Robotic agents will be life-long companions of humans in the foreseeable future. To achieve such successful relationships, people will likely attribute emotions and personality, assign social competencies, and develop a long-lasting attachment to robots. However, without a clear theoretical framework-building on biological, psychological, and technological knowledge-current societal demands for establishing successful human-robot attachment (HRA) as a new form of inter-species interactions might fail. The study of evolutionarily adaptive animal behavior (i.e., ethology) suggests that human-animal behaviors can be considered as a plausible solution in designing and building models of ethorobots-including modeling the inter-species bond between domesticated animals and humans. Evidence shows that people assign emotional feelings and personality characteristics to animal species leading to cooperation and communication-crucial for designing social robots such as companion robots. Because dogs have excellent social skills with humans, current research applies humandog relationships as a template to understand HRA. Our goal of this article is twofold. First, we overview the research on how human-dog interactions are implemented as prototypes of non-human social companions in HRA. Second, we review research about attitudes that humans have for interacting with robotic dogs based on their appearance and behavior, the implications for forming attachments, and human-animal interactions in the rising sphere of robot-assisted therapy. The rationale for this review is to provide a new perspective to facilitate future research among biologists, psychologists, and engineers-contributing to the creation of innovative research practices for studying social behaviors and its implications for society addressing HRA.
We characterized the in vivo interstitial fluid (IF) content of extracellular vesicles (EVs) using the GFP‐4T1 syngeneic murine cancer model to study EVs in‐transit to the draining lymph node. GFP labelling confirmed the IF EV tumour cell origin. Molecular analysis revealed an abundance of IF EV‐associated proteins specifically involved in mitophagy and secretory autophagy. A set of proteins required for sequential steps of fission‐induced mitophagy preferentially populated the CD81+/PD‐L1+ IF EVs; PINK1, TOM20, and ARIH1 E3 ubiquitin ligase (required for Parkin‐independent mitophagy), DRP1 and FIS1 (mitochondrial peripheral fission), VDAC‐1 (ubiquitination state triggers mitophagy away from apoptosis), VPS35, SEC22b, and Rab33b (vacuolar sorting). Comparing in vivo IF EVs to in vitro EVs revealed 40% concordance, with an elevation of mitophagy proteins in the CD81+ EVs for both murine and human cell lines subjected to metabolic stress. The export of cellular mitochondria proteins to CD81+ EVs was confirmed by density gradient isolation from the bulk EV isolate followed by anti‐CD81 immunoprecipitation, molecular sieve chromatography, and MitoTracker export into CD81+ EVs. We propose the 4T1 in vivo model as a versatile tool to functionally characterize IF EVs. IF EV export of fission mitophagy proteins has broad implications for mitochondrial function and cellular immunology.
Osteoarthritis (OA) is the most common form of arthritis and the fastest growing cause of chronic disability in the world. Formation of the ternary IL-1β /IL-1R1/IL-1RAcP protein complex and its downstream signaling has been implicated in osteoarthritis pathology. Current OA therapeutic approaches target either the cytokine IL-1β or the primary receptor IL-1RI but do not exploit the potential of the secondary receptor IL-1RAcP. Our previous work implicated the Arg286 residue of IL-1RAcP as a key mediator of complex formation. Molecular modeling confirmed Arg286 as a high-energy mediator of the ternary IL-1β complex architecture and interaction network. Anti-IL-1RAcP monoclonal antibodies (mAb) targeting the Arg286 residue were created and were shown to effectively reduce the influx of inflammatory cells to damaged joints in a mouse model of osteoarthritis. Inhibitory peptides based on the native sequence of IL-1RAcP were prepared and examined for efficacy at disrupting the complex formation. The most potent peptide inhibitor had an IC50 value of 304 pM in a pull-down model of complex formation, and reduced IL-1β signaling in a cell model by 90% at 2 μM. Overall, therapies that target the Arg286 region surface of IL-1RAcP, and disrupt subsequent interactions with subunits, have the potential to serve as next generation treatments for osteoarthritis.
The next generation of molecular cancer therapeutics will target pivotal protein-protein interaction interfaces participating in immune cell receptor signaling, oncogenes, and suppressor genes. We have created a wholly novel, technology “protein painting” for the rapid direct sequencing of hidden native protein-protein interaction hot spots. Our technology, employs previously unexplored small molecule (12 Å) aryl hydrocarbon dyes or “paints” to cut out, and MS sequence, only the hidden unmodified contact interfaces between two or more interacting native proteins. Novel Technology: Paint chemistries have extremely high affinities (rapid on-rates, and very slow off-rates that are ten to 100 times higher than most protein-protein interactions). When mixed with a native pre-formed protein complex for only 5 minutes at physiologic pH and salinity, the paints non-covalently coat all external sites on the protein without altering the 3D conformation of the complex, but cannot gain access to the solvent inaccessible hidden protein-protein interaction domains. Each paint molecule spans less than 3 amino acids, and has high affinity for protease cleavage consensus sites. Following painting, the proteins are dissociated. This leaves the paint molecules coating surfaces not participating in the interface. Following dissociation, the proteins are linearized, digested with trypsin, and sequenced by standard MS. The paint molecules remain non-covalently bound after the proteins are denatured. Trypsin will not cleave the regions of the protein that are “painted”. Following proteolysis peptides emerging from MS will be generated exclusively from the unmodified opposing points where the proteins were in intimate contact. Results: Protein Painting identified hot spot domains between PD-L1:PD-1, including two surface interface regions that are separated in the linear sequence but adjacent in the 3D structure. We created novel cyclized multivalent inhibitors that block both sides of the PD-L1:PD-1 interface and markedly suppress cell-cell coupling and abolished downstream signaling through this complex in cultured tumor cell immune cell interactions. A very high correlation (p<0.0003) was found for known contact points predicted by crystal structure, with a 97% specificity for true positive hot spots: 95% agreement with Robetta prediction software for known complexes. Protein painting outperforms (425%) hydrogen deuterium exchange and cross linking for number of positive hits and % true positive hits. Conclusions: Protein painting is a new tool to identify highly specific drug targets located within protein interaction interfaces, yielding inhibitors that abolish protein signaling relevant to cancer immunotherapy. Citation Format: Alessandra Luchini, Luisa Paris, Virginia Espina, Kelsey Mitchell, Angela Dailing, Lance A. Liotta. Protein painting identifies PD-1: PDL-1 therapeutic targets at protein-protein interfaces [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 211. doi:10.1158/1538-7445.AM2017-211
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