Extracellular vesicles (EVs) are nanosized vesicles that carry cell-specific biomolecular information. Our previous studies showed that adult human bone marrow mesenchymal stem cell (BM-MSC)-derived ...EVs provide antiproteolytic and proregenerative effects in cultures of smooth muscle cells (SMCs) derived from an elastase-infused rat abdominal aortic aneurysm (AAA) model, and this is promising toward their use as a therapeutic platform for naturally irreversible elastic matrix aberrations in the aortic wall. Since systemically administered EVs poorly home into sites of tissue injury, disease strategies to improve their affinity toward target tissues are of great significance for EV-based treatment strategies. Toward this goal, in this work, we developed a postisolation surface modification strategy to target MSC-derived EVs to the AAA wall. The EVs were surface-conjugated with a short, synthetic, azide-modified peptide sequence for targeted binding to cathepsin K (CatK), a cysteine protease overexpressed in the AAA wall. Conjugation was performed using a copper-free click chemistry method. We determined that such conjugation improved EV uptake into cultured aneurysmal SMCs in culture and their binding to the wall of matrix injured vessels ex vivo. The proregenerative and antiproteolytic effects of MSC-EVs on cultured rat aneurysmal SMCs were also unaffected following peptide conjugation. From this study, it appears that modification with short synthetic peptide sequences seems to be an effective strategy for improving the cell-specific uptake of EVs and may be effective in facilitating AAA-targeted therapy.
Abdominal aortic aneurysms (AAA) are localized expansions of the abdominal aorta that develop due to chronic proteolytic disruption of the structural extracellular matrix (ECM) components (elastin ...and collagen) within the aorta wall. Major limitations in arresting or reversing AAAs lie in naturally poor and aberrant regeneration and repair of elastic matrix structures in the aorta wall. Bone marrow derived mesenchymal stem cells (BM-MSCs) have emerged as a promising regenerative tool and their therapeutic effects are also known to be effected through their paracrine secretions. Extracellular vesicles (EVs) present in these secretions have emerged as critical cellular component in facilitating many therapeutic benefits of MSCs. EV treatment is thus potentially appealing as a stem cell-inspired cell-free approach to avoid possible phenotypic plasticity of MSCs in vivo. In this study, we investigated the thus far unknown effects of BM-MSC derived EVs on vascular elastic matrix repair in the context of AAA treatment. EVs isolated from BM-MSC source were characterized and their pro-regenerative and their anti-proteolytic effects were evaluated on our established in vitro experimental conditions derived from AAA rat model. Our studies revealed the efficacy of BM-MSC derived EVs in attenuating the proteolytic activity and also in imparting elastic matrix regenerative benefits under aneurysmal environment. Interestingly, compared to cell culture conditioned media (CCM), EVs demonstrated superior regenerative and anti-proteolytic benefits in a proteolytic injury culture model of AAA. From these studies, it appears that EVs derived from BM-MSCs could be beneficial in undertaking a reparative effort in AAA induced degeneration of vascular tissue.
Statement of Significance
Abdominal aortic aneurysms (AAAs) are localized, rupture-prone expansions of the aorta which result from loss of wall flexibility due to enzymatic breakdown of elastic fibers. There are no established alternatives to surgery, which possess high risk for the mostly elderly patients. Our previous studies have established the elastic regenerative and reparative effect of cell culture secretions derived from adult stem cell source. In this study, we propose to isolate extracellular vesicles (exosomes) from these secretions and evaluate their regenerative benefits in AAA smooth muscle cell culture model. This simple and innovative treatment approach has the potential to arrest or reverse AAA growth to rupture, not possible so far.
Display omitted
ABSTRACT
Promoting through daily deal sites has become popular in the past few years. Groupon is perhaps the best known provider of these promotions (also known as online discount vouchers) to ...customers. Daily deals differ from traditional coupons on three important dimensions: (i) They are not offered to consumers directly by firms but are offered through an intermediary, (ii) the promotional depth offered by these localized promotions tends to be higher, and (iii) consumers prepay for the discount vouchers, and then the daily deals site reimburses the retailer a prespecified negotiated percentage of each paid voucher. In this study, we build a theoretical model to explore the profitability of undertaking a daily deals campaign by firms. Our analysis identifies the role of types of consumers in the market, relative bargaining power of the local firms, revenue sharing agreements, and market characteristics, such as degree of product substitutability and extent of competition, on the profitability attained through daily deal promotions. Surprisingly, when demand spillovers exist, an asymmetric outcome, with one firm offering an online discount voucher and the competing firm not offering an online discount voucher, is an equilibrium under some conditions.
