RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ...ago, RAS inhibitors were so elusive that RAS was termed 'undruggable'. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRAS
, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.
Microplastics are ubiquitous contaminants in aquatic habitats globally, and wastewater treatment plants (WWTPs) are point sources of microplastics. Within aquatic habitats microplastics are colonized ...by microbial biofilms, which can include pathogenic taxa and taxa associated with plastic breakdown. Microplastics enter WWTPs in sewage and exit in sludge or effluent, but the role that WWTPs play in establishing or modifying microplastic bacterial assemblages is unknown. We analyzed microplastics and associated biofilms in raw sewage, effluent water, and sludge from two WWTPs. Both plants retained >99% of influent microplastics in sludge, and sludge microplastics showed higher bacterial species richness and higher abundance of taxa associated with bioflocculation (e.g. Xanthomonas) than influent microplastics, suggesting that colonization of microplastics within the WWTP may play a role in retention. Microplastics in WWTP effluent included significantly lower abundances of some potentially pathogenic bacterial taxa (e.g. Campylobacteraceae) compared to influent microplastics; however, other potentially pathogenic taxa (e.g. Acinetobacter) remained abundant on effluent microplastics, and several taxa linked to plastic breakdown (e.g. Klebsiella, Pseudomonas, and Sphingomonas) were significantly more abundant on effluent compared to influent microplastics. These results indicate that diverse bacterial assemblages colonize microplastics within sewage and that WWTPs can play a significant role in modifying the microplastic-associated assemblages, which may affect the fate of microplastics within the WWTPs and the environment.
Abstract
The ecological dynamics of microplastic (<5 mm) are well documented in marine ecosystems, but the sources, abundance, and ecological role of microplastic in rivers are unknown and likely to ...be substantial. Microplastic fibers (e.g., synthetic fabrics) and pellets (e.g., abrasives in personal care products) are abundant in wastewater treatment plant (
WWTP
) effluent, and can serve as a point source of microplastic in rivers. The buoyancy, hydrophobic surface, and long transport distance of microplastic make it a novel substrate for the selection and dispersal of unique microbial assemblages. We measured microplastic concentration and bacterial assemblage composition on microplastic and natural surfaces upstream and downstream of
WWTP
effluent sites at nine rivers in Illinois, United States. Microplastic concentration was higher downstream of
WWTP
effluent outfall sites in all but two rivers. Pellets, fibers, and fragments were the dominant microplastic types, and polymers were identified as polypropylene, polyethylene, and polystyrene. Mean microplastic flux was 1,338,757 pieces per day, although the flux was highly variable among nine sites (min = 15,520 per day, max = 4,721,709 per day). High‐throughput sequencing of 16S
rRNA
genes showed bacterial assemblage composition was significantly different among microplastic, seston, and water column substrates. Microplastic bacterial assemblages had lower taxon richness, diversity, and evenness than those on other substrates, and microplastic selected for taxa that may degrade plastic polymers (e.g.,
Pseudomonas
) and those representing common human intestinal pathogens (e.g.,
Arcobacter
). Effluent from
WWTP
s in rivers is an important component of the global plastic “life cycle,” and microplastic serves as a novel substrate that selects and transports distinct bacterial assemblages in urban rivers. Rates of microplastic deposition, consumption by stream biota, and the metabolic capacity of microplastic biofilms in rivers are unknown and merit further research.
Rivers are a major source of microplastic particles (<5 mm) to oceans, but empirical measurements of microplastic movement in freshwater ecosystems are rare. The hard, buoyant surface of microplastic ...is a novel habitat that selects for unique microbial assemblages in rivers, especially downstream of wastewater treatment plant (WWTP) point sources. We measured microplastic in surface water and benthic habitats 50 m upstream and 50, 305, 1115, and 1900 m downstream of the effluent outfall from a large WWTP in an urban river. We used high-throughput sequencing to measure bacterial assemblages on microplastic from surface and benthic habitats and compared them to bacterial assemblages from seston, water, and sediment. Concentrations of total microplastic and microplastic types (fragment, pellet) in surface water did not change with distance downstream of the WWTP. Thus, microplastic transport showed no net deposition or resuspension. Microplastic concentrations were much higher in the benthic zone than surface water. Benthic deposition appears to be a plastic sink over longer time scales, but subsequent studies are needed to resolve microplastic transport dynamics by particle type, size, and habitat. Composition of microplastic-attached bacterial assemblages differed from that of assemblages in water, seston, and sediment and supports domestic wastewater as a point source of microplastic (e.g., gastrointestinal taxa). Shifts in microplastic assemblages with distance from the WWTP suggest succession toward a ‘stream-like’ bacterial assemblage. Future studies are required to quantify the metabolic capacity of microplastic-associated bacteria. Estimates of transport distance, microplastic storage, and microbial interactions are critical to include lotic ecosystems in accountings of global plastic budgets.
