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Summary The human neocortex exhibits characteristic regional patterning (arealization) critical for higher-order cognitive function. Disrupted arealization is strongly implicated in neurodevelopmental disorders (NDDs), but current neocortical organoid models largely fail to recapitulate this patterning, limiting mechanistic understanding. Here, we establish a straightforward method for generating arealized organoids through short-term early exposure to anterior (FGF8) or posterior (BMP4/CHIR-99021) morphogens. These treatments created distinct anterior and posterior signaling centers, supporting long-lasting polarization, which we validated with single-cell RNA sequencing that revealed area-specific molecular signatures matching prenatal human cortex. To demonstrate the utility of this platform, we modeled Fragile X Syndrome (FXS) in organoids with distinct anterior and posterior regional identities. FXS organoids showed highly disrupted SOX4/SOX11 expression gradients along the anterior-posterior axis, consistent with alterations found in autism spectrum disorder (ASD) and demonstrate how regional patterning defects may contribute to NDD pathology. Together, our study provides a robust platform for generating neocortical organoids with anterior-posterior molecular signatures and highlights the importance of modeling NDDs using experimental platforms with neuroanatomic specificity. 

Abstract From single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST), one can extract high-dimensional gene expression patterns that can be described by intercellular communication networks or decoupled gene modules. These two descriptions of information flow are often assumed to occur independently. However, intercellular communication drives directed flows of information that are mediated by intracellular gene modules, in turn triggering outflows of other signals. Methodologies to describe such intercellular flows are lacking. We present FlowSig, a method that infers communication-driven intercellular flows from scRNA-seq or ST data using graphical causal modeling and conditional independence. We benchmark FlowSig using newly generated experimental cortical organoid data and synthetic data generated from mathematical modeling. We demonstrate FlowSig’s utility by applying it to various studies, showing that FlowSig can capture stimulation-induced changes to paracrine signaling in pancreatic islets, demonstrate shifts in intercellular flows due to increasing COVID-19 severity and reconstruct morphogen-driven activator–inhibitor patterns in mouse embryogenesis. 

This work studies compilation of honest-majority semi-honest secure multi-party protocols secure up to additive attacks to maliciously secure computation with abort. Prior work concentrated on arithmetic circuits composed of addition and multiplication gates, while many practical protocols rely on additional types of elementary operations or gates to achieve good performance. In this work we revisit the notion of security up to additive attacks in the presence of additional gates such as random element generation and opening. This requires re-evaluation of functions that can be securely evaluated, extending the notion of protocols secure up to additive attacks, and re-visiting the notion of delayed verification that points to weaknesses in its prior use and designing a mitigation strategy. We transform the computation using dual execution to achieve security in the malicious model with abort and experimentally evaluate the difference in performance of semi-honest and malicious protocols to demonstrate the low cost. 

Motivated by the importance of floating-point computations, we study the problem of securely and accurately summing many floating-point numbers. Prior work has focused on security absent accuracy or accuracy absent security, whereas our approach achieves both of them. Specifically, we show how to implement floating-point superaccumulators using secure multi-party computation techniques, so that a number of participants holding secret shares of floating-point numbers can accurately compute their sum while keeping the individual values private. 

Secure multi-party computation has seen significant performance advances and increasing use in recent years. Techniques based on secret sharing offer attractive performance and are a popular choice for privacy-preserving machine learning applications. Traditional techniques operate over a field, while designing equivalent techniques for a ring Z_2^k can boost performance. In this work, we develop a suite of multi-party protocols for a ring in the honest majority setting starting from elementary operations to more complex with the goal of supporting general-purpose computation. We demonstrate that our techniques are substantially faster than their field-based equivalents when instantiated with a different number of parties and perform on par with or better than state-of-the-art techniques with designs customized for a fixed number of parties. We evaluate our techniques on machine learning applications and show that they offer attractive performance. 

Multilayered microfluidic chips were designed to generate morphogen gradients and topographically organized multi-region forebrain organoids.