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The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca²⁺) uptake supports NVU function by buffering Ca²⁺and stimulating energy production. However, excessive mitochondrial Ca²⁺uptake causes toxic mitochondrial Ca²⁺overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca²⁺uptake and efflux in the brain are mediated by the mitochondrial Ca²⁺uniporter complex (MCU_cx) and sodium/Ca²⁺/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCU_cxinhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca²⁺overloading. These findings suggest that combining MCU_cxinhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCU_cxinhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCU_cx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

 

Laser spectroscopy of the^229mTh nuclear clock transition is necessary for the future construction of a nuclear-based optical clock. Precision laser sources with broad spectral coverage in the vacuum ultraviolet are needed for this task. Here, we present a tunable vacuum-ultraviolet frequency comb based on cavity-enhanced seventh-harmonic generation. Its tunable spectrum covers the current uncertainty range of the^229mTh nuclear clock transition.

 

Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To survive drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced by drying in vitro and in heterologous systems. CAHS proteins have been shown to form gels both in vitro and in vivo, which has been speculated to be linked to their protective capacity. However, the sequence features and mechanisms underlying gel formation and the necessity of gelation for protection have not been demonstrated. Here we report a mechanism of fibrillization and gelation for CAHS D similar to that of intermediate filament assembly. We show that in vitro, gelation restricts molecular motion, immobilizing and protecting labile material from the harmful effects of drying. In vivo, we observe that CAHS D forms fibrillar networks during osmotic stress. Fibrillar networking of CAHS D improves survival of osmotically shocked cells. We observe two emergent properties associated with fibrillization; (i) prevention of cell volume change and (ii) reduction of metabolic activity during osmotic shock. We find that there is no significant correlation between maintenance of cell volume and survival, while there is a significant correlation between reduced metabolism and survival. Importantly, CAHS D's fibrillar network formation is reversible and metabolic rates return to control levels after CAHS fibers are resolved. This work provides insights into how tardigrades induce reversible biostasis through the self‐assembly of labile CAHS gels.

 

Although significant improvements have been made to the prediction and understanding of extreme precipitation events in recent decades, there is still much to learn about these impactful events on the subseasonal time scale. This study focuses on identifying synoptic patterns and precursors ahead of an extreme precipitation event over the contiguous United States (CONUS). First, we provide a robust definition for 14-day “extreme precipitation events” and partition the CONUS into six different geographic regions to compare and contrast the synoptic patterns associated with events in those regions. Then, several atmospheric variables from ERA-Interim (e.g., geopotential height and zonal winds) are composited to understand the evolution of the atmospheric state before and during a 14-day extreme precipitation event. Common synoptic signals seen during events include significant zonally oriented trough–ridge patterns, an energized subtropical jet stream, and enhanced moisture transport into the affected area. Also, atmospheric-river activity increases in the specific region during these events. Modes of climate variability and lagged composites are then investigated for their potential use in lead-time prediction. Key findings include synoptic-scale anomalies in the North Pacific Ocean and regional connections to modes such as the Pacific–North American pattern and the North Pacific Oscillation. Taken together, our results represent a significant step forward in understanding the evolution of 14-day extreme precipitation events for potential damage and casualty mitigation.