Anthropogenic litter (AL; trash) in the environment is increasing and persistent. Rivers are considered a major source of AL to oceans, but AL ecology within rivers is rarely examined. Also, the ...rapidly developing field of AL research will benefit from fundamental approaches in community and ecosystem ecology. We adapted methods for communities of organisms and movement of organic matter to measure density, mass, assemblages, sources, and flux of AL in riparian and benthic zones at 15 sites in five rivers. We compared riverine AL density, mass, and assemblages to marine habitats worldwide. Benthic zones had greater AL mass and a different assemblage than riparian zones. Reach-scale metrics of human activity (e.g., parking spaces) explained more variation in AL assemblages than total urban land use. AL export was driven by material type and hydrology, and turnover time was ≤ 1 yr. Riparian AL density was similar to beaches, but benthic AL density was higher than marine benthic habitats. Finally, AL assemblages in river benthic and riparian zones were similar to assemblages at beaches rather than marine benthic habitats. AL is abundant and mobile in rivers, which show dynamic periods of AL retention and export. Rivers are likely sites of AL breakdown and burial, with significant biotic interactions which have not yet been studied. Comprehensive assessments of AL across ecosystems require continued adaptation of fundamental ecosystem and community ecology tools. Results will integrate riverine AL dynamics with the growing field of marine AL ecology, and inform management of global AL accumulations.
Understanding how nutrient limitation affects algal biomass and production is a long‐standing interest in aquatic ecology. Nutrients can influence these whole‐community characteristics through ...several mechanisms, including shifting community composition. Therefore, incorporating the joint responses of biomass, taxonomic composition, and production of algal communities, and relationships among them, is important for understanding effects of nutrient enrichment.
In shallow subarctic Lake Mývatn, Iceland, benthic algae compose a majority of whole‐lake primary production, support high secondary production, and influence nutrient cycling. Given the importance of these ecosystem processes, the factors that limit benthic algae have a large effect on the function and dynamics of the Mývatn system.
In a 33‐day nutrient enrichment experiment conducted in Lake Mývatn, we measured the joint responses of benthic algal biomass, primary production, and composition to nitrogen (N) and phosphorus (P) supplementation. We enriched N and P using nutrient‐diffusing agar overlain by sediment, with three levels of N and P that were crossed in a factorial design.
We found little evidence of community‐wide nutrient limitation, as chlorophyll‐a concentrations showed a negligible response to nutrients. Gross primary production (GPP) was unaffected by P and inhibited by N enrichment after 10 days, although the inhibitory effect of N diminished by day 33.
In contrast to biomass and primary production, community composition was strongly affected by N and marginally affected by P, with some algal groups increasing and others decreasing with enrichment. The taxa with the most negative and positive responses to N enrichment were Fragilariaceae and Scenedesmus, respectively.
The abundances of particular algal groups, based on standardised cell counts, were related to GPP measured at the end of the experiment. Oocystis was negatively associated with GPP but was unaffected by N or P, while Fragilariaceae and Scenedesmus were positively associated with GPP but had opposite responses to N. As a result, nutrient‐induced compositional shifts did not alter GPP.
Overall, our results show that nutrient enrichment can have large effects on algal community composition while having little effect on total biomass and primary production. Our study suggests that nutrient‐driven compositional shifts may not alter the overall ecological function of algal communities if (1) taxa have contrasting responses to nutrient enrichment but have similar effects on ecological processes, and/or (2) taxa that have strong influences on ecological function are not strongly affected by nutrients.
Competing species may show positive correlations in abundance through time and space if they rely on a shared resource. Such positive correlations might obscure resource partitioning that facilitates ...competitor coexistence. Here, we examine the potential for resource partitioning between two ecologically similar midge species (Diptera: Chironomidae) in Lake Mývatn, Iceland. Tanytarsus gracilentus and Chironomus islandicus show large, roughly synchronized population fluctuations, implying potential reliance on a shared fluctuating resource and thereby posing the question of how these species coexist at high larval abundances. We first considered spatial partitioning of larvae. Abundances of both species were positively correlated in space; thus, spatial partitioning across different sites in the lake did not appear to be strong. We then inferred differences in dietary resources with stable carbon isotopes. T. gracilentus larvae had significantly higher δ13C values than C. islandicus, suggesting interspecific differences in resource use. Differences in resource selectivity, tube-building behavior, and feeding styles may facilitate resource partitioning between these species. Relative to surface sediments, T. gracilentus had higher δ13C values, suggesting that they selectively graze on 13C-enriched resources such as productive algae from the surface of their tubes. In contrast, C. islandicus had lower δ13C values than surface sediments, suggesting reliance on 13C-depleted resources that may include detrital organic matter and associated microbes that larvae selectively consume from the sediment surface or within their burrow walls. Overall, our study illustrates that coexisting and ecologically similar species may show positive correlations in space and time while using different resources at fine spatial scales.Competing species may show positive correlations in abundance through time and space if they rely on a shared resource. Such positive correlations might obscure resource partitioning that facilitates competitor coexistence. Here, we examine the potential for resource partitioning between two ecologically similar midge species (Diptera: Chironomidae) in Lake Mývatn, Iceland. Tanytarsus gracilentus and Chironomus islandicus show large, roughly synchronized population fluctuations, implying potential reliance on a shared fluctuating resource and thereby posing the question of how these species coexist at high larval abundances. We first considered spatial partitioning of larvae. Abundances of both species were positively correlated in space; thus, spatial partitioning across different sites in the lake did not appear to be strong. We then inferred differences in dietary resources with stable carbon isotopes. T. gracilentus larvae had significantly higher δ13C values than C. islandicus, suggesting interspecific differences in resource use. Differences in resource selectivity, tube-building behavior, and feeding styles may facilitate resource partitioning between these species. Relative to surface sediments, T. gracilentus had higher δ13C values, suggesting that they selectively graze on 13C-enriched resources such as productive algae from the surface of their tubes. In contrast, C. islandicus had lower δ13C values than surface sediments, suggesting reliance on 13C-depleted resources that may include detrital organic matter and associated microbes that larvae selectively consume from the sediment surface or within their burrow walls. Overall, our study illustrates that coexisting and ecologically similar species may show positive correlations in space and time while using different resources at fine spatial scales.
