Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence.

There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of "exhausted" NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK "exhaustion" is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of "exhaustion.

Subjective Performance Measures in Optimal Incentive Contracts

Objective measures of performance are seldom perfect. In response, incentive contracts often include important subjective components that mitigate incentive distortions caused by imperfect objective measures. This paper explores the combined use of subjective and objective performance measures in (respectively) implicit and explicit incentive contracts. Naturally, objective and subjective measures often are substitutes, sometimes strikingly so: we show that if objective measures are sufficiently close to perfect then no implicit contracts are feasible (because the firm's fallback position after reneging on an implicit contact is too attractive). We also show, however, that objective and subjective measures can reinforce each other: if objective measures become more accurate then in some circumstances the optimal contract puts more weight on subjective measures (because the improved objective measures increase the value of the ongoing relationship, and so reduce the firm's incentive to renege). We also analyze the use of subjective weights on objective performance measures, and provide case-study evidence consistent with our analyses.

Alien Registration- Murphy, Robert J. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/21956/thumbnail.jp

Alien Registration- Murphy, Robert J. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/21956/thumbnail.jp

Entry, Pricing and Product Design in an Initially Monopolized Market

We analyze entry, pricing and product design in a model with differentiated products. Under plausible conditions, entry into an initially monopolized market leads to higher prices for some, possibly all, consumers. Entry can induce a misallocation of goods to consumers, segment the market in a way that transfers surplus to producers and undermine aggressive pricing by the incumbent. Post entry, firms have strong incentives to modify product designs so as to raise price by strengthening market segmentation. Firms may also forego socially beneficial product improvements in the post-entry equilibrium, because they intensify price competition too much. Multi-product monopoly can lead to better design incentives than the non-cooperative pricing that prevails under competition.

Prosomal-width-to-weight relationships in American horseshoe crabs (Limulus polyphemus): examining conversion factors used to estimate landings

Horseshoe crabs (Limulus polyphemus) are valued by many stakeholders, including the commercial fishing industry, biomedical companies, and environmental interest groups. We designed a study to test the accuracy of the conversion factors that were used by NOAA Fisheries and state agencies to estimate horseshoe crab landings before mandatory reporting that began in 1998. Our results indicate that the NOAA Fisheries conversion factor consistently overestimates the weight of male horseshoe crabs, particularly those from New England populations. Because of the inaccuracy of this and other conversion factors, states are now mandated to report the number (not biomass) and sex of landed horseshoe crabs. However, accurate estimates of biomass are still necessary for use in prediction models that are being developed to better manage the horseshoe crab fishery. We recommend that managers use the conversion factors presented in this study to convert current landing data from numbers to biomass of harvested horseshoe crabs for future assessments