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Across eumetazoans, the ability to perceive and respond to visual stimuli is largely mediated by opsins, a family of proteins belonging to the G protein-coupled receptor (GPCR) superclass. Lineage-specific gains and losses led to a striking diversity in the numbers, types, and spectral sensitivities conferred by visual opsin gene expression. Here, we review the diversity of visual opsins and differences in opsin gene expression from well-studied protostome, invertebrate deuterostome, and cnidarian groups. We discuss the functional significance of opsin expression differences and spectral tuning among lineages. In some cases, opsin evolution has been linked to the detection of relevant visual signals, including sexually selected color traits and host plant features. In other instances, variation in opsins has not been directly linked to functional or ecological differences. Overall, the array of opsin expression patterns and sensitivities across invertebrate lineages highlight the diversity of opsins in the eumetazoan ancestor and the labile nature of opsins over evolutionary time.

The immediate watershed of the Long Island Sound (LIS) is largely composed of car-centric suburban landscapes, with extensive areas of altered, sealed, and even some polluted soils. In such suburban contexts, the lawn represents a particular kind of widespread landscape regime with considerable ecologic influence. Though varying in both size and degree of landscaping, suburban homes generally have yards, often with areas of maintained turfgrass lawn. With concern for eutrophication and hypoxic conditions within the LIS due to excess nutrient input possibly from yards, residents within the LIS watershed were surveyed regarding yard and LIS related practices and perspectives. Eighty-nine of these respondents were randomly selected to collect ecological data from their yards during spring, summer, and fall of 2021. Soil cores were collected in spring and summer, with two random 10 cm depth soil samples from both front and back yards when possible. Soil moisture, pH, nitrate, and ammonium content were determined at the Advanced Science Research Center in New York, NY. Survey data was combined with the collected biophysical data for further interdisciplinary analysis.Average soil ammonium content was found to notably decrease with even one application of fertilizer per year (3.4 g N/kg dry soil to 1.01 kg N/kg dry soil). Average soil nitrate was found to increase with each repeated fertilization event per year (36.56 g N/kg dry soil with zero reported annual applications on one end to 66.22 g N/kg dry soil with five annual applications on the other end). Respondents who said they had increased their fertilizer compared with five years ago had the highest average soil nitrate content (59.43 g N/kg dry soil) and lowest average soil ammonium content (0.45 g N/kg dry soil) amongst all respondents. People who didn’t report using fertilizer had the lowest average soil nitrate content (36.16 g N/kg dry soil) and the highest average soil ammonium content (4.05 g N/kg dry soil). People that reported hiring a professional to fertilize their yard (but not fertilizing it themselves) had the highest average soil moisture content (19.97%), soil nitrate content (56.5 g N/kg dry soil), and pH among respondents (6.21). People that identified as highly aware about recommendations on the use of fertilizer had the highest average soil nitrate content (48.16 g N/kg dry soil), and also the lowest average soil ammonium content among respondents (1.32 g N/kg dry soil).These results demonstrate the impact that yard fertilization practice has on soil chemistry. Most significantly, reported increases in fertilization show increases soil nitrate content, but with corresponding decreases in soil ammonium content. Furthermore, increasing education and outreach around yard fertilization may not inherently decrease yard fertilization, as perhaps individuals who engage with materials related to fertilization recommendations are more likely to even apply fertilizer. Both reported awareness of recommended practices and utilizing a professional for fertilization were associated with higher soil nitrate content. Homeowner yard contexts remain significant with direct influence on the nutrient content of the soils of the LIS watershed.

Households’ willingness to pay (WTP) for water quality improvements—representing their economic value—depends on where improvements occur. Households often hold higher values for improvements close to their homes or iconic areas. Are there other areas where improvements might hold high value to individual households, do effects on WTP vary by type of improvement, and can these areas be identified even if they are not anticipated by researchers? To answer these questions, we integrated a water quality model and map-based, interactive choice experiment to estimate households’ WTP for water quality improvements throughout a river network covering six New England states. The choice experiment was implemented using a push-to-web survey over a sample of New England households. Voting scenarios used to elicit WTP included interactive geographic information system (GIS) maps that illustrated three water quality measures at various zoom levels across the study domain. We captured data on how respondents maneuvered through these maps prior to answering the value-eliciting questions. Results show that WTP was influenced by regionwide quality improvements and improvements surrounding each respondent’s home, as anticipated, but also by improvements in individualized locations identifiable via each respondent’s map interactions. These spatial WTP variations only appear for low-quality rivers and are focused around particular areas of New England. The study shows that dynamic map interactions can convey salient information for WTP estimation and that predicting spatial WTP heterogeneity based primarily on home or iconic locations, as typically done, may overlook areas where water quality has high value.

