c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro

c-fos-induced growth factor/vascular endothelial growth factor D (Figf/Vegf-D) is a secreted factor of the VEGF family that binds to the vessel and lymphatic receptors VEGFR-2 and VEGFR-3. Here we report that Figf/Vegf-D is a potent angiogenic factor in rabbit cornea in vivo in a dose-dependent manner. In vitro Figf/Vegf-D induces tyrosine phosphorylation of VEGFR-2 and VEGFR-3 in primary human umbilical cord vein endothelial cells (HUVECs) and in an immortal cell line derived from Kaposi's sarcoma lesion (KS-IMM). The treatment of HUVECs with Figf/Vegf-D induces dose-dependent cell growth. Figf/VEGF-D also induces HUVEC elongation and branching to form an extensive network of capillary-like cords in three-dimensional matrix. In KS-IMM cells Figf/Vegf-D treatment results in dose-dependent mitogenic and motogenic activities. Taken together with the previous observations that Figf/Vegf-D expression is under the control of the nuclear oncogene c-fos, our data uncover a link between a nuclear oncogene and angiogenesis, suggesting that Figf/Vegf-D may play a critical role in tumor cell growth and invasion.     

Elevation of interleukin 6 levels in patients with chronic hepatitis due to hepatitis C virus

Interleukin 6 (IL-6) is a pleiotropic cytokine produced by a wide variety of lymphoid and nonlymphoid tissues. We studied the relationship between IL-6 and the liver in an attempt to elucidate this cytokine's role in hepatitis C-induced liver inflammation. We investigated the behavior of serum IL-6 in 25 patients with chronic hepatitis C (divided into three groups depending on severity) and in 27 healthy controls. Our results showed a significant elevation (P<0.0001) in serum IL-6 levels in the patients with chronic hepatitis C, correlated with the histological activity index (HAI) and their HCV-RNA serum levels. This rise may represent the expression of the hepatitis C virusinduced inflammatory state.     

Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry

Background

Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis.

Methods

This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n?=?7; MPS II, n?=?2; MPS III, n?=?5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median?+?7× MAD from general newborns.

Results

The cutoffs were as follows: HS-0S?>?90 ng/mL; HS-NS?>?23 ng/mL, DS?>?88 ng/mL; mono-sulfated KS?>?445 ng/mL; di-sulfated KS?>?89 ng/mL and ratio di-KS in total KS?>?32 %. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS, and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03 % based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9 % based upon a combination of HS-0S and HS-NS.

Conclusions

Combination of levels of two or more different GAGs improves separation of MPS patients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.

     

Long‐term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment

Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single‐centre case‐control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1‐45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow‐up after HSCT was 11 years (range 1‐30). The conditioning regimen was busulfan (80.6%) or treosulfan‐based (19.4%). A cohort of 258 age‐sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30‐year overall survival (OS) and thalassemia‐free survival (TFS) were 82.6 ± 2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence of grade II‐IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant‐related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High‐risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31‐3.03) and TFS (OR = 1.54, 95% C.I.=1.12‐2.12). In adult patients, the 23‐years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2 ± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12‐0.67). In conclusion, the 30‐year survival rate of ex‐thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia.     

Achieved systolic blood pressure in older people: a systematic review and meta-analysis

Background

It remains unclear into which level the systolic blood pressure (SBP) should be lowered in order to provide the best cardiovascular protection among older people. Hypertension guidelines recommendation on attaining SBP levels <150 mmHg in this population is currently based on experts’ opinion. To clarify this issue, we systematically reviewed and quantified available evidence on the impact of achieving different SBP levels <150 mmHg on various adverse outcomes in subjects aged ≥60 years old receiving antihypertensive drug treatment.

Methods

We searched 8 databases to identify randomized controlled trials (RCTs) and post-hoc analyses or subanalyses of RCTs reporting the effects of attaining different SBP levels <150 mmHg on the risk of stroke, acute myocardial infarction, heart failure, cardiovascular mortality and all-cause mortality in participants aged ≥60 years. We performed random-effects meta-analyses stratified by study design.

