Population Niche Research Articles

Checkpoint inhibitors first in patients with metastatic non-small cell lung cancer harboring BRAFV600E mutation with PD-L1 90%—a debate in a niche population

Checkpoint inhibitors first in patients with metastatic non-small cell lung cancer harboring BRAFV600E mutation with PD-L1 90%—a debate in a niche population

Abstract IA38: Defining lymphoma reservoirs: Clues from the genomics

Abstract Large-scale technology and advanced computational analyses have revolutionized our understanding of the genomic underpinnings of lymphoma subtypes across the board, providing near-complete genomic encyclopedias. A characteristic feature of indolent lymphomas is their propensity to initially respond to therapeutic intervention, only to subsequently relapse or transform to a more aggressive lymphoma at a later stage. As a consequence, the population disease burden remains significant as, for the majority, their lymphomas are incurable. There is growing evidence that persisting cancer-repopulating cells act as lymphoma reservoirs and are the harbingers for lymphoma recurrence and therapy resistance. Follicular lymphoma (FL) is the best studied of the indolent B-cell lymphomas and represents a tractable model system given its protracted clinical course. The evidence for the existence of a tumor-propagating reservoir in FL (referred to as the common precursor cell, CPC) has primarily arisen from genetic studies in two key areas. The first are unique cases of donor-derived lymphomas, where both donor and recipient of stem cell transplants develop clonally related FL several years later, suggesting precursor cells were transferred at the time of the transplantation. The second include studies of temporal genetic profiling of sequential diagnostic, relapsed, and transformed FL (tFL) tumors from the same individual, undertaken by us and others more recently using higher-resolution next-generation sequencing. This has allowed us to infer the genetic composition of these putative ancestral or reservoir populations and indeed determine that epigenetic alterations such as mutations in the histone-modifying enzymes, CREBBP and KMT2D, represent early lymphoma-initiating events. Recent genomic studies in histologically related entities such as pediatric-type FL and in situ follicular neoplasia (ISFN) have provided further clues to the relevance of the genetic events. A number of crucial questions remain: What is the exact origin, phenotype, and niche of these reservoir populations, and do particular patient-specific niches promote a degree of dormancy and continued molecular evolution of these lymphoma reservoirs? Capturing the characteristics and behavior of these reservoir populations in FL has the potential to reveal novel biomarkers and facilitate new approaches to measuring, monitoring, and tracking this population. Furthermore, defining the characteristics of these populations would allow the generation of murine models that more suitably recapitulate this disease state, providing a resource to guide and test rational novel therapies. In conclusion, we now have early insights into the genetic fingerprints of these persisting tumor-propagating reservoir populations. Targeting these populations, perceived as the “root'' of the cancer, may provide our best chance of preventing relapse and realizing a cure for FL. Citation Format: Jessica Okosun. Defining lymphoma reservoirs: Clues from the genomics [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA38.

Seasonality and interspecific competition shape individual niche variation in co‐occurring tetra fish in Neotropical streams

AbstractThe drivers of intraspecific niche variation and its effects on species interactions are still unclear, especially in species‐rich Neotropical environments. Here, we investigated how ecological opportunity and interspecific competition affect the degree of individual trophic specialization and the population niche breadth in tetra fish. We studied the four ecologically similar species (Psalidodon aff. gymnodontus, P. aff. paranae, P. bifasciatus, and Bryconamericus ikaa) in subtropical headwater streams (three sites with two co‐occurring species and three sites with only one species). We sampled fish in two contrasting seasons (winter/dry and summer/wet) and quantified their trophic niches using gut content analysis. Psalidodon bifasciatus was the only species distributed over all the sampled streams. We observed seasonal differences in population trophic niche breadth of P. bifasciatus just when this species co‐occurred with P. aff. gymnodontus. These findings confirm the complex nature of the effects of interspecific competition, depending, for instance, on the identity of the competitor. The degree of individual specialization of P. bifasciatus was higher in the winter, and it was not influenced by the presence of another species. Conversely, the other two Psalidodon species studied presented greater individual specialization in the summer, when fish consumed a higher proportion of allochthonous items (terrestrial insects and seeds), and there were no effects only for B. ikaa. Herein, our results suggest that seasonality in food‐resource availability is a major driver of niche variation and it has the potential to play an important role in how these similar tetra species interact and coexist.Abstract in Portuguese is available with online material.