Supplementary Figures 1-10

CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8+ T cell–dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNγ were also critical, and CD96-deficient CD8+ T cells promoted greater tumor control than CD96-sufficient CD8+ T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8+ T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti–PD-1 increased the percentage of IFNγ-expressing CD8+ T lymphocytes. Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8+ T cells and IFNγ. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8+ T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth.

Supp Methods and Legends S1-S10

Purpose:Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell–mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell–mediated tumor reactivity.Experimental Design:We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell–mediated cytotoxicity in vitro and in two mouse models.Results:NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT− NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I–deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell–mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell–mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade.Conclusions:Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell–mediated destruction of MHC class I–deficient melanoma, which are refractory to CD8+ T-cell–mediated immunity.See related commentary by Pietra et al., p. 5274

Supplemental Figure 2. CD155 expression in melanoma cells inversely correlates with the TIGIT/CD226 expression ratio in TiNKs.

The mechanisms that generate patterns of cell types unique to humans are poorly understood. In the central region of the human retina, the high-acuity foveola is notable, in part, for its dense packing of green (M) and red (L) cones and absence of blue (S) cones. To identify mechanisms that promote M/L and suppress S cone patterning in the foveola, we examined human fetal retinas and differentiated human retinal organoids. During development, sparse S-opsin-expressing cones are observed in the foveola initially. Later, the foveola contains a mix of cones that either co-express S- and M/L-opsins or express M/L-opsin only. In adulthood, only M/L cones are present. Two signaling pathway regulators are highly and continuously expressed in the central retina: Cytochrome P450 26 subfamily A member 1 (CYP26A1) that degrades retinoic acid (RA) and Deiodinase 2 (DIO2) that promotes thyroid hormone (TH) signaling. CYP26A1null mutant organoids and high RA conditions increased S cones and limited M/L cones in human retinal organoids. Sustained TH signaling promoted the generation of M/L-opsin-expressing cones and induced M/L-opsin expression in S-opsin-expressing cones, showing that cone fate is plastic. Our data suggest that early CYP26A1 degrades RA to specify M/L cones and limit S cones and that continuous DIO2 expression sustains high levels of TH to convert S cones into M/L cones, yielding the M/L cone subtype patterning of the foveola. As the foveola is highly susceptible to impairment in diseases such as macular degeneration, a leading cause of vision loss, our findings inform organoid design for potential therapeutic applications.

Human organoids stand at the forefront of basic and translational research, providing experimentally tractable systems to study human development and disease. These stem cell-derived, in vitro cultures can generate a multitude of tissue and organ types, including distinct brain regions and sensory systems. Neural organoid systems have provided fundamental insights into molecular mechanisms governing cell fate specification and neural circuit assembly and serve as promising tools for drug discovery and understanding disease pathogenesis. In this review, we discuss several human neural organoid systems, how they are generated, advances in 3D imaging and bioengineering, and the impact of organoid studies on our understanding of the human nervous system.

Benefit transfer is the use of pre-existing empirical estimates from one or more settings where research has been conducted previously to predict measures of economic value or related information for other settings. These transfers offer a feasible means to provide information on economic values when time, funding and other constraints impede the use of original valuation studies. The methods used for applied benefit transfers vary widely, however, and it is not always clear why certain procedures were applied or whether alternatives might have led to more credible estimates. Motivated by the importance of benefit transfers for decision-making and the lack of consensus guidance for applied practice, this article provides recommendations for the conduct of valid and reliable transfers, based on the insight from the combined body of benefit transfer research. The primary objectives are to: (a) advance and inform benefit-transfer applications that inform decision making, (b) encourage consensus over key dimensions of best practice for these applications, and (c) focus future research on areas requiring further advances. In doing so, we acknowledge the healthy tension that can exist between best practice as led by the academic literature and practical constraints of real-world applications.

