Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3ß pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.

Columbianadin attenuates doxorubicin-induced cardiac injury, oxidative stress, and apoptosis via Sirt1/FOXO1 signaling pathway.

PURPOSE: Oxidative stress and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Herein, we intended to explore the potential role and molecular basis of CBN in DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were subjected to DOX (15 mg/kg/day, i.p.) to generate DOX-induced cardiotoxicity. CBN (10 mg/kg/day, i.p.) was administered for four week following DOX injection. RESULTS: DOX administered markedly dampened cardiac function, increased cardiac injury, excessive reactive oxygen species (ROS) production, and cardiomyocyte loss. These alterations induced by DOX significantly alleviated by CBN treatment. Mechanistically, our results demonstrated that the CBN exerts cardioprotection role against DOX by up-regulating silent information regulator 1 (Sirt1) and decreasing acetylation of forkhead box O1 (FOXO1). Moreover, Sirt1 inhibition with Ex-527 significantly blunt the beneficial effect of CBN on DOX-induced cardiotoxicity, including cardiac dysfunction, ROS, and apoptosis. CONCLUSION: Collectively, CBN attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity through maintaining Sirt1/FOXO1 signaling pathway. Our results demonstrated that CBN might be used to treat DOX-related cardiotoxicity.

MPS-NeRF: Generalizable 3D Human Rendering From Multiview Images.

There has been rapid progress recently on 3D human rendering, including novel view synthesis and pose animation, based on the advances of neural radiance fields (NeRF). However, most existing methods focus on person-specific training and their training typically requires multi-view videos. This paper deals with a new challenging task - rendering novel views and novel poses for a person unseen in training, using only multiview still images as input without videos. For this task, we propose a simple yet surprisingly effective method to train a generalizable NeRF with multiview images as conditional input. The key ingredient is a dedicated representation combining a canonical NeRF and a volume deformation scheme. Using a canonical space enables our method to learn shared properties of human and easily generalize to different people. Volume deformation is used to connect the canonical space with input and target images and query image features for radiance and density prediction. We leverage the parametric 3D human model fitted on the input images to derive the deformation, which works quite well in practice when combined with our canonical NeRF. The experiments on both real and synthetic data with the novel view synthesis and pose animation tasks collectively demonstrate the efficacy of our method.

VirtualCube: An Immersive 3D Video Communication System.

The VirtualCube system is a 3D video conference system that attempts to overcome some limitations of conventional technologies. The key ingredient is VirtualCube, an abstract representation of a real-world cubicle instrumented with RGBD cameras for capturing the user's 3D geometry and texture. We design VirtualCube so that the task of data capturing is standardized and significantly simplified, and everything can be built using off-the-shelf hardware. We use VirtualCubes as the basic building blocks of a virtual conferencing environment, and we provide each VirtualCube user with a surrounding display showing life-size videos of remote participants. To achieve real-time rendering of remote participants, we develop the V-Cube View algorithm, which uses multi-view stereo for more accurate depth estimation and Lumi-Net rendering for better rendering quality. The VirtualCube system correctly preserves the mutual eye gaze between participants, allowing them to establish eye contact and be aware of who is visually paying attention to them. The system also allows a participant to have side discussions with remote participants as if they were in the same room. Finally, the system sheds lights on how to support the shared space of work items (e.g., documents and applications) and track participants' visual attention to work items.

Physics-Based Noise Modeling for Extreme Low-Light Photography.

