Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid‐β (Aβ) plaque accumulation and ...neuroinflammation in the brain. The current immunotherapy approaches, such as anti‐Aβ monoclonal antibody (mAb) therapy, Aβ vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, Aβ vaccines often induce T helper 1 (Th1) cell‐mediated inflammatory responses. Here, a nanovaccine composed of lipid nanoparticles loaded with Aβ peptides and rapamycin is developed, which targets multiple pathophysiological mechanisms, exhibits the combined effects of anti‐Aβ antibody therapy and adoptive Aβ‐specific Treg cell transfer, and can overcome the limitations of current immunotherapy approaches for AD. The Nanovaccine effectively delivers rapamycin and Aβ peptides to dendritic cells, produces both anti‐Aβ antibodies and Aβ‐specific Treg cells, removes Aβ plaques in the brain, alleviates neuroinflammation, prevents Th1 cell‐mediated excessive immune responses, and inhibits cognitive impairment in mice. The nanovaccine shows higher efficacy in cognitive recovery than an Aβ vaccine. Unlike anti‐Aβ mAb therapy and adoptive Treg cell transfer, both of which require complicated and costly manufacturing processes, the nanovaccine is easy‐to‐prepare and cost‐effective. The nanovaccines can represent a novel treatment option for AD.
Rapamycin‐incorporated lipid nanoparticle containing amyloid‐β (LNP‐R/Aβ) attenuates neuroinflammation and improves cognitive function in a transgenic rodent model of Alzheimer's disease (AD) by inducing tolerogenic dendritic cells and Aβ‐specific regulatory T cells, and generating anti‐amyloid antibodies. Furthermore, LNP‐R/Aβ reduces T helper 1 cells in AD brains, implying lower risks of meningitis, which is the major reason for the failure of conventional Aβ vaccines.
Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment ...and heart failure. Timely resolution of post‐MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time‐consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L‐Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen‐specific regulatory T cells (Tregs). Impressively, intradermal injection of L‐Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing Tregs and an inflammatory‐to‐reparative macrophage polarization, inhibits adverse cardiac remodeling, and improves cardiac function. Nanoparticle‐mediated blocking of excessive inflammation in infarcted myocardium may be an effective intervention to prevent the development of post‐MI heart failure.
Liposomal nanoparticles loaded with both antigen and rapamycin (L‐Ag/Rs) are fabricated as novel therapeutics for myocardial infarction (MI). L‐Ag/Rs generate regulatory T cells and reparative M2 macrophages in infarcted heart, inducing immune tolerance with antigen‐specific manner. The reparative phase elicited by L‐Ag/R inhibits excessive inflammation and adverse cardiac remodeling in infarct region, improving cardiac function.
3D Scene Understanding by Voxel-CRF Byung-Soo Kim; Kohli, Pushmeet; Savarese, Silvio
2013 IEEE International Conference on Computer Vision,
12/2013
Conference Proceeding, Journal Article
Scene understanding is an important yet very challenging problem in computer vision. In the past few years, researchers have taken advantage of the recent diffusion of depth-RGB (RGB-D) cameras to ...help simplify the problem of inferring scene semantics. However, while the added 3D geometry is certainly useful to segment out objects with different depth values, it also adds complications in that the 3D geometry is often incorrect because of noisy depth measurements and the actual 3D extent of the objects is usually unknown because of occlusions. In this paper we propose a new method that allows us to jointly refine the 3D reconstruction of the scene (raw depth values) while accurately segmenting out the objects or scene elements from the 3D reconstruction. This is achieved by introducing a new model which we called Voxel-CRF. The Voxel-CRF model is based on the idea of constructing a conditional random field over a 3D volume of interest which captures the semantic and 3D geometric relationships among different elements (voxels) of the scene. Such model allows to jointly estimate (1) a dense voxel-based 3D reconstruction and (2) the semantic labels associated with each voxel even in presence of partial occlusions using an approximate yet efficient inference strategy. We evaluated our method on the challenging NYU Depth dataset (Version 1 and 2). Experimental results show that our method achieves competitive accuracy in inferring scene semantics and visually appealing results in improving the quality of the 3D reconstruction. We also demonstrate an interesting application of object removal and scene completion from RGB-D images.