It is increasingly clear that the nectin family and its immunoreceptors shape the immune response to cancer through several pathways. Yet, even as antibodies against TIGIT, CD96, and CD112R advance into clinical development, biological and therapeutic questions remain unanswered. Here, we review recent progress, prospects, and challenges to understanding and tapping this family in cancer immunotherapy.

Human retinal organoid transplantation can potentially restore vision in patients with degenerative retinal diseases. How the recipient retina regulates the maturation, fate specification, and migration of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice, conducted histology and single-cell RNA sequencing analyses, and observed two main classes of graft-derived cells. The first class consisted of retinal astrocytes and brain/spinal cord-like neural precursors, absent or rare in cultured organoids, that migrated into all recipient retinal layers and traveled long distances. The second class consisted of retinal progenitor-derived cells, including rods and cones, that remained in the subretinal space and matured more rapidly than photoreceptors in culture. These data suggest that the recipient subretinal space promotes the maturation of transplanted photoreceptors while inducing or expanding migratory cell populations that are not normally derived from retinal progenitors. These findings have important implications for cell-based treatment of retinal diseases.

In the original article, the code used to estimate the meta-regression models (of WTP for coastal marsh habitat changes) erroneously included the natural log of nominal rather than real income as an independent variable.

Prior meta-regression models (MRMs) of wetland values pool value estimates associated with diverse commodity types—for example recreation, flood control, nutrient cycling, habitat provision, nonuse value, and carbon sequestration. Neither theory nor economic intuition justify the inclusion of such dissimilar commodities within a single meta-analytic value function, leading to validity concerns. This article seeks to advance methods for commodity and welfare consistent MRMs, applied to a particular category of wetland values. We develop a wetland value MRM restricted to a specific wetland type (coastal marshes), general location (US and Canada), commodity type (habitat provision and services), and valuation approach (stated preference methods). Results indicate that willingness to pay per household for marsh habitat changes is responsive to scope, spatial scale, market extent, the type of habitat change, household characteristics, and other factors suggested by theory and intuition. Results supersede those of prior wetland value MRMs in terms of statistical performance, estimation of anticipated value surface patterns, and capacity to support conceptually valid benefit transfers. Comparison with an otherwise identical but less commodity consistent MRM demonstrates that commodity consistency leads to improved statistical and benefit transfer performance.

Non‐market goods can be measured on cardinal or relative scales. Consider a marsh of 200 acres, of which 20 acres would be affected by a policy. The same affected area can be measured in cardinal terms (20 acres) or as a relative proportion (10% of the marsh). When relative units such as percentages are a scalar transformation of cardinal units, the units of measurement used for modeling are often inconsequential for single‐site econometric and welfare analysis. However, this seemingly inconsequential transformation can have significant implications for benefit transfer across sites—a simple observation that remains unacknowledged by the literature. This article provides a theoretical and empirical evaluation of variable measurement conventions within benefit transfer, deriving conditions under which different types of measurement scales are expected to enhance validity and reliability. Theoretical results are illustrated using an application of discrete choice experiments to coastal flood adaptation in two Connecticut (United States) communities. Empirical findings validate expectations from the theoretical model, suggesting that transfers over goods measured in relative units may often outperform transfers over goods measured in cardinal units. These findings imply that the outcome of benefit transfer convergent validity tests may hinge on whether goods are measured in cardinal or relative units.

Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB–expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB–expressing Tregs represents a strategy with potential activity across cancer types.

Many animals depend on the sense of vision for survival. In eumetazoans, vision requires specialized, light-sensitive cells called photoreceptors. Light reaches the photoreceptors and triggers the excitation of light-detecting proteins called opsins. Here, we describe the story of visual opsin evolution from the ancestral bilaterian to the extant vertebrate lineages. We explain the mechanisms determining color vision of extant vertebrates, focusing on opsin gene losses, duplications, and the expression regulation of vertebrate opsins. We describe the sequence variation both within and between species that has tweaked the sensitivities of opsin proteins towards different wavelengths of light. We provide an extensive resource of wavelength sensitivities and mutations that have diverged light sensitivity in many vertebrate species and predict how these mutations were accumulated in each lineage based on parsimony. We suggest possible natural and sexual selection mechanisms underlying these spectral differences. Understanding how molecular changes allow for functional adaptation of animals to different environments is a major goal in the field, and therefore identifying mutations affecting vision and their relationship to photic selection pressures is imperative. The goal of this review is to provide a comprehensive overview of our current understanding of opsin evolution in vertebrates.