Ecosystem engineers have large impacts on the communities in which they live, and these impacts may feed back to populations of engineers themselves. In this study, we assessed the effect of ...ecosystem engineering on density-dependent feedbacks for midges in Lake Myvatn, Iceland. The midge larvae reside in the sediment and build silk tubes that provide a substrate for algal growth, thereby elevating benthic primary production. Benthic algae are in turn the primary food source for the midge larvae, setting the stage for the effects of engineering to feed back to the midges themselves. Using a field mesocosm experiment manipulating larval midge densities, we found a generally positive but nonlinear relationship between density and benthic production. Furthermore, adult emergence increased with the primary production per midge larva. By combining these two relationships in a simple model, we found that the positive effect of midges on benthic production weakened negative density dependence at low to intermediate larval densities. However, this benefit disappeared at high densities when midge consumption of primary producers exceeded their positive effects on primary production through ecosystem engineering. Our results illustrate how ecosystem engineering can alter density-dependent feedbacks for engineer populations.
Population cycles can be caused by consumer–resource interactions. Confirming the role of consumer–resource interactions, however, can be challenging due to an absence of data for the resource ...candidate. For example, interactions between midge larvae and benthic algae likely govern the high‐amplitude population fluctuations of Tanytarsus gracilentus in Lake Mývatn, Iceland, but there are no records of benthic resources concurrent with adult midge population counts. Here, we investigate consumer population dynamics using the carbon stable isotope signatures of archived T. gracilentus specimens collected from 1977 to 2015, under the assumption that midge δ13C values reflect those of resources they consumed as larvae. We used the time series for population abundance and δ13C to estimate interactions between midges and resources while accounting for measurement error and possible preservation effects on isotope values. Results were consistent with consumer–resource interactions: high δ13C values preceded peaks in the midge population, and δ13C values tended to decline after midges reached high abundance. One interpretation of this dynamic coupling is that midge isotope signatures reflect temporal variation in benthic algal δ13C values, which we expected to mirror primary production. Following from this explanation, high benthic production (enriched δ13C values) would contribute to increased midge abundance, and high midge abundance would result in declining benthic production (depleted δ13C values). An additional and related explanation is that midges deplete benthic algal abundance once they reach peak densities, causing midges to increase their relative reliance on other resources including detritus and associated microorganisms. Such a shift in resource use would be consistent with the subsequent decline in midge δ13C values. Our study adds evidence that midge–resource interactions drive T. gracilentus fluctuations and demonstrates a novel application of stable isotope time‐series data to understand consumer population dynamics.
Pulsed fluxes of organisms across ecosystem boundaries can exert top-down and bottom-up effects in recipient food webs, through both direct effects on the subsidized trophic levels and indirect ...effects on other components of the system. While previous theoretical and empirical studies demonstrate the influence of allochthonous subsidies on bottom-up and topdown processes, understanding how these forces act in conjunction is still limited, particularly when an allochthonous resource can simultaneously subsidize multiple trophic levels. Using the Lake Mývatn region in Iceland as an example system of allochthony and its potential effects on multiple trophic levels, we analyzed a mathematical model to evaluate how pulsed subsidies of aquatic insects affect the dynamics of a soil–plant–arthropod food web. We found that the relative balance of top-down and bottom-up effects on a given food web compartment was determined by trophic position, subsidy magnitude, and top predators’ ability to exploit the subsidy. For intermediate trophic levels (e.g., detritivores and herbivores), we found that the subsidy could either alleviate or intensify top-down pressure from the predator. For some parameter combinations, alleviation and intensification occurred sequentially during and after the resource pulse. The total effect of the subsidy on detritivores and herbivores, including topdown and bottom-up processes, was determined by the rate at which predator consumption saturated with increasing size of the allochthonous subsidy, with greater saturation leading to increased bottom-up effects. Our findings illustrate how resource pulses to multiple trophic levels can influence food web dynamics by changing the relative strength of bottom-up and top-down effects, with bottom-up predominating top-down effects in most scenarios in this subarctic system.
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