Individual specialization in the use of space by frugivorous bats.

Natural populations are not homogenous systems but sets of individuals that occupy subsets of the species' niche. This phenomenon is known as individual specialization. Recently, several studies found evidence of individual specialization in animal diets. Diet is a critical dimension of a species' niche that affects several other dimensions, including space use, which has been poorly studied under the light of individual specialization. In this study, which harnesses the framework of the movement ecology paradigm and uses yellow-shouldered bats Sturnira lilium as a model, we ask how food preferences lead individual bats of the same population to forage mainly in different locations and habitats. Ten individual bats were radiotracked in a heterogeneous Brazilian savanna. First, we modelled intraspecific variation in space use as a network of individual bats and the landscape elements visited by them. Second, we developed two novel metrics, the spatial individual specialization index (SpatIS) and the spatial individual complementary specialization index (SpatICS). Additionally, we tested food-plant availability as a driver of interindividual differences in space use. There was large interindividual variation in space use not explained by sex or weight. Our results point to individual specialization in space use in the studied population of S. lilium, most probably linked to food-plant distribution. Individual specialization affects not only which plant species frugivores consume, but also the way they move in space, ultimately with consequences for seed dispersal and landscape connectivity.

The dynamic trophic niche of an island bird of prey.

Optimal foraging theory predicts an inverse relationship between the availability of preferred prey and niche width in animals. Moreover, when individuals within a population have identical prey preferences and preferred prey is scarce, a nested pattern of trophic niche is expected if opportunistic and selective individuals can be identified. Here, we examined intraspecific variation in the trophic niche of a resident population of striated caracara (Phalcoboenus australis) on Isla de los Estados (Staten Island), Argentina, using pellet and stable isotope analyses. While this raptor specializes on seabird prey, we assessed this population's potential to forage on terrestrial prey, especially invasive herbivores as carrion, when seabirds are less accessible. We found that the isotopic niche of this species varies with season, age, breeding status, and, to a lesser extent, year. Our results were in general consistent with classic predictions of the optimal foraging theory, but we also explore other possible explanations for the observed pattern. Isotopic niche was broader for groups identified a priori as opportunistic (i.e., nonbreeding adults during the breeding season and the whole population during the nonbreeding season) than it was for individuals identified a priori as selective. Results suggested that terrestrial input was relatively low, and invasive mammals accounted for no more than 5% of the input. The seasonal pulse of rockhopper penguins likely interacts with caracara's reproductive status by constraining the spatial scale on which individuals forage. Niche expansion in spatially flexible individuals did not reflect an increase in terrestrial prey input; rather, it may be driven by a greater variation in the types of marine prey items consumed.

Wild guanacos as scapegoat for continued overgrazing by livestock across southern Patagonia

Abstract In a recently published paper, Oliva et al. concluded that domestic grazing pressure across Patagonian rangelands approached carrying capacity due to decades of stock adjustment, but that guanaco overpopulation may have altered that balance. The authors argued that unless guanaco numbers are controlled, they will reduce forage available for domestic stock and will negatively affect rangelands. We consider that the herbivore‐stock analysis presented is inaccurate and deserves revision, and that the stated conclusions lack empirical support. When the spatial distribution of herbivores is accounted for in the Oliva et al. analysis, domestic stock is far above carrying capacity, indicating that domestic overgrazing continues. Theoretical and empirical evidence on bottom‐up regulation and competitive exclusion challenges the supposed guanaco overpopulation and the hypothetical reduction of forage available for livestock. Even if guanaco numbers are reduced, grassland degradation and production losses will continue because their main drivers, domestic overstock and heterogeneous grazing, are still operating. Synthesis and applications. Oversimplified models with poor ecological insight can lead to erroneous conclusions and misguide management decisions. The incorrect inference that Patagonian domestic stock is adjusted to carrying capacity could help to consolidate current domestic overgrazing by reducing incentives to improve livestock management practices. Regarding guanacos, a controversial species in an unfavourable context, control‐oriented harvest without a clear justification threatens populations’ viability and genuine attempts of productive diversification. Addressing relevant ecological processes, such as niche partitioning, competitive exclusion and population regulation, is essential to correctly assess joint carrying capacity in multi‐herbivore systems, as well as to identify the true factors driving degradation processes and to optimize rangeland use on a sustainable basis.