Development is often driven by signaling and lineage-specific cues, yielding highly uniform and reproducible outcomes. Development also involves mechanisms that generate noise in gene expression and random patterns across tissues. Cells sometimes randomly choose between two or more cell fates in a mechanism called stochastic cell fate specification. This process diversifies cell types in otherwise homogenous tissues. Stochastic mechanisms have been extensively studied in prokaryotes where noisy gene activation plays a pivotal role in controlling cell fates. In eukaryotes, transcriptional repression stochastically limits gene expression to generate random patterns and specify cell fates. Here, we review our current understanding of repressive mechanisms that produce random patterns of gene expression and cell fates in flies, plants, mice, and humans.

Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). Here, we investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. We find that the ss locus is in a compact state in undifferentiated cells. An early enhancer drives ss transcription in all R7 precursors to open the ss locus. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives decompaction and then compaction represses transcription, controls stochastic cell fate specification.

This article discusses prospects and challenges related to the use of meta-regression models (MRMs) for ecosystem service benefit transfer, with an emphasis on validity criteria and post-estimation procedures given sparse attention in the ecosystem services literature. We illustrate these topics using a meta-analysis of willingness to pay for water quality changes that support aquatic ecosystem services and the application of this model to estimate water quality benefits under alternative riparian buffer restoration scenarios in New Hampshire's Great Bay Watershed. These illustrations highlight the advantages of MRM benefit transfers, together with the challenges and data needs encountered when quantifying ecosystem service values.

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement. V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.

Prioritising investments to minimise or mitigate natural hazards such as wildfires and storms is of increasing importance to hazard managers. Prioritisation of this type can be strengthened by considering benefit and cost impacts. To evaluate benefits and costs, managers require an understanding of both the tangible economic benefits and costs of mitigation decisions, and the often intangible values associated with environmental, social and health-related outcomes. We review the state of non-market valuation studies that provide monetary equivalent estimates for the intangible benefits and costs that can be affected by natural hazard events or their mitigation. We discuss whether managers can usefully call upon these available estimates, with a view to using the benefit transfer approach to include non-market values in economic decision frameworks. Additional context-specific non-market valuation studies are required to provide a more accurate selection of value estimates for natural hazard decision making. Decision making would benefit from considering these values explicitly in prioritising natural hazard investments.

Obtaining valid stated preference welfare estimates for changes in biophysical systems requires identification of the ecological endpoints valued by respondents. Challenges for scenario design can occur if endpoints differ across respondents, because it may be infeasible to provide scenario information on all possible endpoints. We explore an approach to choice experiments that tailors attributes to empirically identified population groups. Results suggest that different endpoints are relevant to different groups, and that one-size-fits-all scenarios common in the literature may not enable valid welfare estimation for all groups. These findings suggest that endpoint heterogeneity should be considered when designing valuation studies.

CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8+ T cell–dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNγ were also critical, and CD96-deficient CD8+ T cells promoted greater tumor control than CD96-sufficient CD8+ T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8+ T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti–PD-1 increased the percentage of IFNγ-expressing CD8+ T lymphocytes. Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8+ T cells and IFNγ. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8+ T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth.

Existing studies that estimate losses in home values due to being located in a designated flood zone, such as a Special Flood Hazard Area (SFHA) in the U.S., focus exclusively on either coastal or interior regions, or include both, but do not estimate separate risk effects. Using a rich data set on home sales for five counties in Connecticut, controlling for a plethora of potentially confounding effects, and applying state-of-the art doubly-robust matching methods, we show that SFHA-related risk losses can vary dramatically by location relative to the coast line, with near-coastal losses exceeding interior effects by sevenfold. We take this as evidence that home buyers hold beliefs of elevated flood risks in coastal zones, even though the official Flood Insurance Rate Map designation for those homes is identical to that of interior counterparts. To the extent that these beliefs align with objective risks, our results provide ammunition for calls for a more spatially refined rate setting policy for federal flood insurance.

