Plant size-dependent influence of foliar fungal pathogens promotes diversity through allometric growth.

The effect of pathogens on host diversity has attracted much attention in recent years, yet how the influence of pathogens on individual plants scales up to affect community-level host diversity remains unclear. Here, we assessed the effects of foliar fungal pathogens on plant growth and species richness using allometric growth theory in population-level and community-level foliar fungal pathogen exclusion experiments. We calculated growth scaling exponents of 24 species to reveal the intraspecific size-dependent effects of foliar fungal pathogens on plant growth. We also calculated the intercepts to infer the growth rates of relatively larger conspecific individuals. We found that foliar fungal pathogens inhibited the growth of small conspecific individuals more than large individuals, resulting in a positive allometric growth. After foliar fungal pathogen exclusion, species-specific growth scaling exponents and intercepts decreased, but became positively related to species' relative abundance, providing a growth advantage for individuals of abundant species with a higher growth scaling exponent and intercept compared with rare species, and thus reduced species diversity. By adopting allometric growth theory, we elucidate the size-dependent mechanisms through which pathogens regulate species diversity and provide a powerful framework to incorporate antagonistic size-dependent processes in understanding species coexistence.

Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases.

The cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway is an emerging therapeutic target for the prophylaxis and therapy of a variety of diseases, ranging from cancer, infectious diseases, to autoimmune disorders. As a cytosolic double stranded DNA (dsDNA) sensor, cGAS can bind with relatively long dsDNA, resulting in conformational change and activation of cGAS. Activated cGAS catalyzes the conversion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) into cGAMP, a cyclic dinucleotide (CDN). CDNs, including 2'3'-cGAMP, stimulate adapter protein STING on the endoplasmic membrane, triggering interferon regulatory factor 3 (IRF3) phosphorylation and nuclear factor kappa B (NF-κB) activation. This results in antitumor and antiviral type I interferon (IFN-I) responses. Moreover, cGAS-STING overactivation and the resulting IFN-I responses have been associated with a number of inflammatory and autoimmune diseases. This makes cGAS-STING appealing immunomodulatory targets for the prophylaxis and therapy of various related diseases. However, drug development of CDNs and CDN derivatives is challenged by their limited biostability, difficult formulation, poor pharmacokinetics, and inefficient tissue accumulation and cytosolic delivery. Though recent synthetic small molecular CDN- or non-CDN-based STING agonists have been reported with promising preclinical therapeutic efficacy, their therapeutic efficacy and safety remain to be fully evaluated preclinically and clinically. Therefore, it is highly desirable and clinically significant to advance drug development for cGAS-STING activation by innovative approaches, such as drug delivery systems and drug development for pharmacological immunomodulation of cGAS. In this Account, we summarize our recent research in the engineering and delivery of immunostimulatory or immunoregulatory modulators for cGAS and STING for the immunotherapy of cancer and autoimmune diseases. To improve the delivery efficiency of CDNs, we developed ionizable and pH-responsive polymeric nanocarriers to load STING agonists, aiming to improve the cellular uptake and facilitate the endosomal escape to induce efficient STING activation. We also codelivered STING agonists with complementary immunostimulatants in nanoparticle-in-hydrogel composites to synergetically elicit potent innate and adaptive antitumor responses that eradicate local and distant large tumors. Further, taking advantage of the simplicity of manufacturing and the established nucleic acid delivery system, we developed oligonucleotide-based cGAS agonists as immunostimulant immunotherapeutics as well as adjuvants for peptide antigens for cancer immunotherapy. To suppress the overly strong proinflammatory responses associated with cGAS-STING overactivation in some of the autoimmune disorders, we devised nanomedicine-in-hydrogel (NiH) that codelivers a cGAS inhibitor and cell-free DNA (cfDNA)-scavenging cationic nanoparticles (cNPs) for systemic immunosuppression in rheumatoid arthritis (RA) therapy. Lastly, we discussed current drug development by targeting cGAS-STING for cancer, infectious diseases, and autoimmune diseases, as well as the potential opportunities for utilizing cGAS-STING pathway for versatile applications in disease treatment.