Enhancing the visibility in extreme low-light environments is a challenging task. Under nearly lightless condition, existing image denoising methods could easily break down due to significantly low SNR. In this paper, we systematically study the noise statistics in the imaging pipeline of CMOS photosensors, and formulate a comprehensive noise model that can accurately characterize the real noise structures. Our novel model considers the noise sources caused by digital camera electronics which are largely overlooked by existing methods yet have significant influence on raw measurement in the dark. It provides a way to decouple the intricate noise structure into different statistical distributions with physical interpretations. Moreover, our noise model can be used to synthesize realistic training data for learning-based low-light denoising algorithms. In this regard, although promising results have been shown recently with deep convolutional neural networks, the success heavily depends on abundant noisy-clean image pairs for training, which are tremendously difficult to obtain in practice. Generalizing their trained models to images from new devices is also problematic. Extensive experiments on multiple low-light denoising datasets - including a newly collected one in this work covering various devices - show that a deep neural network trained with our proposed noise formation model can reach surprisingly-high accuracy. The results are on par with or sometimes even outperform training with paired real data, opening a new door to real-world extreme low-light photography.

Face Restoration via Plug-and-Play 3D Facial Priors.

State-of-the-art face restoration methods employ deep convolutional neural networks (CNNs) to learn a mapping between degraded and sharp facial patterns by exploring local appearance knowledge. However, most of these methods do not well exploit facial structures and identity information, and only deal with task-specific face restoration (e.g., face super-resolution or deblurring). In this paper, we propose cross-tasks and cross-models plug-and-play 3D facial priors to explicitly embed the network with the sharp facial structures for general face restoration tasks. Our 3D priors are the first to explore 3D morphable knowledge based on the fusion of parametric descriptions of face attributes (e.g., identity, facial expression, texture, illumination, and face pose). Furthermore, the priors can easily be incorporated into any network and are very efficient in improving the performance and accelerating the convergence speed. Firstly, a 3D face rendering branch is set up to obtain 3D priors of salient facial structures and identity knowledge. Secondly, for better exploiting this hierarchical information (i.e., intensity similarity, 3D facial structure, and identity content), a spatial attention module is designed for the image restoration problems. Extensive face restoration experiments including face super-resolution and deblurring demonstrate that the proposed 3D priors achieve superior face restoration results over the state-of-the-art algorithms.

A γ-adducin cleavage fragment induces neurite deficits and synaptic dysfunction in Alzheimer's disease.

Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD.

Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression: ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD.

TREM2 ectodomain and its soluble form in Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor mainly expressed on the surface of microglia. It mediates multiple pathophysiological processes in various diseases. Recently, TREM2 has been found to play a role in the development of Alzheimer's disease (AD). TREM2 is a transmembrane protein that is specifically expressed on microglia in the brain. It contains a long ectodomain that directly interacts with the extracellular environment to regulate microglial function. The ectodomain of TREM2 is processed by a disintegrin and metalloprotease, resulting in the release of a soluble form of TREM2 (sTREM2). Recent studies have demonstrated that sTREM2 is a bioactive molecule capable of binding ligands, activating microglia, and regulating immune responses during the AD continuum. Clinical studies revealed that sTREM2 level is elevated in cerebrospinal fluid (CSF) of AD patients, and the sTREM2 level is positively correlated with the levels of classical CSF biomarkers, namely t-tau and p-tau, indicating that it is a reliable predictor of the early stages of AD. Herein, we summarize the key results on the generation, structure, and function of sTREM2 to provide new insights into TREM2-related mechanisms underlying AD pathogenesis and to promote the development of TREM2-based therapeutic strategy.

P75 Involved in the Ubiquitination of α-synuclein in Rotenone-based Parkinson's Disease Models.

For Parkinson's disease (PD), the regulatory mechanism of α-synuclein (α-syn) aggregation remains to be clarified. Ubiquitination modification is crucial for α-syn aggregation, with implications for Lewy body formation. Besides, ubiquitin ligase absentia homolog (siAH) is involved in the ubiquitination of α-syn. We investigated whether the p75 receptor can act as a potential regulator of α-syn accumulation through ubiquitination. Western blot, immunoprecipitation, gene transfection, and RNA interference technology were employed to detect the effect of p75 in in vivo and in vitro models. In a rotenone-based stereotactic (ST) infusion in vivo model of PD, p75 receptor and siAH expression was increased significantly compared with the control group. In cellular models of rotenone-mediated neurotoxicity, the interactions between p75 and siAH were revealed by immunoprecipitation; the colocalization of p75 with α-syn was observed in the cytoplasm; p75 promoted nuclear expression of NF-κB (p65), which might interact with the promoter of the siAH gene. Moreover, siRNA-mediated p75 depletion reduced the upregulation of α-syn and nuclear expression of p65 and protected against cell apoptosis induced by rotenone. Thus, aberrant expression of p75 may regulate the increased expression of α-syn, which is related to siAH-mediated ubiquitination and nuclear expression of p65.

HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by irreversible dopaminergic neuron loss and intra-neuronal α-synuclein aggregation. High mobility group box 1 (HMGB1) has been proven to be involved in autophagy dysfunction induced by α-synuclein accumulation, and the Beclin1-vacuolar protein sorting 34 (Vps34) complex is of great importance to the initiation of autophagy. Nevertheless, the concrete interaction mechanism between HMGB1, α-synuclein and autophagy remains elusive, especially in the context of PD. Here in this study, we investigated the interaction between HMGB1 and α-synuclein in rotenone-induced PD cell models and their roles in autophagy flux. Results revealed elevated expression and cytosolic translocation of endogenous HMGB1 upon rotenone exposure. Besides, HMGB1 was found to be able to co-localize and interact with α-synuclein. Moreover, it had also been proven that HMGB1 could aggravate α-synuclein aggregation induced autophagy dysfunction via perturbing Beclin1-Vps34 complex formation. Based on these findings, we propose that HMGB1 is involved in rotenone-induced dopaminergic cell death via interacting with α-synuclein, perturbing the autophagy process, aggravating protein aggregation and finally propelling dopaminergic neurons to move from morbidity to mortality.

Go-ICP: A Globally Optimal Solution to 3D ICP Point-Set Registration.

The Iterative Closest Point (ICP) algorithm is one of the most widely used methods for point-set registration. However, being based on local iterative optimization, ICP is known to be susceptible to local minima. Its performance critically relies on the quality of the initialization and only local optimality is guaranteed. This paper presents the first globally optimal algorithm, named Go-ICP, for Euclidean (rigid) registration of two 3D point-sets under the L2 error metric defined in ICP. The Go-ICP method is based on a branch-and-bound scheme that searches the entire 3D motion space SE(3). By exploiting the special structure of SE(3) geometry, we derive novel upper and lower bounds for the registration error function. Local ICP is integrated into the BnB scheme, which speeds up the new method while guaranteeing global optimality. We also discuss extensions, addressing the issue of outlier robustness. The evaluation demonstrates that the proposed method is able to produce reliable registration results regardless of the initialization. Go-ICP can be applied in scenarios where an optimal solution is desirable or where a good initialization is not always available.

Fenpropathrin, a Widely Used Pesticide, Causes Dopaminergic Degeneration.

Fenpropathrin is one of the widely used pyrethroids in agriculture and household and also reported to have neurotoxic effects in rodent models. In our Parkinson's disease (PD) clinic, there was a unique patient with a history of daily exposure to fenpropathrin for 6 months prior to developing Parkinsonian symptoms progressively. Since whether fenpropathrin is related to any dopaminergic degeneration was unknown, we aimed in this study to evaluate the neurotoxic effects of fenpropathrin on the dopaminergic system and associated mechanisms in vitro and in vivo. In cultured SH-SY5Y cells, fenpropathrin caused cell death, reactive oxygen species generation, Lewy body-associated proteins aggregation, and Lewy body-like intracytoplasmic inclusions formation. In rodent animals, two different injections of fenpropathrin were used for administrations, intraperitoneal (i.p), or stereotaxical (ST). The rats exhibited lower number of pokes 60 days after first i.p injection, while the rats in ST group showed a significant upregulation of apomorphine-evoked rotations 60 days after first injection. Decreased tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) immunoreactivity, while increased dopamine transporter (DAT) immunoreactivity were observed in rats of either i.p or ST group 60 days after the last exposure to fenpropathrin. However, the number of TH-positive cells in the substantia nigra was more reduced 120 days after the first i.p injection than those of 60 days. Our data demonstrated that exposure to fenpropathrin could mimic the pathologic and pathogenetic features of PD especially in late onset cases. These results imply fenpropathrin as a DA neurotoxin and a possible environmental risk factor for PD.

