OBJECTIVE Personalization of hemodynamic modeling plays a crucial role in functional prediction of the cardiovascular system (CVS). While reduced-order models of one-dimensional (1D) blood vessel models with zero-dimensional (0D) blood vessel and heart models have been widely recognized to be an effective tool for reasonably estimating the hemodynamic functions of the whole CVS, practical personalized models are still lacking. In this paper, we present a novel 0-1D coupled, personalized hemodynamic model of the CVS that can predict both pressure waveforms and flow velocities in arteries. METHODS We proposed a methodology by combining the multiscale CVS model with the Levenberg-Marquardt optimization algorithm for effectively solving an inverse problem based on measured blood pressure waveforms. Hemodynamic characteristics including brachial arterial pressure waveforms, artery diameters, stroke volumes, and flow velocities were measured noninvasively for 62 volunteers aged from 20 to 70 years for developing and validating the model. RESULTS The estimated arterial stiffness shows a physiologically realistic distribution. The model-fitted individual pressure waves have an averaged mean square error (MSE) of 7.1 mmHg 2; simulated blood flow velocity waveforms in carotid artery match ultrasound measurements well, achieving an average correlation coefficient of 0.911. CONCLUSION The model is efficient, versatile, and capable of obtaining well-fitting individualized pressure waveforms while reasonably predicting flow waveforms. SIGNIFICANCE The proposed methodology of personalized hemodynamic modeling may therefore facilitate individualized patient-specific assessment of both physiological and pathological functions of the CVS.Lateral posterior nucleus (LP) of thalamus, the rodent homologue of primate pulvinar, projects extensively to sensory cortices. However, its functional role in sensory cortical processing remains largely unclear. Here, bidirectional activity modulations of LP or its projection to the primary auditory cortex (A1) in awake mice reveal that LP improves auditory processing in A1 supragranular-layer neurons by sharpening their receptive fields and frequency tuning, as well as increasing the signal-to-noise ratio (SNR). This is achieved through a subtractive-suppression mechanism, mediated largely by LP-to-A1 axons preferentially innervating specific inhibitory neurons in layer 1 and superficial layers. LP is strongly activated by specific sensory signals relayed from the superior colliculus (SC), contributing to the maintenance and enhancement of A1 processing in the presence of auditory background noise and threatening visual looming stimuli respectively. Thus, a multisensory bottom-up SC-pulvinar-A1 pathway plays a role in contextual and cross-modality modulation of auditory cortical processing. © 2020, Chou et al.Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTPσ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-synaptic adhesions of PTPσ, suggesting that the cytoplasmic domains of PTPσ, known to have tyrosine phosphatase activity and mediate protein-protein interactions, are important. In line with this, phosphotyrosine levels of presynaptic proteins, including neurexin-1, are strongly increased in PTPσ-mutant mice. Behaviorally, PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition. These results suggest that presynaptic PTPσ regulates postsynaptic NMDAR function through trans-synaptic and direct adhesion-independent mechanisms and novelty recognition in social and reward contexts. © 2020, Kim et al.Mitochondria generate ATP and building blocks for cell growth and regeneration, using pyruvate as the main substrate. Here we introduce PyronicSF, a user-friendly GFP-based sensor of improved dynamic range that enables real-time subcellular quantitation of mitochondrial pyruvate transport, concentration and flux. We report that cultured mouse astrocytes maintain mitochondrial pyruvate in the low micromolar range, below cytosolic pyruvate, which means that the mitochondrial pyruvate carrier MPC is poised to exert ultrasensitive control on the balance between respiration and anaplerosis/gluconeogenesis. The functionality of the sensor in living tissue is demonstrated in the brain of Drosophila melanogaster larvae. Mitochondrial subpopulations are known to coexist within a given cell, which differ in their morphology, mobility, membrane potential, and vicinity to other organelles. The present tool can be used to investigate how mitochondrial diversity relates to metabolism, to study the role of MPC in disease, and to screen for small-molecule MPC modulators. © 2020, Arce-Molina et al.An ideal tool for gene therapy would enable efficient gene integration at predetermined sites in the human genome. KN-62 inhibitor Here we demonstrate biased genome-wide integration of the Sleeping Beauty (SB) transposon by combining it with components of the CRISPR/Cas9 system. We provide proof-of-concept that it is possible to influence the target site selection of SB by fusing it to a catalytically inactive Cas9 (dCas9) and by providing a single guide RNA (sgRNA) against the human Alu retrotransposon. Enrichment of transposon integrations was dependent on the sgRNA, and occurred in an asymmetric pattern with a bias towards sites in a relatively narrow, 300 bp window downstream of the sgRNA targets. Our data indicate that the targeting mechanism specified by CRISPR/Cas9 forces integration into genomic regions that are otherwise poor targets for SB transposition. Future modifications of this technology may allow the development of methods for specific gene insertion for precision genetic engineering. © 2020, Kovač et al.