Wildfire and the ecological niche: Diminishing habitat suitability for an indicator species within semi-arid ecosystems.

Globally accelerating frequency and extent of wildfire threatens the persistence of specialist wildlife species through direct loss of habitat and indirect facilitation of exotic invasive species. Habitat specialists may be especially prone to rapidly changing environmental conditions because their ability to adapt lags behind the rate of habitat alteration. As a result, these populations may become increasingly susceptible to ecological traps by returning to suboptimal breeding habitats that were dramatically altered by disturbance. We demonstrate a multistage modeling approach that integrates habitat selection and survival during the key nesting life‐stage of a bird species of high conservation concern, the greater sage‐grouse (Centrocercus urophasianus; hereafter, sage‐grouse). We applied these spatially explicit models to a spatiotemporally robust dataset of sage‐grouse nest locations and fates across wildfire‐altered sagebrush ecosystems of the Great Basin ecoregion, western United States. Female sage‐grouse exhibited intricate habitat selection patterns that varied across regional gradients of ecological productivity among sagebrush communities, but often selected nest sites that disproportionately resulted in nest failure. For example, 23% of nests occurred in wildfire‐affected habitats characterized by reduced sagebrush cover and greater composition of invasive annual grasses. We found survival of nests was negatively associated with wildfire‐affected areas, but positively associated with higher elevations with increased ruggedness and overall shrub cover. Strong site fidelity likely drove sage‐grouse to continue nesting in habitats degraded by wildfire. Hence, increasing frequency and extent of wildfire may contribute disproportionately to reduced reproductive success by creating ecological traps that act as population sinks. Identifying such habitat mismatches between selection and survival facilitates deeper understanding of the mechanisms driving reduced geographic niche space and population decline at broad spatiotemporal scales, while guiding management actions to areas that would be most beneficial to the species.

Beyond ecological opportunity: Prey diversity rather than abundance shapes predator niche variation

AbstractEcological opportunity (i.e. the diversity of available resources) has a pivotal role in shaping niche variation and trophic specialisation of animals. However, ecological opportunity can be described with regard to both diversity and abundance of resources. The degree to which these two components contribute to niche variation remains unexplored.To address this, we used an extensive dataset on fish diet and benthic invertebrate diversity and density from 73 sampling events in three Norwegian rivers in order to explore realised trophic niches and the response of dietary niche variation along gradients of resource diversity (potential trophic niches), resource density (as a proxy of resource abundance) and fish density (as a proxy of inter‐ and intra‐specific competition) in a freshwater top predator (the brown trout,Salmo truttaL.).Linear models indicated that individual and population niche variation increased with increasing ecological opportunity in terms of prey diversity. However, no simple cause‐and‐effect associations between niche indices and prey abundance were found. Our multiple regression analyses indicated that the abundance of certain resources (e.g. Chironomidae) can interact with prey diversity to determine individual and population realised trophic niches. Niche variation (within‐individual component and inter‐individual diet variation) decreased with increasing inter‐ and intra‐specific competition.This study extends prevailing trophic ecology theory by identifying diversity, rather than density, of available prey resources as a primary driver of niche variation in fish of temperate riverine systems with no extensive resource limitation. The study also shows that ecological opportunity may mask the direction of the effect (compression or expansion) of competition on niche variation when food resources are diverse.Our study provides novel empirical insight to the driving forces behind niche variation and reveals that diversity, rather than density, of available prey resources may be a primary driver of niche variation in freshwater fish. Our study supports the view that a broader potential trophic niche promotes broader realised trophic niche variation by individuals, which leads to individual niche diversification by opening access to alternatives resources, resulting in a concomitant rise in the realised trophic niche width of the population.

