The relative importance of seed competition, resource competition and perturbations on community structure

While the regional climate is the primary selection pressure for whether a plant strategy can survive, however, competitive interactions strongly affect the relative abundances of plant strategies within communities. Here, we investigate the relative importance of competition and perturbations on the development of vegetation community structure. To do so, we develop DIVE (Dynamics and Interactions of VEgetation), a simple general model that links plant strategies to their competitive dynamics, using growth and reproduction characteristics that emerge from climatic constraints. The model calculates population dynamics based on establishment, mortality, invasion and exclusion in the presence of different strengths of perturbations, seed and resource competition. The highest levels of diversity were found in simulations without competition as long as mortality is not too high. However, reasonable successional dynamics were only achieved when resource competition is considered. Under high levels of competition, intermediate levels of perturbations were required to obtain coexistence. Since succession and coexistence are observed in plant communities, we conclude that the DIVE model with competition and intermediate levels of perturbation represents an adequate way to model population dynamics. Because of the simplicity and generality of DIVE, it could be used to understand vegetation structure and functioning at the global scale and the response of vegetation to global change

The role of plant functional trade-offs for biodiversity changes and biome shifts under scenarios of global climatic change

The global geographic distribution of biodiversity and biomes is determined by species-specific physiological tolerances to climatic constraints. Current vegetation models employ empirical bioclimatic relationships to predict present-day vegetation patterns and to forecast biodiversity changes and biome shifts under climatic change. In this paper, we consider trade-offs in plant functioning and their responses under climatic changes to forecast and explain changes in plant functional richness and shifts in biome geographic distributions. <br><br> The Jena Diversity model (JeDi) simulates plant survival according to essential plant functional trade-offs, including ecophysiological processes such as water uptake, photosynthesis, allocation, reproduction and phenology. We use JeDi to quantify changes in plant functional richness and biome shifts between present-day and a range of possible future climates from two SRES emission scenarios (A2 and B1) and seven global climate models using metrics of plant functional richness and functional identity. <br><br> Our results show (i) a significant loss of plant functional richness in the tropics, (ii) an increase in plant functional richness at mid and high latitudes, and (iii) a pole-ward shift of biomes. While these results are consistent with the findings of empirical approaches, we are able to explain them in terms of the plant functional trade-offs involved in the allocation, metabolic and reproduction strategies of plants. We conclude that general aspects of plant physiological tolerances can be derived from functional trade-offs, which may provide a useful process- and trait-based alternative to bioclimatic relationships. Such a mechanistic approach may be particularly relevant when addressing vegetation responses to climatic changes that encounter novel combinations of climate parameters that do not exist under contemporary climate

A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned

Mouse model of liver ischemia and reperfusion injury: method for studying reactive oxygen and nitrogen metabolites in vivo

The mouse model of liver ischemia and reperfusion injury has proven to be valuable for our understanding of the role that reactive oxygen and nitrogen metabolites play in postischemic tissue injury. This methods paper provides a detailed protocol for inducing partial liver ischemia followed by reperfusion. Liver ischemia is induced in anesthetized mice by cross-clamping the hepatic artery and portal vein for varying lengths of time resulting in deprivation of blood flow to approximately of 70% of the liver. Restoration of blood flow to the ischemic lobes enhances superoxide production concomitant with a rapid and marked decrease in the bioavailability of nitric oxide resulting in alterations in the redox state of the liver in favor of a more oxidative environment. This hepatocellular oxidative stress induces the activation of oxidant-sensitive transcription factors followed by the upregulation of pro-inflammatory cytokines and mediators that ultimately lead to liver injury. This model can be induced in any strain or sex of mouse and requires 1-2 months of practice to become proficient in the surgery and animal manipulation. The role of different reactive metabolites of oxygen and nitrogen may be evaluated using genetically-engineered mice as well as selective molecular, cellular and/or pharmacological agents

Decomposing uncertainties in the future terrestrial carbon budget associated with emission scenarios, climate projections, and ecosystem simulations using the ISI-MIP results

We examined the changes to global net primary production (NPP), vegetation biomass carbon (VegC), and soil organic carbon (SOC) estimated by six global vegetation models (GVMs) obtained from the Inter-Sectoral Impact Model Intercomparison Project. Simulation results were obtained using five global climate models (GCMs) forced with four representative concentration pathway (RCP) scenarios. To clarify which component (i.e., emission scenarios, climate projections, or global vegetation models) contributes the most to uncertainties in projected global terrestrial C cycling by 2100, analysis of variance (ANOVA) and wavelet clustering were applied to 70 projected simulation sets. At the end of the simulation period, changes from the year 2000 in all three variables varied considerably from net negative to positive values. ANOVA revealed that the main sources of uncertainty are different among variables and depend on the projection period. We determined that in the global VegC and SOC projections, GVMs are the main influence on uncertainties (60 % and 90 %, respectively) rather than climate-driving scenarios (RCPs and GCMs). Moreover, the divergence of changes in vegetation carbon residence times is dominated by GVM uncertainty, particularly in the latter half of the 21st century. In addition, we found that the contribution of each uncertainty source is spatiotemporally heterogeneous and it differs among the GVM variables. The dominant uncertainty source for changes in NPP and VegC varies along the climatic gradient. The contribution of GVM to the uncertainty decreases as the climate division becomes cooler (from ca. 80 % in the equatorial division to 40 % in the snow division). Our results suggest that to assess climate change impacts on global ecosystem C cycling among each RCP scenario, the long-term C dynamics within the ecosystems (i.e., vegetation turnover and soil decomposition) are more critical factors than photosynthetic processes. The different trends in the contribution of uncertainty sources in each variable among climate divisions indicate that improvement of GVMs based on climate division or biome type will be effective. On the other hand, in dry regions, GCMs are the dominant uncertainty source in climate impact assessments of vegetation and soil C dynamics

