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Yeh, R.

Publications and source records attributed to Yeh, R..

4 recordsLinked to original sources

3D markerless tracking of speech movements with submillimeter accuracy

Speech movements are highly complex and require precise tuning of both spatial and timing of oral articulators to support intelligible communication. These properties also make measurement of speech movements challenging, often requiring extensive physical sensors placed around the mouth and face that are not easily tolerated by certain populations such as young children. Recent progress in machine learning-based markerless facial landmark tracking technology demonstrated its potential to provide lip tracking without the need for physical sensors, but whether such technology can provide submillimeter precision and accuracy in 3D remains unknown. Moreover, it is also unclear whether such technology can be applied to track speech movements in young children. Here, we developed a novel approach that integrates Shape Preserving Facial Landmarks with Graph Attention Networks (SPIGA), a facial landmark detector, and CoTracker, a transformer-based neural network model that jointly tracks dense points across a video sequence. We further examined and validated this novel approach by assessing its tracking precision and accuracy. The findings revealed that our approach that integrates SPIGA and CoTracker was more precise ({approx} 0.15 mm in standard deviation) than SPIGA alone ({approx} 0.35 mm). In addition, its 3D tracking performance was comparable to electromagnetic articulography ({approx} 0.29 mm RMSE against simultaneously recorded articulograph data). Importantly, the approach performed similarly well across adults and young children (i.e., 3- and 4-year-olds). Because our framework is built upon open-source pretrained models that are fully trained, it promotes accessibility and open science while saving computing resources. Furthermore, given that this framework combines a landmark detection model (SPIGA) with a tracker model (CoTracker) to improve precision/accuracy, our novel approach serves as a proof-of-concept for enhancing the performance of a wide variety of commonly used markerless tracking applications in biology and neuroscience. Author summaryIn this work, we examined whether machine learning based markerless tracking is feasible for tracking 3D lip movements in adults and young children. We developed a novel approach that integrates a landmark detection model (SPIGA) with a tracker model (CoTracker). Our combined CoTracker-based approach demonstrated submillimeter precision and accuracy desired for speech kinematic recording. In addition, our approach does not involve training and validation for each population (e.g., young children vs. adults), saving time and computing resources. We foresee that the proposed general framework of fusing a landmark detection model with a tracker model can be generalized for a wide variety of tracking applications in biology and neuroscience that require high precision and accuracy, including studying cell behaviors, animal motions, and other types of human movements.

neuroscience↗

Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.

neuroscience↗

Designed Endocytosis-Triggering Proteins mediate Targeted Degradation and amplify signaling

Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by interaction with endogenous ligands. Therapeutic approaches such as LYTAC1,2 and KineTAC3, have taken advantage of this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. While powerful, these approaches can be limited by possible competition with the endogenous ligand(s), the requirement in some cases for chemical modification that limits genetic encodability and can complicate manufacturing, and more generally, there may not be natural ligands which stimulate endocytosis through a given receptor. Here we describe general protein design approaches for designing endocytosis triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for the IGF-2R, ASGPR, Sortillin, and Transferrin receptors, and show that fusing these tags to proteins which bind to soluble or transmembrane protein leads to lysosomal trafficking and target degradation; as these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. The modularity and genetic encodability of EndoTags enables AND gate control for higher specificity targeted degradation, and the localized secretion of degraders from engineered cells. The tunability and modularity of our genetically encodable EndoTags should contribute to deciphering the relationship between receptor engagement and cellular trafficking, and they have considerable therapeutic potential as targeted degradation inducers, signaling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody drug and RNA conjugates.

synthetic biology↗

FLASH and Conventional Radiation Induce Differential Immune Responses in Diffuse Intrinsic Pontine Glioma, Highlighting Potential for Combination Immunotherapy

PurposeDiffuse Midline Glioma (DMG) is a fatal tumor traditionally treated with radiotherapy (RT) and previously characterized as having a non-inflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose rate, which is associated with decreased toxicity and effective tumor control. However, the effect of FLASH and conventional (CONV) RT on the DMG TIME have not yet been explored. MethodsHere, we perform single-cell RNA sequencing and flow cytometry on immune cells isolated from an orthotopic syngeneic murine model of brainstem DMG following the use of FLASH (90Gy/sec) or CONV (2Gy/min) dose-rate RT, and compare to unirradiated tumor (SHAM). ResultsAt day 4 post-RT, FLASH exerts similar effects as CONV in the predominant microglial (MG) population, including the presence of two activated subtypes. However, at day 10 post-RT, we observe a significant increase in type 1 interferon alpha receptor (IFNAR+) in MG in CONV and SHAM compared to FLASH. In the non-resident myeloid clusters of macrophages (MACs) and dendritic cells (DCs), we find increased type 1 interferon (IFN1) pathway enrichment for CONV compared to FLASH and SHAM by scRNA-seq. We observe this trend by flow cytometry at day 4 post-RT in IFNAR+ MACs and DCs, which equalizes by day 10 post-RT. DMG control and murine survival are equivalent between RT dose rates. ConclusionOur work is the first to map CONV and FLASH immune alterations of the DMG TIME with single-cell resolution. While DMG tumor control and survival are similar between CONV and FLASH, we find that changes in immune compartments differ over time. Importantly, while both RT modalities increase IFN1, we find that the timing of this response is cell-type and dose-rate dependent. These temporal differences, particularly in the context of tumor control, warrant further study.

immunology↗