Effectiveness of traditional Chinese medicine as an adjunct therapy for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Idiopathic Parkinson disease (PD) is a common neurodegenerative disease that seriously hinders limb activities and affects patients' lives. We performed a meta-analysis aiming to systematically review and quantitatively synthesize the efficacy and safety of traditional Chinese medicine (TCM) as an adjunct therapy for clinical PD patients. METHODS: An electronic search was conducted in PubMed, Cochrane Controlled Trials Register, China National Knowledge Infrastructure, Chinese Scientific Journals Database and Wanfang data to identify randomized trials evaluating TCM adjuvant therapy versus conventional treatment. The change from baseline of the Unified Parkinson's Disease Rating Scale score (UPDRS) was used to estimate the effectiveness of the therapies. RESULTS: Twenty-seven articles involving 2314 patients from 1999 to 2013 were included. Potentially marked improvements were shown in UPDRS I (SMD 0.68, 95%CI 0.38, 0.98), II (WMD 2.41, 95%CI 1.66, 2.62), III (WMD 2.45, 95%CI 2.03, 2.86), IV (WMD 0.32, 95%CI 0.15, 049) and I-IV total scores (WMD 6.18, 95%CI 5.06, 7.31) in patients with TCM plus dopamine replacement therapy (DRT) compared to DRT alone. Acupuncture add-on therapy was markedly beneficial for improving the UPDRS I-IV total score of PD patients (WMD 10.96, 95%CI 5.85, 16.07). However, TCM monotherapy did not improve the score. The effectiveness seemed to be more obvious in PD patients with longer adjunct durations. TCM adjuvant therapy was generally safe and well tolerated. CONCLUSIONS: Although the data were limited by methodological flaws in many studies, the evidence indicates the potential superiority of TCM as an alternative therapeutic for PD treatment and justifies further high-quality studies.

Impulsive and compulsive behaviors in Parkinson's disease.

BACKGROUND: Impulsive and compulsive behaviors (ICBs) are a heterogeneous group of conditions that may be caused by long-term dopaminergic replacement therapy (DRT) of Parkinson's disease (PD). The spectrum of ICBs includes dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs). CONTENTS: We made a detailed review regarding the epidemiology, pathology, clinical characteristics, risk factors, diagnosis as well as treatment of ICBs. RESULTS: The prevalence of ICBs in PD patients is approximately 3-4% for DDS, 0.34-4.2% for punding, and 6-14% for ICDs, with higher prevalence in Western populations than in Asian. Those who take high dose of levodopa are more prone to have DDS, whereas, ICDs are markedly associated with dopamine agonists. Different subtypes of ICBs share many risk factors such as male gender, higher levodopa equivalent daily dose, younger age at PD onset, history of alcoholism, impulsive, or novelty-seeking personality. The Questionnaire for Impulsive-Compulsive Disorder in Parkinson's Disease-Rating Scale seems to be a rather efficacious instrument to obtain relevant information from patients and caregivers. Treatment of ICBs is still a great challenge for clinicians. Readjustment of DRT remains the primary method. Atypical antipsychotics, antidepressants, amantadine, and psychosocial interventions are also prescribed in controlling episodes of psychosis caused by compulsive DRT, but attention should be drawn to balance ICBs symptoms and motor disorders. Moreover, deep brain stimulation of the subthalamic nucleus might be a potential method in controlling ICBs. CONCLUSION: The exact pathophysiological mechanisms of ICBs in PD remains poorly understood. Further researches are needed not only to study the pathogenesis, prevalence, features, and risk factors of ICBs, but to find efficacious therapy for patients with these devastating consequences.