The deposition of pathological tau is a common feature in several neurodegenerative tauopathies. Although equal ratios of tau isoforms with 3 (3R) and 4 (4R) microtubule-binding repeats are expressed ...in the adult human brain, the pathological tau from different tauopathies have distinct isoform compositions and cell type specificities. The underlying mechanisms of tauopathies are unknown, partially due to the lack of proper models. Here, we generate a new transgenic mouse line expressing equal ratios of 3R and 4R human tau isoforms (6hTau mice). Intracerebral injections of distinct human tauopathy brain-derived tau strains into 6hTau mice recapitulate the deposition of pathological tau with distinct tau isoform compositions and cell type specificities as in human tauopathies. Moreover, through in vivo propagation of these tau strains among different mouse lines, we demonstrate that the transmission of distinct tau strains is independent of strain isoform compositions, but instead intrinsic to unique pathological conformations.
Comorbidity is a common phenotype in Parkinson's disease (PD). Patients with PD not only have motor deficit symptoms, but also have heterogeneous non-motor symptoms, including cognitive impairment ...and emotional changes, which are the featured symptoms observed in patients with Alzheimer's disease (AD), frontotemporal dementia (FTD) and cerebrovascular disease. Moreover, autopsy studies have also confirmed the concomitant protein pathogenesis, such as the co-existences of α-synuclein, amyloid-β and tau pathologies in PD and AD patients' brains. Here, we briefly summarize the recent reports regarding the comorbidity issues in PD from both clinical observations and neuropathological evidences. Furthermore, we provide some discussion about the perspective potential mechanisms underlying such comorbidity phenomenon, with a focus on PD and related neurodegenerative diseases.
Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Cell culture and animal studies showed that tau fibrils can undergo ...cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the ongoing global pandemic that poses substantial challenges to public health ...worldwide. A subset of COVID-19 patients experience systemic inflammatory response, known as cytokine storm, which may lead to death. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important mediator of inflammation and cell death. Here, we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection. We found evidence of RIPK1 activation in human COVID-19 lung pathological samples, and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2. Inhibition of RIPK1 using multiple small-molecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids. Furthermore, therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load, and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice. Mechanistically, we found that the RNA-dependent RNA polymerase of SARS-CoV-2, NSP12, a highly conserved central component of coronaviral replication and transcription machinery, promoted the activation of RIPK1. Furthermore, NSP12 323L variant, encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy, Italy, that carries a Pro323Leu amino acid substitution in NSP12, showed increased ability to activate RIPK1. Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells. Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19.
Classical lossless compression algorithm highly relies on artificially designed encoding and quantification strategies for general purposes. With the rapid development of deep learning, data-driven ...methods based on the neural network can learn features and show better performance on specific data domains. We propose an efficient deep lossless compression algorithm, which uses arithmetic coding to quantify the network output. This scheme compares the training effects of Bi-directional Long Short-Term Memory (Bi-LSTM) and Transformers on minute-level power data that are not sparse in the time-frequency domain. The model can automatically extract features and adapt to the quantification of the probability distribution. The results of minute-level power data show that the average compression ratio (CR) is 4.06, which has a higher compression ratio than the classical entropy coding method.
Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in
...(valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly
mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly
is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.
Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer’s disease (AD). Several molecular chaperones have been reported to bind Tau and ...impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a
Drosophila
tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.
The canonical transient receptor potential channels (TRPCs) are Ca²⁺-permeable nonselective cation channels with various physiological functions. Here, we report that TRPC6, a member of the TRPC ...family, promotes hippocampal neuron dendritic growth. The peak expression of TRPC6 in rat hippocampus was between postnatal day 7 and 14, a period known to be important for maximal dendritic growth. Overexpression of TRPC6 increased phosphorylation of Ca²⁺/calmodulin-dependent kinase IV (CaMKIV) and cAMP-response-element binding protein (CREB) and promoted dendritic growth in hippocampal cultures. Downregulation of TRPC6 by short hairpin RNA interference against TRPC6 suppressed phosphorylation of both CaMKIV and CREB and impaired dendritic growth. Expressing a dominant-negative form of CaMKIV or CREB blocked the TRPC6-induced dendritic growth. Furthermore, inhibition of Ca²⁺ influx suppressed the TRPC6 effect on dendritic growth. Finally, in TRPC6 transgenic mice, the phosphorylation of CaMKIV and CREB was enhanced and the dendritic growth was also increased. In conclusion, TRPC6 promoted dendritic growth via the CaMKIV-CREB pathway. Our results thus revealed a novel role of TRPC6 during the development of the central nervous system (CNS).
The verification of copyright and authenticity for medical images is critical in telemedical applications. Watermarking is a key technique for protecting medical images and can be mainly divided into ...three categories: region of interest (ROI) lossless watermarking, reversible watermarking and zero-watermarking. However, ROI lossless watermarking causes biases on diagnosis. Reversible watermarking can hardly provide a continuous verification function and may face verification disputes after image recovering. Zero-watermarking requires third-party storage which may cause additional security problems. To address these issues, a hybrid reversible-zero watermarking (HRZW) is proposed in this paper to effectively combine the complementary advantages of reversible watermarking and zero-watermarking. In our scheme, a novel hybrid structure is designed including a zero-watermarking component and a reversible watermarking component. In the first component, ownership share is generated by mapping nearest neighbor grayscale residual (NNGR) based features and watermark information. In the second component, the generated ownership share is embedded reversibly based on Slantlet Transform, Singular Value Decomposition and Quantization Index Modulation (SLT-SVD-QIM). Experimental results demonstrate that our proposed scheme not only yields remarkable watermarking imperceptibility, distinguishability and robustness, but also provides continuous verification function without any dispute or third-party storage, which outperforms existing watermarking schemes for medical images.
PDF