Distribution of the European turtle dove (Streptopelia turtur) at the edge of the South-Western Palaearctic: transboundary differences and conservation prospects

The European turtle dove (Streptopelia turtur) is classified as vulnerable by the IUCN. In this context, it is important to explore the factors affecting its abundance and the ways in which it can be effectively managed for conservation. This study compares the distribution of this dove in Spain and Morocco. These countries, which are separated by the Strait of Gibraltar, are each occupied by a different subspecies (i.e. Streptopelia turtur turtur in Spain and S. t. arenicola in Morocco) that may be adapted to different environmental conditions. Such differentiation could result in differences in the species’ abundance between the two countries. The occurrence of this dove was assessed by means of road counts, and the resulting records were used to explore the niche overlap between the two subspecies. The niches of both populations overlapped, suggesting the selection of similar environmental conditions in the two countries. However, the species occurred more frequently in Morocco than in Spain. To study the potential role of local effects on the observed differences in abundance, 494 sampling points were surveyed in four different sectors of Spain and Morocco. These additional counts indicated that, after controlling for the effect of local habitat structure and climate, the European turtle dove is more frequent in Morocco than in Spain. Differences between the two countries, in relation to hunting pressure, agricultural intensification and the abandonment of marginal cultures and woodlands, could account for the observed transboundary differences in the abundance of European turtle dove and help to explain its severe decline in Spain.

Phylogenomic approaches reveal how climate shapes patterns of genetic diversity in an African rain forest tree species.

The world's second largest expanse of tropical rainforest is in Central Africa, and it harbours enormous species diversity. Population genetic studies have consistently revealed significant structure across Central African rainforest plants. In particular, previous studies have repeatedly demonstrated a north-south genetic discontinuity around the equatorial line, in a continuous expanse of rainforest where a climatic inversion is documented. Here, we took a phylogeographic approach by sequencing 351 nuclear markers in 112 individuals across the distribution of the African rainforest tree species Annickia affinis (Annonaceae). We showed for the first time that the north-south divide is the result of a single, major colonization event across the climatic inversion from an ancestral population located in Gabon. We suggested that differences in ecological niche of populations located on either side of this inversion may have contributed to this phylogenetic discontinuity. We found evidence for inland dispersal, predominantly in northern areas, and variable demographic histories among genetic clusters, indicating that populations responded differently to past climate change. We show how newly developed genomic tools can provide invaluable insights into our understanding of tropical rainforest evolutionary dynamics.

Learning machine approach reveals microbial signatures of diet and sex in dog.

The characterization of the microbial population of many niches of the organism, as the gastrointestinal tract, is now possible thanks to the use of high-throughput DNA sequencing technique. Several studies in the companion animals field already investigated faecal microbiome in healthy or affected subjects, although the methodologies used in the different laboratories and the limited number of animals recruited in each experiment does not allow a straight comparison among published results. In the present study, we report data collected from several in house researches carried out in healthy dogs, with the aim to seek for a variability of microbial taxa in the faeces, caused by factors such as diet and sex. The database contains 340 samples from 132 dogs, collected serially during dietary intervention studies. The procedure of samples collection, storage, DNA extraction and sequencing, bioinformatic and statistical analysis followed a standardized pipeline. Microbial profiles of faecal samples have been analyzed applying dimensional reduction discriminant analysis followed by random forest analysis to the relative abundances of genera in the feces as variables. The results supported the responsiveness of microbiota at a genera taxonomic level to dietary factor and allowed to cluster dogs according this factor with high accuracy. Also sex factor clustered dogs, with castrated males and spayed females forming a separated group in comparison to intact dogs, strengthening the hypothesis of a bidirectional interaction between microbiota and endocrine status of the host. The findings of the present analysis are promising for a better comprehension of the mechanisms that regulate the connection of the microorganisms living the gastrointestinal tract with the diet and the host. This preliminary study deserves further investigation for the identification of the factors affecting faecal microbiome in dogs.

Isotopic niche of the American pika (Ochotona princeps) through space and time

Anthropogenic climate change is influencing the ecology and distribution of animals. The American pika (Ochotona princeps (Richardson, 1828)) is considered a model species for studying the effects of climate on small alpine mammals and has experienced local extirpation across its range. Using stable isotope analysis of two seasonal molts and bone collagen, we characterize the isotopic carbon and nitrogen niche of pika populations across their range and through time. We find pika isotopic diet to be stable across both time and space compared with other animals and considering the geographic and environmental extent of their range. We find that climatic, not geographic, factors explain part of the isotopic variation across their range. Both δ13C and δ15N from the fall-onset molt decrease with relative humidity of the environment and δ15N values from bone collagen increase with temperature and precipitation. We find a small but significant seasonal difference in δ13C, which could be explained by microbial enrichment of cached haypiles. We establish a baseline of pika isotopic diet and patterns related to climate across their range. We conclude that differences in isotopic signature between pika populations likely reflect the physiology of their forage plants in different environmental conditions.

Classification of 16S rRNA reads is improved using a niche-specific database constructed by near-full length sequencing.

Surveys of microbial populations in environmental niches of interest often utilize sequence variation in the gene encoding the ribosomal small subunit (the 16S rRNA gene). Generally, these surveys target the 16S genes using semi-degenerate primers to amplify portions of a subset of bacterial species, sequence the amplicons in bulk, and assign to putative taxonomic categories by comparison to databases purporting to connect specific sequences in the main variable regions of the gene to specific organisms. Due to sequence length constraints of the most popular bulk sequencing platforms, the primers selected amplify one to three of the nine variable regions, and taxonomic assignment is based on relatively short stretches of sequence (150–500 bases). We demonstrate that taxonomic assignment is improved through reduced unassigned reads by including a survey of near-full-length sequences specific to the target environment, using a niche of interest represented by the upper respiratory tract (URT) of cattle. We created a custom Bovine URT database from these longer sequences for assignment of shorter, less expensive reads in comparisons of the upper respiratory tract among individual animals. This process improves the ability to detect changes in the microbial populations of a given environment, and the accuracy of defining the content of that environment at increasingly higher taxonomic resolution.

Path Planning of Coastal Tourism Based on the Improved Firefly Algorithm

Zhou, X., 2020. Path planning of coastal tourism based on the improved firefly algorithm. In: Gong, D.; Zhang, M., and Liu, R. (eds.), Advances in Coastal Research: Engineering, Industry, Economy, and Sustainable Development. Journal of Coastal Research, Special Issue No. 106, pp. 263–266. Coconut Creek (Florida), ISSN 0749-0208.To optimize the path of coastal tourism, a niche firefly algorithm (NFA) is proposed. First, according to the characteristics of environment, a reasonable path-planning model is established, and the objective function of the firefly algorithm (FA) is set as moving steps. It has redesigned the brightness formula, initialization method, and firefly movement mode. Second, on the basis of the FA, the introduction of niche technology needs to join the shared information among niche populations. Simulation experiments show that NFA can get several optimal operations compared with FA; the average number of moving steps decreased by 7.14%, and the objective function of NFA decreased by 6.76%. The average value of firefly brightness has increased by 8.33%. Compared with the genetic algorithm, NFA's moving steps have decreased by 7.14%, and the mean of objective function decreased by 9.79%. The results show that NFA is better in algorithm performance.