Results

Eleven studies (> 33,600 participants) were included. Compared with attaining SBP levels ≥140 mmHg, levels of 130 to <140 mmHg were not associated with lower risk of outcomes in the meta-analysis of RCTs, whereas there was an associated reduction of cardiovascular mortality (RR 0.72, 95% CI 0.59–0.88) and all-cause mortality (RR 0.86, 95% CI 0.75–0.99) in the meta-analysis of post-hoc analyses or subanalyses of RCTs. Limited and conflicting data were available for the SBP levels of <130 mmHg and 140 to <150 mmHg.

Conclusions

Among older people, there is suggestive evidence that achieving SBP levels of 130 to <140 mmHg is associated with lower risks of cardiovascular and all-cause mortality. Future trials are required to confirm these findings and to provide additional evidence regarding the <130 and 140 to <150 mmHg SBP levels.

     

Prevalence and clinical characteristics of urinary incontinence in elderly individuals of a low income

To estimate the prevalence of urinary incontinence (UI) in elderly individuals of low income assisted by the primary health care system in S?o Paulo, Brazil. In this community-based, observational, cross-sectional study, participants assisted by the health family program in S?o Paulo, Brazil, were sampled and interviewed face to face by questionnaire. Participants (n=388) were selected from the collaborative program developed by the 10/66 Dementia Research Group, an International Network of investigators. Demographics, health history and a detailed assessment of UI and urinary symptoms were obtained. Prevalence of UI was calculated. Other variables included age, body mass index (BMI), duration of incontinence and characteristics of the symptoms. The association between UI and the variables was estimated using the Kruskal-Wallis test, Chi-squared test and Fisher test (depending on normality of the distribution and expected frequencies). Prevalence of UI was 38.4%. UI was more common in women than in men (50% vs. 18.3%, p<0.001). Diabetes, obesity and hypertension were associated with UI. Almost 36.2% of the cases were of mixed incontinence, 26.8% of urge incontinence and 24.2% of stress incontinence. Men were more likely to have urge-incontinence, while women were more likely to have mixed incontinence (p=0.001). UI is prevalent in the elderly of low income living in S?o Paulo and rates are higher than most previous studies. Chronic conditions such as hypertension, diabetes and obesity were associated with UI.     

Characteristics associated with synthetic cannabinoid use among patients treated in a public psychiatric emergency setting

Background: Growing evidence of adverse outcomes following synthetic cannabinoid use has engendered interest into populations at risk. The existing literature reports that synthetic cannabinoid use is predominant among young, white males. However, reports from local Departments of Health have found contrary evidence, showing that synthetic cannabinoid use is prevalent in populations other than those of young, white men. Objectives: This study sought to examine sociodemographic characteristics associated with self-reported synthetic cannabinoid use among a clinical psychiatric population within a public hospital in New York City. Methods: A cross-sectional medical record review was conducted on synthetic cannabinoid users and non-users in an emergency psychiatric setting. A total of 948 patients who presented at the emergency psychiatric setting in 2014 were included in this sample, 110 (11.6%) of whom were synthetic cannabinoid users. Logistic regressions were used to determine the sociodemographic correlates of synthetic cannabinoid use. Results: The most prominent correlate of synthetic cannabinoid use was homelessness/residing in a shelter during time of treatment (AOR = 17.77, 95% CI = 9.74–32.5). Male (AOR = 5.37, 95% CI = 2.04–14.1), non-white (AOR = 2.74, 95% CI = 1.36–5.54), and younger age (AOR = .961, 95% CI = .940–.980) were also significant correlates of synthetic cannabinoid use. Conclusion: Synthetic cannabinoid use among the homeless and mentally ill is a growing public health concern, representing a population with unique clinical and social needs. Areas and populations with high rates of homelessness should be targeted for synthetic cannabinoid prevention and treatment efforts, particularly in urban and racial/ethnic minority communities.     