An expanding literature addresses spatial dimensions related to the elicitation, estimation, interpretation and aggregation of stated preference (SP) welfare measures. Recognizing the relevance of spatial dimensions for SP welfare analysis and the breadth of associated scholarly work, this article reviews the primary methods, findings, controversies and frontiers in this important area of contemporary research. This review is grounded in a typology that characterizes analytical methods based on theoretical foundations and the type of statistical modelling applied. The resulting interpretive appraisal seeks to (1) summarize and contrast different theoretical arguments and points of departure within the spatial SP literature, (2) synthesize findings, insights and methods from the literature to promote a more holistic perspective on the treatment of spatial dimensions within SP welfare analysis, (3) evaluate and reconcile divergent approaches in terms of theoretical grounding, ability to identify relevant empirical effects, and relevance for SP valuation, and (4) discuss outstanding questions and research frontiers.

Trichromacy is unique to primates among mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similarM- andL-opsinmRNAs.M-opsin, but notL-opsin, was observed during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in theNR2F2gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.

Cones are the color-detecting photoreceptors of the vertebrate eye. Cones are specialized into subtypes whose functions are determined by the expression of color-sensitive opsin proteins. Organisms differ greatly in the number and patterning of cone subtypes. Despite these differences, thyroid hormone is an important regulator of opsin expression in most vertebrates. In this chapter, we outline how the timing of thyroid hormone signaling controls cone subtype fates during retinal development. We first examine our current understanding of cone subtype specification in model organisms and then describe advances in human stem cell-derived organoid technology that identified mechanisms controlling development of the human retina.

Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that produced from aDrosophilafemale germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combined histone labeling with DNA Oligopaints to distinguish old versus new histone distribution and visualize their inheritance patterns at single-gene resolution in asymmetrically dividing cellsin vivo. This strategy can be widely applied to other biological contexts involving cell fate establishment during development or tissue homeostasis in multicellular organisms.

Purpose: Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell–mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell–mediated tumor reactivity. Experimental Design: We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell–mediated cytotoxicity in vitro and in two mouse models. Results: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT− NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I–deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell–mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell–mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade. Conclusions: Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell–mediated destruction of MHC class I–deficient melanoma, which are refractory to CD8+ T-cell–mediated immunity. See related commentary by Pietra et al., p. 5274

This article summarizes the current state and future prospects for benefit transfer of environmental and resource values. Benefit transfer is the use of pre-existing empirical estimates from primary studies at one or more sites or contexts where research has been conducted to predict welfare estimates such as willingness to pay at other, typically unstudied sites or contexts. We orient the discussion around theory, methods and practice, focusing on progress, challenges and frontiers in the literature since the review of Johnston and Rosenberger (2010, Journal of Economic Surveys). The article begins with a brief history of benefit transfer and a summary of areas in which there is methodological consensus. It then presents questions regarding the approaches most likely to promote valid and reliable transfers, and recent research to address these questions. We conclude with an examination of the gap between research and practice, and a discussion of future prospects and research needs.

Stated preference analyses seeking to determine the public's value for air quality improvements often estimate willingness to pay (WTP) for days at a specified minimum quality threshold (e.g., days with clean air), but do not consider the temporal distribution of pollution levels below this threshold. This paper develops a choice experiment designed to evaluate WTP for a more complete distribution of air quality improvements, including the number of days per year at multiple air quality levels. The model is applied to a case study of air quality improvement in the core districts of Xi'an City, China. Results from a linearly constrained mixed logit model demonstrate that average household WTP for improving a lightly polluted, moderately polluted, heavily polluted, or severely polluted day to a clean air day is 7.42, 8.90, 13.06, and 24.28 RMB per year, respectively. These results show that WTP depends not only on the total number of clean air days, but on the total distribution of pollution levels across all days of the year. Results are directly relevant to the development of clean air policies in China, for which benefit estimates are currently unavailable.

The benefits of coastal adaptation depend on both the conservation of coastal assets and effects on other ecosystem services. Evaluating these benefits requires approaches that can disentangle valu...