The effects of phenotypic plasticity on the fixation probability of mutant cancer stem cells

The cancer stem cell hypothesis claims that tumor growth and progression are driven by a (typically) small niche of the total cancer cell population called cancer stem cells (CSCs). These CSCs can go through symmetric or asymmetric divisions to differentiate into specialised, progenitor cells or reproduce new CSCs. While it was once held that this differentiation pathway was unidirectional, recent research has demonstrated that differentiated cells are more plastic than initially considered. In particular, differentiated cells can de-differentiate and recover their stem-like capacity. Two recent papers have considered how this rate of plasticity affects the evolutionary dynamic of an invasive, malignant population of stem cells and differentiated cells into existing tissue (Mahdipour-Shirayeh et al., 2017; Wodarz, 2018). These papers arrive at seemingly opposing conclusions, one claiming that increased plasticity results in increased invasive potential, and the other that increased plasticity decreases invasive potential. Here, we show that what is most important, when determining the effect on invasive potential, is how one distributes this increased plasticity between the compartments of resident and mutant-type cells. We also demonstrate how these results vary, producing non-monotone fixation probability curves, as inter-compartmental plasticity changes when differentiated cell compartments are allowed to continue proliferating, highlighting a fundamental difference between the two models. We conclude by demonstrating the stability of these qualitative results over various parameter ranges. Keywords: cancer stem cells, plasticity, de-differentiation, fixation probability.

Sociodemographic management indicators of the state of the economy (a case study of Russian statistics)

PurposeThe purpose of this research is to relate the pattern of economic growth with demographic data based on the natural population changes.Design/methodology/approachThe methodological foundation of this research consists in the structural and functional approach to the comprehension of the social system, methods of mathematical simulation of the dynamics of expansion and extension of the ecological niche of population and methodologies that are currently used for calculation of gross domestic product (GDP).FindingsThe research finding consists in the development of the theory of social evolution in the form of horizontal and vertical social differentiation, which is conditional upon the growing production of the excess product, which leads to the simulation of relation between the natural population changes and the production of GDP, expanding the boundaries of the ecological niche.Research limitations/implicationsThe relevance of the problem under study is driven by the need for theoretic interpretation of interrelation between the pattern of economic growth and demographic data based on the natural population changes.Originality/valueThe research leads us to the conclusion that there is a functional (for closed societies) and correlative (for open societies) relationship between the GDP growth and natural population changes with the property that the positive or negative population growth depends on the quantity of the total consumed costs (TCC) and its critical values.

Inferring Gene Networks in Bone Marrow Hematopoietic Stem Cell-Supporting Stromal Niche Populations.

SummaryThe cardinal property of bone marrow (BM) stromal cells is their capacity to contribute to hematopoietic stem cell (HSC) niches by providing mediators assisting HSC functions. In this study we first contrasted transcriptomes of stromal cells at different developmental stages and then included large number of HSC-supportive and non-supportive samples. Application of a combination of algorithms, comprising one identifying reliable paths and potential causative relationships in complex systems, revealed gene networks characteristic of the BM stromal HSC-supportive capacity and of defined niche populations of perivascular cells, osteoblasts, and mesenchymal stromal cells. Inclusion of single-cell transcriptomes enabled establishing for the perivascular cell subset a partially oriented graph of direct gene-to-gene interactions. As proof of concept we showed that R-spondin-2, expressed by the perivascular subset, synergized with Kit ligand to amplify ex vivo hematopoietic precursors. This study by identifying classifiers and hubs constitutes a resource to unravel candidate BM stromal mediators.

Hybridization Between Yuccas From Baja California: Genomic and Environmental Patterns.