Ecosystem heterogeneity determines the ecological resilience of the Amazon to climate change

Amazon forests, which store ∼50% of tropical forest carbon and play a vital role in global water, energy, and carbon cycling, are predicted to experience both longer and more intense dry seasons by the end of the 21st century. However, the climate sensitivity of this ecosystem remains uncertain: several studies have predicted large-scale die-back of the Amazon, whereas several more recent studies predict that the biome will remain largely intact. Combining remote-sensing and ground-based observations with a size- and age-structured terrestrial ecosystem model, we explore the sensitivity and ecological resilience of these forests to changes in climate. We demonstrate that water stress operating at the scale of individual plants, combined with spatial variation in soil texture, explains observed patterns of variation in ecosystem biomass, composition, and dynamics across the region, and strongly influences the ecosystem’s resilience to changes in dry season length. Specifically, our analysis suggests that in contrast to existing predictions of either stability or catastrophic biomass loss, the Amazon forest’s response to a drying regional climate is likely to be an immediate, graded, heterogeneous transition from high-biomass moist forests to transitional dry forests and woody savannah-like states. Fire, logging, and other anthropogenic disturbances may, however, exacerbate these climate change-induced ecosystem transitions.Amazonia consists of 815 million ha of rainforest, transitional forest, and tropical savannahs; stores approximately half of tropical forest carbon (1); and plays a vital role in global water, energy, and carbon cycling (2). Although uncertainties in climate predictions for the region remain large (3), recent analyses imply that significant portions of the basin will experience both longer and more intense dry seasons by the end of the 21st century (3–6). There is particular concern about southern Amazonian forests that experience longer dry seasons than forests in central and western Amazonia (3) and where a trend of increasing dry season length (DSL) and intensity has already been observed (7). Despite the importance of this region for regional and global climate, the climate sensitivity of the Amazon forests remains uncertain: model predictions range from a large-scale die-back of the Amazon (8, 9) to predictions that the biome will remain largely intact, and may even increase in biomass (10–12). Although some of these differences can be attributed to differences in the predicted future climate forcing of the region (13, 14), accurate predictions of how changes in climate will affect Amazonian forests also rely on an accurate characterization of how the ecosystem is affected by a given change in climate forcing. In this study, we examine the climate sensitivity of the Amazon ecosystem, focusing on the mechanisms underpinning changes in forest dynamics and their implications for the timing and nature of basin-wide shifts in biomass in response to a drying climate.Variation in forest biomass across the Amazon basin (15–17) has been shown to correlate with DSL (16–18) (Fig. 1), soil texture (16), shifts in stem turnover rate (19), and forest composition (20). In general, high-biomass moist tropical forests occur where DSL, defined here as the number of months in which precipitation is <100 mm (6, 9), is short, and low-biomass, savannah-like ecosystems are primarily found when DSLs are long (Fig. 1A). In addition, a significant relationship is observed between regional-scale spatial heterogeneity in above-ground biomass (AGB > 2 kg of carbon per square meter) and DSL, with drier places having greater spatial heterogeneity: This pattern is seen both at the scale of 1° (Fig. 1C; r² = 0.88, P < 0.01 for remote sensing-based AGB estimates) and at smaller spatial scales (SI Appendix, section S1). In other words, in moist areas, where DSL is short, forests have relatively homogeneous levels of AGB, whereas in drier areas, forests are increasingly heterogeneous. As we show below, this observed heterogeneity in response to increasing DSL has important implications for how the structure, composition, and dynamics of Amazon forests will be affected by changes in climate.Open in a separate windowFig. 1.(A) Change in AGB with DSL for remote sensing-based estimates (black and gray circles), ground-based plot measurements (blue triangles), ED2 model output (green circles), and ED2-BL model output (purple circles). (B) Distribution of AGB in the observations and the two models. (C) Change in the percentage of biomass variability, with the coefficient of variation (CV) defined as 1σ/mean. Results are for undisturbed primary vegetation forests. Data are from Baccini et al. (1), Saatchi et al. (48), and Baker et al. (20, 49).The Ecosystem Demography Biosphere (ED2) model, a process-based terrestrial biosphere model that represents individual plant-level dynamics, including competition for light and water (21, 22), was used to investigate the impact of ecosystem heterogeneity on the Amazon forest’s ecological resilience to climate perturbations (SI Appendix, section S3). Here, the term “ecological resilience” is used to describe the ability of a forest to maintain fundamental characteristics, such as carbon pools, composition, and structure, despite changes in climate (23). ED2 model simulations for the Amazon region, forced with a regional climate dataset derived from in situ measurements and remote-sensing observations, correctly reproduce the observed pattern of AGB variability as a function of DSL and soil texture (Fig. 1 and SI Appendix, section S4). In addition, ED2 model simulations for sites with detailed ground-based soil texture, forest structure, turnover, and composition measurements are also consistent with the observed patterns of variation in these quantities (SI Appendix, section S4).An ensemble of model simulations with varying soil texture was used to investigate the mechanisms that underpin the observed variable response to increasing DSL (SI Appendix, section S3). In the model, individual plant productivity is modified by a measure of plant water stress (γ_WS) that integrates soil texture, precipitation, and plant transpiration demand such that, as γ_WS increases, the plants close their stomata to reduce water loss. In the ED2 ensemble simulations, plot biomass is highly correlated with the average γ_WS for the forested sites (defined here as AGB > 3 kg of carbon per square meter) (Fig. 2C; r² = 0.96–0.99, P < 0.01; SI Appendix, section S5). Associated with changes in AGB that occur as water stress increases are correlated changes in the productivity and composition of the plant canopy (SI Appendix, section S6).Open in a separate windowFig. 2.Impact of changes in soil clay fraction (A and B) and plant water stress (C and D) on AGB in the ED2 (A and C) and ED2-BL (B and D) model simulations. Four climatological conditions are shown, a 2-month dry season, a 4-month dry season, a 6-month dry season, and an 8-month dry season.The important role that water stress operating at the scale of individual plants plays in generating these responses is illustrated by comparing the native ED2 model predictions with output from a horizontally and vertically averaged version of the model (ED2-BL), analogous to a conventional “big leaf” terrestrial biosphere model that represents the canopy in an aggregated manner (SI Appendix, section S3). In the ED2-BL simulations, there is no significant relationship between the spatial heterogeneity of forested sites and DSL (Fig. 1 A and C; r² = 0.24, P = 0.32). The absence of individual-level plant dynamics in the ED2-BL model results in a markedly different response to variations in soil texture and DSL than the native model formulation: Biomass initially declines as a function of increasing water stress, but a tipping point is then reached, beyond which the high-biomass forest is no longer stable and is replaced by a low-biomass savannah (Fig. 2). The result is a bimodal distribution of AGB across the basin in the ED2-BL model simulations, in contrast to the continuous distribution seen in the native model formulation and the observations (Fig. 1B). This response mirrors the response seen in other big-leaf-type ecosystem models (9). In native ED2 simulations, when water stress is prevented from influencing plant productivity, DSL and soil texture no longer have an impact on AGB (SI Appendix, section S5 and Fig. S5). Taken together, these simulations indicate that the driving mechanism behind the observed heterogeneous response to changes in DSL is the differential performance of individuals within the canopy to declining water availability, and how this response is modulated by soils with different hydrological properties. Specifically, the size and age structure of the ED2 plant canopy results in individuals’ differential access to both light and soil water, influencing the dynamics of individual plant growth and mortality (SI Appendix, section S6). Due to the nonlinear nature of functions governing plant growth, mortality, and recruitment, this heterogeneity results in a more continuous, graded response to changes in water stress than the big leaf (ED2-BL) formulation (Fig. 2). The consequence of this heterogeneity in plant-level responses to changes in soil moisture is that soil texture is likely to become increasingly important for controlling AGB as DSL increases. Soil fertility gradients also influence Amazonian AGB (16–18); however, as we show in SI Appendix, section S2, they do not account for the observed regional-scale pattern of increasing biomass heterogeneity with increasing DSL.The ED2 biosphere model was used to investigate the expected patterns and time scales of Amazonian ecosystem response to a 1- to 4-month change in DSL over the 21st century (6). Earlier analyses have suggested that by accurately representing the dynamics of individual trees, models such as ED2 that incorporate plant-level dynamics are likely to provide more realistic estimates of forest successional change (21). Forests with a 4-month dry season (24% of the Amazon basin) are projected to lose ∼20% of their biomass with a 2-month increase in DSL (range of 11–58% loss of AGB dependent on clay content), whereas drier forests (6-month DSL) respond more rapidly to changes in climate, losing ∼29% (20–37% loss dependent on clay content) of their biomass with a 1-mo increase in DSL (Fig. 3A and SI Appendix, section S7). As the forests adjust to the new climate regime, the spatial heterogeneity of forest structure, composition, and biomass