High potential for weathering and climate effects of non-vascular vegetation in the Late Ordovician

It has been hypothesized that predecessors of today’s bryophytes significantly increased global chemical weathering in the Late Ordovician, thus reducing atmospheric CO2 concentration and contributing to climate cooling and an interval of glaciations. Studies that try to quantify the enhancement of weathering by non-vascular vegetation, however, are usually limited to small areas and low numbers of species, which hampers extrapolating to the global scale and to past climatic conditions. Here we present a spatially explicit modelling approach to simulate global weathering by non-vascular vegetation in the Late Ordovician. We estimate a potential global weathering flux of 2.8 (km3 rock) yr−1, defined here as volume of primary minerals affected by chemical transformation. This is around three times larger than today’s global chemical weathering flux. Moreover, we find that simulated weathering is highly sensitive to atmospheric CO2 concentration. This implies a strong negative feedback between weathering by non-vascular vegetation and Ordovician climate

Quantifying uncertainties in soil carbon responses to changes in global mean temperature and precipitation

Soil organic carbon (SOC) is the largest carbon pool in terrestrial ecosystems and may play a key role in biospheric feedbacks with elevated atmospheric carbon dioxide (CO2) in a warmer future world. We examined the simulation results of seven terrestrial biome models when forced with climate projections from four representative-concentration-pathways (RCPs)-based atmospheric concentration scenarios. The goal was to specify calculated uncertainty in global SOC stock projections from global and regional perspectives and give insight to the improvement of SOC-relevant processes in biome models. SOC stocks among the biome models varied from 1090 to 2650 Pg C even in historical periods (ca. 2000). In a higher forcing scenario (i.e., RCP8.5), inconsistent estimates of impact on the total SOC (2099–2000) were obtained from different biome model simulations, ranging from a net sink of 347 Pg C to a net source of 122 Pg C. In all models, the increasing atmospheric CO2 concentration in the RCP8.5 scenario considerably contributed to carbon accumulation in SOC. However, magnitudes varied from 93 to 264 Pg C by the end of the 21st century across biome models. Using the time-series data of total global SOC simulated by each biome model, we analyzed the sensitivity of the global SOC stock to global mean temperature and global precipitation anomalies (ΔT and ΔP respectively) in each biome model using a state-space model. This analysis suggests that ΔT explained global SOC stock changes in most models with a resolution of 1–2 °C, and the magnitude of global SOC decomposition from a 2 °C rise ranged from almost 0 to 3.53 Pg C yr−1 among the biome models. However, ΔP had a negligible impact on change in the global SOC changes. Spatial heterogeneity was evident and inconsistent among the biome models, especially in boreal to arctic regions. Our study reveals considerable climate uncertainty in SOC decomposition responses to climate and CO2 change among biome models. Further research is required to improve our ability to estimate biospheric feedbacks through both SOC-relevant and vegetation-relevant processes

Comparing projections of future changes in runoff and water resources from hydrological and ecosystem models in ISI-MIP

Projections of future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed. Projections of change from the baseline period (1981–2010) to the future (2070–2099) from a number of different ecosystems and hydrological models were studied. The differences between projections from the two types of model were looked at globally and regionally. Typically, across different regions the ecosystem models tended to project larger increases and smaller decreases in runoff than the hydrological models. However, the differences varied both regionally and seasonally. Sensitivity experiments were also used to investigate the contributions of varying CO2 and allowing vegetation distribution to evolve on projected changes in runoff. In two out of four models which had data available from CO2 sensitivity experiments, allowing CO2 to vary was found to increase runoff more than keeping CO2 constant, while in two models runoff decreased. This suggests more uncertainty in runoff responses to elevated CO2 than previously considered. As CO2 effects on evapotranspiration via stomatal conductance and leaf-area index are more commonly included in ecosystems models than in hydrological models, this may partially explain some of the difference between model types. Keeping the vegetation distribution static in JULES runs had much less effect on runoff projections than varying CO2, but this may be more pronounced if looked at over a longer timescale as vegetation changes may take longer to reach a new state

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma