Targeting TYK2 to target 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.
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.
Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer’s disease model mice
The Aβ42/Aβ40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer’s disease (AD)1, but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral Aβ, including Aβ42/Aβ40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ42/Aβ40 ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ42/Aβ40 ratios and high CSF NfL and t-tau concentrations when compared to Aβ42/Aβ40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the Aβ42/Aβ40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In AppNL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF Aβ42/Aβ40 ratio. Together, the results suggest that the Aβ42/Aβ40 ratio in CSF might better reflect brain levels of soluble Aβ protofibrils than insoluble Aβ fibrils in plaques in AD. Furthermore, elevated concentrations of NfL and t-tau in CSF might be triggered by increased brain levels of soluble Aβ protofibrils.
DeltaC and DeltaD ligands play different roles in the segmentation clock dynamics
The vertebrate segmentation clock drives periodic somite segmentation during embryonic development. Her1 and Her7 clock proteins generate oscillatory expression of their own genes as well as that of deltaC in zebrafish. In turn, DeltaC and DeltaD ligands activate Notch signaling, which then activates transcription of clock genes in neighboring cells. While DeltaC and DeltaD proteins form homo- and heterodimers, only DeltaC-containing oscillatory dimers were expected to be functional. To investigate the contributions of DeltaC and DeltaD proteins on the transcription of her1 and her7 segmentation clock genes, we counted their transcripts by performing single molecule fluorescent in situ hybridization imaging in different genetic backgrounds of zebrafish embryos. Surprisingly, we found that DeltaD homodimers are also functional. We further found that Notch signaling promotes transcription of both deltaC and deltaD genes, thereby creating a previously unnoticed positive feedback loop. Our computational model highlighted the intriguing differential roles of DeltaC and DeltaD dimers on the clock synchronization and transcript numbers, respectively. We anticipate that a mechanistic understanding of the Notch signaling pathway will not only shed light on the mechanism driving robust somite segmentation but also inspire similar quantitative studies in other tissues and organs.
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