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Creators/Authors contains: "Frangieh, Chris J."

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  1. ; ; ; ; ; ; ; ; ; ; et al ( , Nature Biotechnology)
    Abstract

    Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited in scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq by incorporating algorithms applied to random, low-dimensional observations. Compressed Perturb-seq measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq with an order of magnitude cost reduction and greater power to learn genetic interactions. We identified known and novel regulators of immune responses and uncovered evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing genome-wide association studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.

     
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  2. ; ; ; ; ; ; ; ; ( , Nature Biomedical Engineering)
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  3. ; ; ; ( , Magnetic Resonance in Medicine)
    Purpose

    Undiagnosed dehydration compromises health outcomes across many populations. Existing dehydration diagnostics require invasive bodily fluid sampling or are easily confounded by fluid and electrolyte intake, environment, and physical activity limiting widespread adoption. We present a portable MR sensor designed to measure intramuscular fluid shifts to identify volume depletion.

     Methods

    Fluid loss is induced via a mouse model of thermal dehydration (37°C; 15‐20% relative humidity). We demonstrate quantification of fluid loss induced by hyperosmotic dehydration with multicomponent T2 relaxometry using both a benchtop NMR system and MRI localized to skeletal muscle tissue. We then describe a miniaturized (~1000 cm3) portable (~4 kg) MR sensor (0.28 T) designed to identify dehydration‐induced fluid loss. T2 relaxometry measurements were performed using a Carr‐Purcell‐Meiboom‐Gill pulse sequence in ~4 min.

     Results

    T2 values from the portable MR sensor exhibited strong (R2= 0.996) agreement with benchtop NMR spectrometer. Thermal dehydration induced weight loss of 4 to 11% over 5 to 10 h. Fluid loss induced by thermal dehydration was accurately identified via whole‐animal NMR and skeletal muscle. The portable MR sensor accurately identified dehydration via multicomponent T2 relaxometry.

     Conclusion

    Performing multicomponent T2 relaxometry localized to the skeletal muscle with a miniaturized MR sensor provides a noninvasive, physiologically relevant measure of dehydration induced fluid loss in a mouse model. This approach offers sensor portability, reduced system complexity, fully automated operation, and low cost compared with MRI. This approach may serve as a versatile and portable point of care technique for dehydration monitoring.

     
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