the physical limit, have shaped the evolution of this canonical sensory-motor behavior.

Background: Intensity-modulated proton therapy (IMPT) using pencil beam technique scans tumor in a layer by layer, then spot by spot manner. It can provide highly conformal dose to tumor targets and spare nearby organs-at-risk (OAR). Fast delivery of IMPT can improve patient comfort and reduce motion-induced uncertainties. Since energy layer switching time dominants the plan delivery time, reducing the number of energy layers is important for improving delivery efficiency. Although various energy layer optimization (ELO) methods exist, they are rarely experimentally validated or clinically implemented, since it is technically challenging to integrate these methods into commercially available treatment planning system (TPS) that is not open-source.

Purpose: This work develops and experimentally validates an in-house TPS (IH-TPS) that incorporates a novel ELO method for the purpose of fast IMPT.

Methods: The dose calculation accuracy of IH-TPS is verified against the measured beam data and the RayStation TPS. For treatment planning, a novel ELO method via greed selection algorithm is proposed to reduce energy layer switching time and total plan delivery time. To validate the planning accuracy of IH-TPS, the 3D gamma index is calculated between IH-TPS plans and RayStation plans for various scenarios. Patient-specific quality-assurance (QA) verifications are conducted to experimentally verify the delivered dose from the IH-TPS plans for several clinical cases.

Results: Dose distributions in IH-TPS matched with those from RayStation TPS, with 3D gamma index results exceeding 95% (2mm, 2%). The ELO method significantly reduced the delivery time while maintaining plan quality. For instance, in a brain case, the number of energy layers was reduced from 78 to 40, leading to a 62% reduction in total delivery time. Patient-specific QA validation with the IBA Proteus^®ONE proton machine confirmed a >95% pass rate for all cases.

Conclusions: An IH-TPS equipped with a novel ELO algorithm is developed and experimentally validated for the purpose of fast IMPT, with enhanced delivery efficiency and preserved plan quality.

Understanding the neurobiology of opioid use disorder (OUD) using resting-state functional magnetic resonance imaging (rs-fMRI) may help inform treatment strategies to improve patient outcomes. Recent literature suggests temporal characteristics of rs-fMRI blood oxygenation level-dependent (BOLD) signals may offer complementary information to functional connectivity analysis. However, existing studies of OUD analyze BOLD signals using measures computed across all time points. This study, for the first time in the literature, employs data-driven machine learning (ML) modeling of rs-fMRI BOLD features representing multiple time points to identify region(s) of interest that differentiate OUD subjects from healthy controls (HC). Following the triple network model, we obtain rs-fMRI BOLD features from the default mode network (DMN), salience network (SN), and executive control network (ECN) for 31 OUD and 45 HC subjects. Then, we use the Boruta ML algorithm to identify statistically significant BOLD features that differentiate OUD from HC, identifying the DMN as the most salient functional network for OUD. Furthermore, we conduct brain activity mapping, showing heightened neural activity within the DMN for OUD. We perform 5-fold cross-validation classification (OUD vs. HC) experiments to study the discriminative power of functional network features with and without fusing demographic features. The DMN shows the most discriminative power, achieving mean AUC and F1 scores of 80.91% and 73.97%, respectively, when fusing BOLD and demographic features. Follow-up Boruta analysis using BOLD features extracted from the medial prefrontal cortex, posterior cingulate cortex, and left and right temporoparietal junctions reveals significant features for all four functional hubs within the DMN.

Wearable accelerometry (actigraphy) has provided valuable data for clinical insights since the 1970s and is increasingly important as wearable devices continue to become widespread. The effectiveness of actigraphy in research and clinical contexts is heavily dependent on the modeling architecture utilized. To address this, we developed the Pretrained Actigraphy Transformer (PAT)-the first pretrained and fully attention-based model designed specifically to handle actigraphy. PAT was pretrained on actigraphy from 29,307 participants in NHANES, enabling it to deliver state-of-the-art performance when fine-tuned across various actigraphy prediction tasks in the mental health domain, even in data-limited scenarios. For example, when trained to predict benzodiazepine usage using actigraphy from only 500 labeled participants, PAT achieved an 8.8 percentage-point AUC improvement over the best baseline. With fewer than 2 million parameters and built-in model explainability, PAT is robust yet easy to deploy in health research settings. GitHub: https://github.com/njacobsonlab/Pretrained-Actigraphy-Transformer/.

Many structures in science, engineering, and art can be viewed as curves in 3-space. The entanglement of these curves plays a crucial role in determining the functionality and physical properties of materials. Many concepts in knot theory provide theoretical tools to explore the complexity and entanglement of curves in 3-space. However, classical knot theory primarily focuses on global topological properties and lacks the consideration of local structural information, which is critical in practical applications. In this work, two localized models based on the Jones polynomial, namely the multiscale Jones polynomial and the persistent Jones polynomial, are proposed. The stability of these models, especially the insensitivity of the multiscale and persistent Jones polynomial models to small perturbations in curve collections, is analyzed, thus ensuring their robustness for real-world applications.

A cornerstone of our understanding of both biological and artificial neural networks is that they store information in the strengths of connections among the constituent neurons. However, in contrast to the well-established theory for quantifying information encoded by the firing patterns of neural networks, little is known about quantifying information encoded by its synaptic connections. Here, we develop a theoretical framework using continuous Hopfield networks as an exemplar for associative neural networks, and data that follow mixtures of broadly applicable multivariate log-normal distributions. Specifically, we analytically derive the Shannon mutual information between the data and singletons, pairs, triplets, quadruplets, and arbitrary n-tuples of synaptic connections within the network. Our framework corroborates well-established insights about storage capacity of, and distributed coding by, neural firing patterns. Strikingly, it discovers synergistic interactions among synapses, revealing that the information encoded jointly by all the synapses exceeds the 'sum of its parts'. Taken together, this study introduces an interpretable framework for quantitatively understanding information storage in neural networks, one that illustrates the duality of synaptic connectivity and neural population activity in learning and memory.