Hybridization can occur when two geographically isolated species are reproductively compatible and have come into sympatry due to range shifts. Yucca and yucca moths exhibit obligate pollination mutualism; yucca moths are responsible for the gene flow mediated by pollen among yucca populations. In the Baja California Peninsula, there are two yucca sister species, Y. capensis and Y. valida, that have coevolved with the same pollinator, Tegeticula baja. Both yucca species are endemic to the peninsula, and their current distributions are allopatric. Based on their morphological characteristics, it has been suggested that some plants growing in the southern part of the Magdalena flatland, a spatially disjunct part of Yucca valida’s range, have hybrid origins. We conducted genomic and climatic analyses of the two yucca species as well as the putative hybrid populations. We genotyped 3,423 single nucleotide polymorphisms in 120 individuals sampled from 35 localities. We applied Bayesian tests and geographic cline analyses to the genomic data. Using climatic information from the occurrence sites, we projected species distribution models in different periods to assess changes in the distributional range, and we performed a statistical test to define the niche divergence between the paternal species and the putative hybrid populations. Structure analysis revealed mixed ancestry in the genome of hybrid populations, and the Bayesian models supported a scenario of post-divergence gene flow between the yucca species. Our species distribution models reveal that the geographical ranges of the parental species overlapped mainly during the Last Glacial Maximum, which could facilitate genetic admixture between those species. Finally, we found that most of the assessed environmental axes between the parents and hybrid populations are divergent, indicating that the climatic niche of the hybrid populations is shifting from that of the populations’ progenitors. Our results show that the populations in the southern part of the Magdalena flatland are the result of combination of the genetic components of two species. Hybrid individuals with this novel genomic combination arose in a different habitat than their parental species, and they exhibit ecological divergence, which contributes to reproductive isolation through spatial and temporal barriers.

Shifting clinical trial and value demonstration models for cell and gene therapies: present & future critical success factors

Background & Aim Clinical trial models have been changing over the past decade, influenced by emergence of innovative technologies, increasing focus on subgroups and niche populations, competition over patients, and need to capture transformative health outcomes. Approximately half of rare disease and oncology therapies today are launched from fast-track pathways with a single-arm study, creating challenges in shaping a comprehensive value proposition sufficient to meet the needs of clinicians, regulators and payers. In addition, uncertainties remain around demonstration of transformative magnitude, duration and patient-centric effects, which require strong data-analytic and real-world evidence development strategies. This session will discuss how the evolution of clinical trial models is shifting us towards requirements to consider a comprehensive approach to value demonstration that meets provider, regulator, payer decision needs. Methods, Results & Conclusion Mr. Faulkner will open the session by reviewing key clinical design issues in cell and gene therapy trials and common gaps that must be filled outside the trial, including leveraging outcomes research and real-world evidence solutions, highlighting recent global research on cell and gene therapy regulatory and HTA decisions in North America and the EU. Dr. Theocharous will consider key clinical trial design and execution best practices from a manufacturer perspective, drawing from common development challenges, and Dr. Koh will compliment this with clinical trial and patient treatment considerations from the perspective of a practicing physician executing cell and gene therapies in the field. Mr. Morgese will discuss recent US and EU policy issues that flow from cell and gene therapy evidence issues and highlight steps that the cell and gene therapy community are taking to address. The panel will debate the top critical success factors necessary for linking clinical trial designs to other gap-fill strategies to meet downstream approval, access and uptake requirements.

Morphological variation associated with trophic niche expansion within a lake population of a benthic fish

Ecological theory suggests that generalist species should have traits with multiple adaptive peaks. Consequently, in heterogeneous environments such adaptive landscapes may lead to phenotypic divergence that becomes fixed in populations via reproductive isolation, thus driving speciation. However, contrary to this expectation, the process of ecological diversification in wild populations is not always associated with obvious trait divergence and reproductive isolation due to some ecological and geographic constrains. To examine the ecological conditions that promote (or inhibit) divergence is quite important to improve our understanding of the underlying mechanisms. Here we examine how the patterns of trait variation (divergence/non-divergence) are determined in relation to ecological niche expansion and gene flow using a benthic fish, Pseudogobio esocinus, in the Lake Biwa system, Japan. The fish exhibited various patterns of morphological variation in mouth parts among populations. Lake fish tended to have a smaller mouth compared with river fish and also showed remarkable individual variations within some local samples. Lake fish utilized chironomid larvae as the primary prey, as in riverine fish. But, fish with smaller and narrower mouths utilized significantly higher proportions of amphipods (a novel prey unique to the lake) as their secondary prey. Microsatellite analysis detected no genetic structuring in the Lake Biwa catchment, suggesting no reproductive separation among eco-morphologically divergent individuals. Our results exemplify population niche expansion associated with continuous eco-morphological variation without divergence, and provide insights into the role of non-discrete diversification for thriving in heterogeneous environments.