Present investigation was aimed at developing an oral insulin delivery system based on hydroxypropyl β cyclodextrin–insulin (HPβCD–I) complex encapsulated polymethacrylic acid-chitosan-polyether ...(polyethylene glycol-polypropylene glycol copolymer) (PMCP) nanoparticles. Nanoparticles were prepared by the free radical polymerization of methacrylic acid in presence of chitosan and polyether in a solvent/surfactant free medium. Dynamic light scattering (DLS) experiment was conducted with particles dispersed in phosphate buffer (pH 7.4) and size distribution curve was observed in the range of 500–800
nm. HPβCD was used to prepare non-covalent inclusion complex with insulin and complex was analyzed by Fourier transform infrared (FTIR) and fluorescence spectroscopic studies. HPβCD complexed insulin was encapsulated into PMCP nanoparticles by diffusion filling method and their
in vitro release profile was evaluated at acidic/alkaline pH. PMCP nanoparticles displayed good insulin encapsulation efficiency and release profile was largely dependent on the pH of the medium. Enzyme linked immuno sorbent assay (ELISA) study demonstrated that insulin encapsulated inside the particles was biologically active. Trypsin inhibitory effect of PMCP nanoparticles was evaluated using
N-α-benzoyl-
l-arginine ethyl ester (BAEE) and casein as substrates. Mucoadhesive studies of PMCP nanoparticles were conducted using freshly excised rat intestinal mucosa and the particles were found fairly adhesive. From the preliminary studies, cyclodextrin complexed insulin encapsulated mucoadhesive nanoparticles appear to be a good candidate for oral insulin delivery.
•Predicting mobility vital for business decisions, especially with market shocks.•Multiple dimensions of consumers’ risk perceptions drive their mobility decisions.•Requires ...multicollinearity-alleviating method needed to leverage new data sources.•Our predictive mobility algorithm could be used to improve retail forecasting.
The COVID-19 pandemic has changed consumer behavior substantially. In this study, we explore the drivers of consumer mobility in several metropolitan areas in the United States under the perceived risks of COVID-19. We capture multiple dimensions of perceived risk using local and national cases and death counts of COVID-19, along with real-time Google Trends data for personal protective equipment (PPE). While Google Trends data are popular inputs in many studies, the risk of multicollinearity escalates with the addition of more relevant terms. Therefore, multicollinearity-alleviating methods are needed to appropriately leverage information provided by Google Trends data. We develop and utilize a novel optimization scheme to induce linear models containing strictly significant covariates and minimal multicollinearity. We find that there are a variety of unique factors that drive mobility in different geographic locations, as well as several factors that are common to all locations.
Consumers purchase conspicuous goods, such as luxury cars, to satisfy both social and functional needs. Heterogeneity in the emphases that consumers place on these two drivers of utility in ...conspicuous goods markets creates two broad groups: functionality-oriented and exclusivity-oriented consumer segments. A game-theoretic model reveals how this segmentation affects the equilibrium extent of value enhancements in functionality and exclusivity, prices and profits. We show that firms increase value enhancements in their product when functionality-oriented consumers perceive greater product differentiation. In contrast, firms reduce value enhancements in their product if exclusivity-oriented consumers perceive greater product differentiation. We also show that, in the presence of such heterogeneous consumers, lower perceived product differentiation is consistent with higher profitability. We also find conditions in which firm profits could decrease with a higher proportion of exclusivity-oriented consumers. The proposed model helps explain why conspicuous good manufacturers pursue lower within-category product differentiation (as validated empirically with an application to the automotive industry). These findings also provide prescriptions for firms' product value enhancement decisions—in equilibrium, increase in the size of the functionality-oriented consumer segment leads to reduced value enhancements in functionality and exclusivity.
The objective of this article is to study the impact of differentiation and firm positioning on firm's pricing decisions in a horizontally differentiated competitive market. We build a parsimonious ...game-theoretic model and analyse simultaneous entry of firms. The effect of differentiation is modelled as an additional cost incurred by both firms based on the degree of differentiation between the firms. The cost of positioning is modelled as a market level cost affecting both firms whereby firms incur a cost if they want to position themselves away from the centre of distribution of consumers. Our analysis provides some surprising results, explains some conflicting empirical observations documented in previous research and may also be useful for further empirical research in this area by providing sharper predictions about the impact of various types of costs on market outcomes. For example, we find that if the cost of positioning is sufficiently high, then a firm with lower cost of differentiation charges a higher price in equilibrium, even when no differences in exogenous costs exist. We also find that under some circumstances the cost disadvantaged firm can enjoy higher price-cost margins compared to the cost leader thereby suggesting that higher costs could be a blessing in disguise.
In the last two decades, organized retailing has transformed the retailing landscape in emerging economies, where unorganized retailing has traditionally been dominant. In this paper, we build a ...theoretical model of unorganized and organized retailing in emerging economies by carefully modeling key characteristics of the retailing environment, the retailers, the consumers, and product categories. The primary insight that we obtain is that in a competitive market comprising of only unorganized retailers, the advent of organized retailing injects efficiency into the market leading to a reduction in the number of unorganized retailers. This, in turn, makes the market less competitive. Building on this basic insight, we obtain a number of counterintuitive results. For instance, (i) the presence of organized retailing may increase the prices charged by unorganized retailers; (ii) as the consumers’ transportation cost to the unorganized retailers increases, the market share of the unorganized retailing sector may increase; (iii) as the probability of bulk consumption increases and consumers prefer to purchase more from the organized retailer, prices and profits at the organized retailer may decrease; and (iv) the presence of organized retailing can lead to both consumer and social surplus being lower because consumers face higher prices at unorganized retailers and there is wastage in the economy due to bulk purchasing at organized retailers. Our model offers an explanation for certain surprising empirical observations related to retailing in emerging markets, such as why in the last few years in the Indian market the unorganized retailers who have survived the advent of organized retailing seem to be doing better. Implications from our research can provide guidance to policy makers grappling with issues related to the balanced growth of unorganized and organized retailing in emerging markets.