Host plant height explains the effect of nitrogen enrichment on arbuscular mycorrhizal fungal communities.

Nitrogen (N) enrichment is widely known to affect the root-associated arbuscular mycorrhizal fungal (AMF) community in different ways, for example, via altering soil properties and/or shifting host plant functional structure. However, empirical knowledge of their relative importance is still lacking. Using a long-term N addition experiment, we measured the AMF community taxonomic and phylogenetic diversity at the single plant species (roots of 15 plant species) and plant community (mixed roots) levels. We also measured four functional traits of 35 common plant species along the N addition gradient. We found divergent responses of AMF diversity to N addition for host plants with different innate heights (i.e. plant natural height under unfertilized treatment). Furthermore, our data showed that species-specific responses of AMF diversity to N addition were negatively related to the change in maximum plant height. When scaling up to the community level, N addition affected AMF diversity mainly through increasing the maximum plant height, rather than altering soil properties. Our results highlight the importance of plant height in driving AMF community dynamics under N enrichment at both species and community levels, thus providing important implications for understanding the response of AMF diversity to anthropogenic N deposition.

Low soil moisture suppresses the thermal compensatory response of microbial respiration.

The thermal compensatory response of microbial respiration contributes to a decrease in warming-induced enhancement of soil respiration over time, which could weaken the positive feedback between the carbon cycle and climate warming. Climate warming is also predicted to cause a worldwide decrease in soil moisture, which has an effect on the microbial metabolism of soil carbon. However, whether and how changes in moisture affect the thermal compensatory response of microbial respiration are unexplored. Here, using soils from an 8-year warming experiment in an alpine grassland, we assayed the thermal response of microbial respiration rates at different soil moisture levels. The results showed that relatively low soil moisture suppressed the thermal compensatory response of microbial respiration, leading to an enhanced response to warming. A subsequent moisture incubation experiment involving off-plot soils also showed that the response of microbial respiration to 100 d warming shifted from a slight compensatory response to an enhanced response with decreasing incubation moisture. Further analysis revealed that such respiration regulation by moisture was associated with shifts in enzymatic activities and carbon use efficiency. Our findings suggest that future drought induced by climate warming might weaken the thermal compensatory capacity of microbial respiration, with important consequences for carbon-climate feedback.

Microbial respiratory thermal adaptation is regulated by r-/K-strategy dominance.

Microbial thermal adaptation is considered to be one of the core mechanisms affecting soil carbon cycling. However, the role of microbial community composition in controlling thermal adaptation is poorly understood. Using microbial communities from the rhizosphere and bulk soils in an 8-year warming experiment as a model, we experimentally demonstrate that respiratory thermal adaptation was much stronger in microbial K-strategist-dominated bulk soils than in microbial r-strategist-dominated rhizosphere soils. Soil carbon availability exerted strong selection on the dominant ecological strategy of the microbial community, indirectly influencing respiratory thermal adaptation. Our findings shed light on the linchpin of the dominant ecological strategy exhibited by the microbial community in determining its respiratory thermal adaptation, with implications for understanding soil carbon losses under warming.

Host diversity positively affects the temporal stability of foliar fungal diseases in a Tibetan alpine meadow.

BACKGROUND AND AIMS: Plant disease can dramatically affect population dynamics, community composition and ecosystem functions. However, most empirical studies focus on diseases at a certain time point and largely ignore their temporal stability, which directly affects our ability to predict when and where disease outbreaks will occur. METHODS: Using a removal experiment that manipulates plant diversity (i.e. a plant biodiversity and ecosystem function experiment) and a fertilization experiment in a Tibetan alpine meadow, we investigated how different plant biodiversity indices and nitrogen fertilization affect the temporal stability of foliar fungal diseases (measured as the mean value of community pathogen load divided by its standard deviation) over seven consecutive years. KEY RESULTS: We found that the temporal stability of foliar fungal diseases increased with plant diversity indices in the plant biodiversity and ecosystem function experiment. Meanwhile, we observed a weakly positive relationship between host diversity and temporal stability in the fertilization experiment. However, the nitrogen treatment did not affect temporal stability, given that fertilization increased both the mean and standard deviation of pathogen load by roughly the same magnitude. CONCLUSIONS: We conclude that host diversity regulates the temporal stability of pathogen load, but we note that this effect may be attenuated under rapid biodiversity loss in the Anthropocene.

The allometry of plant height explains species loss under nitrogen addition.

Light asymmetry, with a higher light acquisition per unit biomass for larger plants, has been proposed as a major mechanism of species loss after nitrogen addition. However, solid evidence for this has been scarce. We measured the allometric size-height relationships of 25 plant species along a nitrogen addition gradient manipulated annually for eight years in a speciose alpine meadow and found that the positive relationship between species relative abundance and the height scaling exponent in natural conditions disappeared after nitrogen addition. Those species with lower height scaling exponents increased in relative abundance after nitrogen addition, thereby decreasing the community weighted mean and dispersion of the height scaling exponent and ultimately the species richness. Our results provided some unique evidence for light asymmetry induced species loss after nitrogen addition and a new insight from the perspective of allometric scaling to explain biodiversity maintenance in the face of global changes.

Host plant environmental filtering drives foliar fungal community assembly in symptomatic leaves.

Foliar fungi (defined as all fungal species in leaves after surface sterilization; hereafter, 'FF') are of great importance to host plant growth and health, and can also affect ecosystem functioning. Despite this importance, few studies have explicitly examined the role of host filtering in shaping local FF communities, and we know little about the differences of FF community assembly between symptomatic (caused by fungal pathogens) and asymptomatic leaves, and whether there is phylogenetic congruence between host plants and FF. We examined FF communities from 25 host plant species (for each species, symptomatic and asymptomatic leaves, respectively) in an alpine meadow of the Tibetan Plateau using MiSeq sequencing of ITS1 gene biomarkers. We evaluated the phylogenetic congruence of FF-plant interactions based on cophylogenetic analysis, and examined α- and ß-phylogenetic diversity indices of the FF communities. We found strong support for phylogenetic congruence between host plants and FF for both asymptomatic and symptomatic leaves, and a host-caused filter appears to play a major role in shaping FF communities. Most importantly, we provided independent lines of evidence that host environmental filtering (caused by fungal infections) outweighs competitive exclusion in driving FF community assembly in symptomatic leaves. Our results help strengthen the foundation of FF community assembly by demonstrating the importance of host environmental filtering in driving FF community assembly.

Shifts in plant community composition weaken the negative effect of nitrogen addition on community-level arbuscular mycorrhizal fungi colonization.

Nitrogen addition affects plant-arbuscular mycorrhizal fungi (AMF) association greatly. However, although the direct effect of nitrogen addition on AMF colonization has received investigation, its indirect effect through shifts in plant community composition has never been quantified. Based on a 7-year nitrogen addition experiment in an alpine meadow of Qinghai-Tibet Plateau, we investigated the effects of nitrogen addition on plant community, AMF diversity and colonization, and disentangled the direct and indirect effects of nitrogen addition on community AMF colonization. At plant species level, nitrogen addition significantly decreased root colonization rate and altered AMF community composition, but with no significant effect on AMF richness. At plant community level, plant species richness and AMF colonization rate decreased with nitrogen addition. Plant species increasing in abundance after nitrogen addition were those with higher AMF colonization rates in natural conditions, resulting in an increased indirect effect induced by alternation in plant community composition with nitrogen addition, whereas the direct effect was negative and decreased with nitrogen addition. Overall, we illustrate the effect of nitrogen addition and plant species in influencing the AMF diversity, demonstrate how shifts in plant community composition (indirect effect) weaken the negative direct effect of nitrogen addition on community-level AMF colonization rate, and emphasize the importance of plant community-mediated mechanisms in regulating ecosystem functions.

Thiolated Nanoparticles Overcome the Mucus Barrier and Epithelial Barrier for Oral Delivery of Insulin.

Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymer-based nanodrug delivery system in the form of poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.

Warming affects foliar fungal diseases more than precipitation in a Tibetan alpine meadow.

The effects of global change on semi-natural and agro-ecosystem functioning have been studied extensively. However, less well understood is how global change will influence fungal diseases, especially in a natural ecosystem. We use data from a 6-yr factorial experiment with warming (simulated using infrared heaters) and altered precipitation treatments in a natural Tibetan alpine meadow ecosystem, from which we tested global change effects on foliar fungal diseases at the population and community levels, and evaluated the importance of direct effects of the treatments and community-mediated (indirect) effects (through changes in plant community composition and competence) of global change on community pathogen load. At the population level, we found warming significantly increased fungal diseases for nine plant species. At the community level, we found that warming significantly increased pathogen load of entire host communities, whereas no significant effect of altered precipitation on community pathogen load was detected. We concluded that warming influences fungal disease prevalence more than precipitation does in a Tibetan alpine meadow. Moreover, our study provides new experimental evidence that increases in disease burden on some plant species and for entire host communities is primarily the direct effects of warming, rather than community-mediated (indirect) effects.

Species decline under nitrogen fertilization increases community-level competence of fungal diseases.

The artificial fertilization of soils can alter the structure of natural plant communities and exacerbate pathogen emergence and transmission. Although the direct effects of fertilization on disease resistance in plants have received some research attention, its indirect effects of altered community structure on the severity of fungal disease infection remain largely uninvestigated. We designed manipulation experiments in natural assemblages of Tibetan alpine meadow vegetation along a nitrogen-fertilization gradient over 5 years to compare the relative importance of direct and indirect effects of fertilization on foliar fungal infections at the community level. We found that species with lower proneness to pathogens were more likely to be extirpated following fertilization, such that community-level competence of disease, and thus community pathogen load, increased with the intensity of fertilization. The amount of nitrogen added (direct effect) and community disease competence (indirect effect) provided the most parsimonious combination of parameters explaining the variation in disease severity. Our experiment provides a mechanistic explanation for the dilution effect in fertilized, natural assemblages in a highly specific pathogen-host system, and thus insights into the consequences of human ecosystem modifications on the dynamics of infectious diseases.

Warming and fertilization alter the dilution effect of host diversity on disease severity.

An essential ecosystem service is the dilution effect of biodiversity on disease severity, yet we do not fully understand how this relationship might change with continued climate warming and ecosystem degradation. We designed removal experiments in natural assemblages of Tibetan alpine meadow vegetation by manipulating plot-level plant diversity to investigate the relationship between different plant biodiversity indices and foliar fungal pathogen infection, and how artificial fertilization and warming affect this relationship. Although pathogen group diversity increased with host species richness, disease severity decreased as host diversity rose (dilution effect). The dilution effect of phylogenetic diversity on disease held across different levels of host species richness (and equal abundances), meaning that the effect arises mainly in association with enhanced diversity itself rather than from shifting abundances. However, the dilution effect was weakened by fertilization. Among indices, phylogenetic diversity was the most parsimonious predictor of infection severity. Experimental warming and fertilization shifted species richness to the most supported predictor. Compared to planting experiments where artificial communities are constructed from scratch, our removal experiment in natural communities more realistically demonstrate that increasing perturbation adjusts natural community resistance to disease severity.

A Combination of Species Evenness and Functional Diversity Is the Best Predictor of Disease Risk in Multihost Communities.

Although accumulated evidence has shown that biodiversity can play an important role in disease transmission and prevalence, it remains unclear how different measures of diversity based on taxonomy or function perform in predicting disease risk. In this article, we assess the relative ability of species richness, Shannon's evenness index, single functional traits, and several functional diversity metrics and their interactions to predict disease risk in both nonequilibrium and equilibrium communities simulated by a multihost epidemiological model. On the basis of generalized linear models and Akaike's information criterion, we found that Shannon's evenness index outperforms species richness as a single variable in explaining variation in disease risk, while the best combination consists of Shannon's evenness index and functional diversity. This study is, to our knowledge, the first to demonstrate the important role played by species evenness and functional diversity in accounting for variation in disease risk in multihost communities.

Dispersal limitation favors more fecund species in the presence of fitness-equalizing demographic trade-offs.

Demographic equivalence is the central assumption of the neutral theory of species diversity and has attracted much criticism, since species clearly differ from each other in many traits. Two simple answers--that is, dispersal limitation and demographic trade-offs--have been suggested to resolve this problem. Both processes are considered to be capable of making interspecific differences in fitness smaller on their own, thus potentially reconciling neutrality with reality. However, when the two mechanisms operate simultaneously, as they must do in natural communities, we are surprised to find that they interfere with each other in such a way that dispersal limitation favors more fecund species. Fitness equivalence is no longer guaranteed by a perfect trade-off, and contrary to popular belief, dispersal limitation is found to impede rather than facilitate the stochastic coexistence of species. Still, more species can coexist than allowed through demographic equivalence, providing a potentially alternative explanation for biodiversity maintenance in nature.

Explaining maximum variation in productivity requires phylogenetic diversity and single functional traits.

Many community experiments have shown a positive relationship between plant biodiversity and community productivity, with biodiversity measured in multiple ways based on taxonomy, function, and phylogeny. Whether these different measures of biodiversity and their interactions explain variation in productivity in natural assemblages has rarely been tested. In a removal experiment using natural alpine assemblages in the Tibetan Plateau, we manipulated species richness and functional diversity to examine how different measures of biodiversity predict aboveground biomass production. We combined different biodiversity measures (functional, phylogenetic, richness, evenness) in generalized linear models to determine which combinations provided the most parsimonious explanations of variation in biomass production. Although multivariate functional diversity indices alone consistently explained more variation in productivity than other single measures, phylogenetic diversity and plant height represented the most parsimonious combination. In natural assemblages, single metrics alone cannot fully explain ecosystem function. Instead, a combination of phylogenetic diversity and traits with weak or no phylogenetic signal is required to explain the effects of biodiversity loss on ecosystem function.

Thirteen Nonpharmacological Interventions for Increasing the Quality of Life in Patients with Advanced Cancer: A Network Meta-analysis.

BACKGROUND: A variety of nonpharmacological interventions that improve the quality of life of patients with advanced cancer have been difficult for medical staff to select through randomized controlled trials or traditional meta-analyses. Thus, a network meta-analysis is necessary. OBJECTIVE: This study used network meta-analysis to analyze the effect of 13 different nonpharmacological interventions on improving the living quality of patients with advanced cancer. METHODS: Five English databases were searched up to January 2019. The search strategy only included terms relating to or describing the intervention. RESULTS: The study included 13 different nonpharmacological interventions. The overall efficacy was summarized through a holistic study of quality of life. The study found that the combined effect sizes of 13 nonpharmacological interventions crossed the invalid line (weighted mean difference, -13 [95% confidence interval, -33 to 8.5] to 1.7 [95% confidence interval, -18 to 22]), indicating that none of the intervention was significantly different from each other. By evaluating the heterogeneity of this outcome, no significant evidence of heterogeneity ( P > .05) was observed. Probability ranking according to the surface under the cumulative ranking curve showed that there was a great possibility for the CanWalk intervention and structured multidisciplinary intervention to improve outcomes for cancer patients. CONCLUSIONS: Thirteen nonpharmacological interventions did not significantly impact quality of life. Regarding the probability rank, CanWalk intervention may be the most promising way that advanced cancer patients can help themselves to a better life. Because of the limitations of the current studies, the conclusion needs further evidence. IMPLICATIONS FOR PRACTICE: Nurses should consider recommending moderate physical activity for patients with advanced cancer.

Engineering cGAS-agonistic oligonucleotides as therapeutics for cancer immunotherapy.

Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I) responses. Yet, current approaches to cGAS-STING activation rely on STING agonists, which suffer from difficult formulation, poor pharmacokinetics, and marginal clinical therapeutic efficacy. Here, we report nature-inspired oligonucleotide, Svg3, as a cGAS agonist for cGAS-STING activation in tumor combination immunotherapy. The hairpin-shaped Svg3 strongly binds to cGAS and enhances phase separation to form Svg3-cGAS liquid-like droplets. This results in cGAS-specific immunoactivation and robust IFN-I responses. Remarkably, Svg3 outperforms several state-of-the-art STING agonists in murine and human cells/tissues. Nanoparticle-delivered Svg3 reduces tumor immunosuppression and potentiates immune checkpoint blockade therapeutic efficacy of multiple syngeneic tumor models in wild-type mice, but in neither cGas-/- nor Sting-/- mice. Overall, these results demonstrate the great potential of Svg3 as a cGAS agonistic oligonucleotide for cancer combination immunotherapy.

Influences of elevational gradient on flower size and number of Gentiana lawrencei var. farreri.

Plants can adapt to environmental changes by adjusting their functional traits and biomass allocation. The size and number of flowers are functional traits related to plant reproduction. Life history theory predicts that there is a trade-off between flower size and number, and the trade-off can potentially explain the adaptability of plants. Elevation gradients in mountains provide a unique opportunity to test how plants will respond to climate change. In this study, we tried to better explain the adaptability of the alpine plant Gentiana lawrencei var. farreri in response to climate change. We measured the flower size and number, individual size, and reproductive allocation of G. lawrencei var. farreri during the flowering period along an elevation gradient from 3200 to 4000 m, and explored their relationships using linear mixed-effect models and the structural equation model. We found that with elevation increasing, individual size and flower number decreased and flower size increased, while reproductive allocation remained unchanged. Individual size positively affected flower number, but was not related to flower size; reproductive allocation positively affected flower size, but was not related to flower number; there is a clear trade-off between flower size and number. We also found that elevation decreased flower number indirectly via directly reducing individual size. In sum, this study suggests that G. lawrencei var. farreri can adapt to alpine environments by the synergies or trade-offs among individual size, reproductive allocation, flower size, and flower number. This study increases our understanding of the adaptation mechanisms of alpine plants to climate change in alpine environments.

Hybrid niche-neutral models outperform an otherwise equivalent neutral model for fitting coral reef data.

Niche theory and neutral theory are two major developments aiming at explaining patterns of biodiversity observed in nature. Both theories have been found relevant either separately or simultaneously in some real communities, and it has been theoretically demonstrated that they can produce similar species abundance distributions. However, it remains controversial whether the two theories can produce similar patterns via different mechanisms, or can interact to jointly produce the observed diversity patterns, or whether the patterns generated by the neutral model are robust to niche structure. Here we show that, although the neutral model proposed for spatially discrete communities remains robust to strong niche structure for high-diversity communities, the inclusion of more realistic niche differentiation modes greatly improves the goodness of fit to Indo-Pacific coral reefs. Actually, the multiple discrete communities' neutral model, due to its underestimation of the number or abundance of common species, fails to capture the combination of many rare species and a few highly abundant species that characterize the Indo-Pacific coral reef communities. By incorporating niche structure into the multiple discrete communities' model, the hybrid niche-neutral models can successfully reproduce both the species-based and individual-based abundance distribution patterns observed in the coral reefs. We proposed that both niche theory and neutral theory may be involved in explaining the structure of such communities. Our results also suggest a negative relationship between per capita birth to death ratio and immigration among different guilds of coral species, which clearly deserves further investigation.