Quantitative chemoproteomics reveals dopamine’s protective modification of Tau
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Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss
Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.
Dopamine in the tail of the striatum facilitates avoidance in threat–reward conflicts
Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.
The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors
Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains debated, as does its potential for misuse. A key component at the intersection of mood and reward processing is the dopaminergic system. In this study, we evaluated the effects of esketamine in locomotion, anxiety tests and operant responding and we used in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multifaceted effects of esketamine on neurotransmitter dynamics. In freely behaving mice, esketamine increased locomotion and increased extracellular dopamine tone -by impairing dopamine clearance rather than promoting dopamine release- while decreasing glutamatergic activity. However, it decreased dopamine spontaneous release event frequency and impaired reward-evoked dopamine release, leading to a reduction in operant responding rates. These dopaminergic effects were partially, and conditionally, blocked by the opioid antagonist naloxone and required glutamatergic input. In summary, our study reveals a complex interaction between neurotransmitter systems, suggesting that the neurochemical effects of esketamine are both circuit- and state-dependent.
Alzheimer’s disease biological PET staging using plasma p217+tau
Plasma phospho-tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s disease (AD) neuropathology. However, their ability to substitute for tau PET to identify AD biological stage is unclear.
A multipath error cancellation method based on antenna jitter
Global Navigation Satellite System signals are often affected by multipath errors, which impact the accuracy of positioning measurements. Traditional methods frequently fail to effectively mitigate multipath errors across different environments, primarily due to their inherent sensitivity to varying conditions. Here, we propose a multipath error cancellation method that utilizes antenna jitter, which mitigates multipath errors by rapidly changing the relative phases of direct and multipath signals without requiring changes to the receiver structure. The model that combines theoretical analysis with experimental verification is conducted to identify the minimum jitter amplitude required for effective error reduction in straight-line jitter scenarios. Moreover, extensive satellite data collection and verification were performed in Changsha, China, from December 2023 to August 2024. The results indicate that the proposed method enhances robustness and applicability across various environments compared to traditional approaches. Notably, it enables a vehicle-mounted antenna, priced at just a few dollars, to achieve positioning accuracy comparable to that of high-precision antennas costing thousands of dollars, making advanced positioning technology more accessible.
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