Current treatments for wound healing engage in passive healing processes and rarely participate in stimulating skin cell behaviors for active wound healing. Electric potential difference‐derived ...electrical fields (EFs) are known to modulate skin cell behaviors. Here, a piezoelectric dermal patch is developed that can be applied on skin wound site and EF is generated to promote wound healing. The one‐directionally aligned zinc oxide nanorod‐based piezoelectric patch generates piezoelectric potential upon mechanical deformations induced by animal motion, and induces EF at the wound bed. In vitro and in vivo data demonstrate that the piezoelectric patch promotes the wound healing process through enhanced cellular metabolism, migration, and protein synthesis. This modality may lead to a clinically relevant piezoelectric dermal patch therapy for active wound healing.
A piezoelectric patch that can be applied on skin wounds and generate electric fields (EFs) to promote wound healing is developed. The zinc oxide nanorod‐based patch generates piezoelectric potential upon skin movements, and induces EF at the wound bed. In vitro and in vivo data suggest the patch promotes skin regeneration through enhanced cellular metabolism, migration, and protein synthesis.
Exosomes and extracellular nanovesicles (NV) derived from mesenchymal stem cells (MSC) may be used for the treatment of ischemic stroke owing to their multifaceted therapeutic benefits that include ...the induction of angiogenesis, anti-apoptosis, and anti-inflammation. However, the most serious drawback of using exosomes and NV for ischemic stroke is the poor targeting on the ischemic lesion of brain after systemic administration, thereby yielding a poor therapeutic outcome. In this study, we show that magnetic NV (MNV) derived from iron oxide nanoparticles (IONP)-harboring MSC can drastically improve the ischemic-lesion targeting and the therapeutic outcome. Because IONP stimulated expressions of therapeutic growth factors in the MSC, MNV contained greater amounts of those therapeutic molecules compared to NV derived from naive MSC. Following the systemic injection of MNV into transient middle-cerebral-artery-occlusion (MCAO)-induced rats, the magnetic navigation increased the MNV localization to the ischemic lesion by 5.1 times. The MNV injection and subsequent magnetic navigation promoted the anti-inflammatory response, angiogenesis, and anti-apoptosis in the ischemic brain lesion, thereby yielding a considerably decreased infarction volume and improved motor function. Overall, the proposed MNV approach may overcome the major drawback of the conventional MSC-exosome therapy or NV therapy for the treatment of ischemic stroke.
Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often ...lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.
Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, ...insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI.
Stem cell therapy has emerged as a potential modality for myocardial infarction treatment. Mesenchymal stem cells (MSCs) exert reparative actions in the injured myocardium mainly through the ...secretion of paracrine factors. In addition, the overexpression of connexin 43 (Cx43), a gap junction protein, promotes cardiac repair and function restoration. It is known that MSCs in a spheroid form, which have enhanced cell–cell interaction, exhibit enhanced expression of paracrine factors and Cx43. However, cell‐extracellular matrix (ECM) interactions, which also contribute to growth factor expression, are very limited in MSC spheroids. Reduced graphene oxide (RGO) shows high affinity toward ECM proteins, such as fibronectin (FN), and high electrical conductivity. In this study, by incorporating FN‐adsorbed RGO flakes into MSC spheroids, it is possible to enhance the cell–ECM interactions and, subsequently, the paracrine factor expression in the MSCs in spheroids. Cx43 is also upregulated likely due to the enhanced paracrine factor expression and electrical conductivity of RGO. The injection of MSC–RGO hybrid spheroids into the infarcted hearts enhances cardiac repair compared with the injection of RGO flakes or MSC spheroids. This study demonstrates that RGO can effectively improve the therapeutic efficacy of MSCs for ischemic heart diseases.
Reduced graphene oxide flakes can stimulate the expression of angiogenic growth factors and a gap junction protein in mesenchymal stem cells. Therefore, the incorporation of reduced graphene oxide flakes into mesenchymal stem cell spheroids can enhance the therapeutic efficacy of the stem cells for the treatment of myocardial infarction.
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