130 research outputs found

    Scalable production of iPSC-derived human neurons to identify tau-lowering compounds by high-content screening

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    Lowering total tau levels is an attractive therapeutic strategy for Alzheimer's disease and other tauopathies. High-throughput screening in neurons derived from human induced pluripotent stem cells (iPSCs) is a powerful tool to identify tau-targeted therapeutics. However, such screens have been hampered by heterogeneous neuronal production, high cost and low yield, and multi-step differentiation procedures. We engineered an isogenic iPSC line that harbors an inducible neurogenin 2 transgene, a transcription factor that rapidly converts iPSCs to neurons, integrated at the AAVS1 locus. Using a simplified two-step protocol, we differentiated these iPSCs into cortical glutamatergic neurons with minimal well-to-well variability. We developed a robust high-content screening assay to identify tau-lowering compounds in LOPAC and identified adrenergic receptors agonists as a class of compounds that reduce endogenous human tau. These techniques enable the use of human neurons for high-throughput screening of drugs to treat neurodegenerative disease

    Report on the Challenges of Air Transportation Experienced by People with Disabilities

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    Boarding an airplane is difficult for persons with mobility impairments and increases the risk of injury to both passengers and employees. Airplane seats are uncomfortable and lack the necessary support for many individuals with disabilities. Additionally, airplane restrooms can be inaccessible to wheelchair users. Potential solutions for these issues include the use of detachable plane seats or personal wheelchairs on board and an airplane redesign to provide additional restroom space. The number of service and emotional support animals being brought on airplanes have also increased substantially over the past few years. Passengers that travel with their service animals must contend with having to follow different rules for different airlines carriers and not having sufficient space for animals to be safe and comfortable

    Mechanisms of Cisplatin Nephrotoxicity

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    Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention

    Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

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    Marja-Liisa Lokki työryhmien Generation Scotland Consortium, LifeLines Cohort Study ja GIANT Consortium jäsenPeer reviewe

    Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

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    Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

    Optimizing a deep learning model for the prediction of electric field induced by transcranial magnetic stimulation for mild to moderate traumatic brain injury patients

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    Transcranial magnetic stimulation (TMS) is a non-invasive method for treating neurological and psychiatric disorders. It is being tested as an experimental treatment for patients with mild to moderate traumatic brain injuries (mTBI). Due to the complex, heterogeneous composition of the brain, it is difficult to determine if targeted brain regions receive the correct amount of electric field (E-field) induced by the TMS coil. E-field distributions can be calculated by running time-consuming finite element analysis (FEA) simulations of TMS on patient head models. Using machine learning, the E-field can be predicted in real-time. Our prior work used a Deep Convolutional Neural Network (DCNN) to predict the E-field in healthy patients. This study applies the same DCNN to mTBI patients and investigates how model depth and color space of E-field images affect model performance. Nine DCNNs were created using combinations of 3, 4, or 5 encoder and decoder blocks with the color spaces RGB, LAB, and YCbCr. As depth increased, training and testing peak signal-to-noise ratios (PSNR) increased and mean squared errors (MSE) decreased. The depth 5 YCbCr model had the highest training and testing PSNRs of 34.77 and 29.08 dB and lowest training and testing MSEs of 3.335∗10−4 and 1.237∗10−3 respectively. Compared to the model in our prior work, models of depth 5 have higher testing PSNRs and lower MSEs and, except for RGB. Thus, DCNNs with depth 5 and alternative color spaces, despite losing information through color space conversions, resulted in higher PSNRs and lower MSEs
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