132 research outputs found

    Control of hierarchical polymer mechanics with bioinspired metal-coordination dynamics.

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    In conventional polymer materials, mechanical performance is traditionally engineered via material structure, using motifs such as polymer molecular weight, polymer branching, or block copolymer design. Here, by means of a model system of 4-arm poly(ethylene glycol) hydrogels crosslinked with multiple, kinetically distinct dynamic metal-ligand coordinate complexes, we show that polymer materials with decoupled spatial structure and mechanical performance can be designed. By tuning the relative concentration of two types of metal-ligand crosslinks, we demonstrate control over the material's mechanical hierarchy of energy-dissipating modes under dynamic mechanical loading, and therefore the ability to engineer a priori the viscoelastic properties of these materials by controlling the types of crosslinks rather than by modifying the polymer itself. This strategy to decouple material mechanics from structure is general and may inform the design of soft materials for use in complex mechanical environments. Three examples that demonstrate this are provided

    Perceptual Requirements for World-Locked Rendering in AR and VR

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    Stereoscopic, head-tracked display systems can show users realistic, world-locked virtual objects and environments. However, discrepancies between the rendering pipeline and physical viewing conditions can lead to perceived instability in the rendered content resulting in reduced realism, immersion, and, potentially, visually-induced motion sickness. The requirements to achieve perceptually stable world-locked rendering are unknown due to the challenge of constructing a wide field of view, distortion-free display with highly accurate head- and eye-tracking. In this work we introduce new hardware and software built upon recently introduced hardware and present a system capable of rendering virtual objects over real-world references without perceivable drift under such constraints. The platform is used to study acceptable errors in render camera position for world-locked rendering in augmented and virtual reality scenarios, where we find an order of magnitude difference in perceptual sensitivity between them. We conclude by comparing study results with an analytic model which examines changes to apparent depth and visual heading in response to camera displacement errors. We identify visual heading as an important consideration for world-locked rendering alongside depth errors from incorrect disparity

    Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages

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    Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2+ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair. SIGNIFICANCE STATEMENT: There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research. In this report, using in vitro and in vivo models of relevance to traumatic spinal cord injury (SCI), new data indicate that stochastic activation of toll-like and c-type lectin receptors on macrophages causes neuroprotection or neurotoxicity, respectively. Although this manuscript focuses on SCI, these two innate immune receptor subtypes are also involved in developmental processes and become activated in macrophages that respond to various neurological diseases

    ATR Prevents Ca\u3csup\u3e2+\u3c/sup\u3e Overload-Induced Necrotic Cell Death Through Phosphorylation-Mediated Inactivation of PARP1 Without DNA Damage Signaling

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    Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid-induced necrotic death of cells including SH-SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR-mediated anti-necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling

    Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

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    The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

    Overview of the Large-Scale Biosphere–Atmosphere Experiment in Amazonia Data Model Intercomparison Project (LBA-DMIP)

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    A fundamental question connecting terrestrial ecology and global climate change is the sensitivity of key terrestrial biomes to climatic variability and change. The Amazon region is such a key biome: it contains unparalleled biological diversity, a globally significant store of organic carbon, and it is a potent engine driving global cycles of water and energy. The importance of understanding how land surface dynamics of the Amazon region respond to climatic variability and change is widely appreciated, but despite significant recent advances, large gaps in our understanding remain. Understanding of energy and carbon exchange between terrestrial ecosystems and the atmosphere can be improved through direct observations and experiments, as well as through modeling activities. Land surface/ecosystem models have become important tools for extrapolating local observations and understanding to much larger terrestrial regions. They are also valuable tools to test hypothesis on ecosystem functioning. Funded by NASA under the auspices of the LBA (the Large-Scale Biosphere–Atmosphere Experiment in Amazonia), the LBA Data Model Intercomparison Project (LBA-DMIP) uses a comprehensive data set from an observational network of flux towers across the Amazon, and an ecosystem modeling community engaged in ongoing studies using a suite of different land surface and terrestrial ecosystem models to understand Amazon forest function. Here an overview of this project is presented accompanied by a description of the measurement sites, data, models and protocol

    Migratory Dermal Dendritic Cells Act as Rapid Sensors of Protozoan Parasites

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    Dendritic cells (DC), including those of the skin, act as sentinels for intruding microorganisms. In the epidermis, DC (termed Langerhans cells, LC) are sessile and screen their microenvironment through occasional movements of their dendrites. The spatio-temporal orchestration of antigen encounter by dermal DC (DDC) is not known. Since these cells are thought to be instrumental in the initiation of immune responses during infection, we investigated their behavior directly within their natural microenvironment using intravital two-photon microscopy. Surprisingly, we found that, under homeostatic conditions, DDC were highly motile, continuously crawling through the interstitial space in a Gαi protein-coupled receptor–dependent manner. However, within minutes after intradermal delivery of the protozoan parasite Leishmania major, DDC became immobile and incorporated multiple parasites into cytosolic vacuoles. Parasite uptake occurred through the extension of long, highly dynamic pseudopods capable of tracking and engulfing parasites. This was then followed by rapid dendrite retraction towards the cell body. DDC were proficient at discriminating between parasites and inert particles, and parasite uptake was independent of the presence of neutrophils. Together, our study has visualized the dynamics and microenvironmental context of parasite encounter by an innate immune cell subset during the initiation of the immune response. Our results uncover a unique migratory tissue surveillance program of DDC that ensures the rapid detection of pathogens