across the range of soil textures gradually increase. As seen in Fig. 3B, the model predicts that forests in soils with low clay content will be relatively unaffected by the change in climate regime; however, in soils with high clay content, the increase in levels of water stress caused by the onset of a longer dry season will result in marked changes in forest AGB and composition, beginning approximately 3 years after the perturbation (Fig. 3C). The time scale of the predicted initial ecosystem response is consistent with the results from two field-based through-fall exclusion experiments, which showed declining biomass 3–4 years after a drought was introduced (24, 25). Underlying these predicted changes in AGB and canopy composition are reductions in plant growth and increases in mortality rates (SI Appendix, Figs. S14 and S15). Whereas the majority of the change in AGB occurs in the first 100 y, the composition and structure of the forest continue to reorganize for more than 200 years after the perturbation (Fig. 3C). Specifically, the simulations predict a substantial decline in the abundance of late-successional trees in soils with high clay content. This prediction arises as a consequence of the slower rate of growth of late-successional trees that makes them more vulnerable to water stress-induced increases in mortality rates and less competitive against mid-successional species that are favored by drought-induced increases in understory light levels. This prediction of increased vulnerability of late-successional trees to increases in water stress is as yet untested; however, more generally, our analysis highlights how shifts in climate forcing are likely to drive significant shifts in tropical forest composition and structure over decadal and centennial time scales.Open in a separate windowFig. 3.Predicted response of forest AGB and composition to an increase in DSL. (A) Change in AGB after 100 y as a result of increasing DSL for forests with historic DSLs of 2, 4, and 6 months for the range of soil textures simulated in the ensemble model simulations (n = 30). The magnitude of the change in AGB is influenced by soil clay fraction: The mean (solid line), 1σ deviation (shaded region), and minimum and maximum values (dashed lines) are shown. (B and C) Bar plots illustrating the impact of a 2-month increase in dry season (from 4 to 6 months) on a forest situated on a low clay content soil and a forest situated on a high clay content soil. The color of the bars indicates the contribution of mid- and late-successional trees, illustrating the shift in composition caused by the increase in DSL.Recent work has hypothesized that two stable ecosystem states may exist along the boundaries of tropical forests and that a tipping point may occur once a climatological moisture threshold is passed (26, 27). Instead, by combining field observations, remote-sensing estimates, and a terrestrial biosphere model, we find no evidence that an irreversible rapid transition or dieback of Amazon forests will occur in response to a drying climate (8, 9) or that forests will be unresponsive (11, 12). Rather, our results suggest that, at least in the case of Amazonian forests, the ecosystem will exhibit an immediate but heterogeneous response to changes in its climate forcing and that a continuum of transitional forest ecosystem states exists. These conclusions are consistent with experimental observations across Amazonia of short-term drought impacts (28). Furthermore, we find that future climate-induced shifts between a moist tropical forest and a dry forest will be a more graded transition accompanied by increasing spatial heterogeneity in forest AGB, composition, and dynamics across gradients in soil texture. The ability of Amazonian forests to undergo reorganization of their structure and composition in response to climate-induced changes in levels of plant water stress acts as an important buffer against more drastic threshold changes in vegetation state that would otherwise occur; however, it also means that the forests are more sensitive to smaller magnitude changes in their climate forcing than previous studies have suggested.The analysis conducted here intentionally focused on the direct impacts of changes in climate forcing on vegetation, and did not incorporate the effects of soil nutrients, climate-driven changes in fire frequency, the effects of increasing atmospheric CO₂ concentrations, the impacts of land transformation, and biosphere/atmosphere feedbacks. With regard to soil nutrients, at the basin scale, analyses indicate that forest composition, structure, biomass, and dynamics also vary across a gradient in soil fertility (16, 17), with the younger, more fertile soils of western Amazonia supporting forests with lower AGB and higher rates of biomass productivity and stem turnover relative to the forests of the central Amazon and Guianan Shield, which are located on older, more nutrient-poor soils. Meanwhile, landscape-scale studies in central (29) and northwestern (30) Amazonia have found that more fertile clay soils have higher AGB than nutrient-poor sandy soils. Further discussion of the impact of soil nutrients can be found in SI Appendix, section S2).Plant water availability is affected by both the hydraulic properties of soils and plant hydraulic architecture. Our findings of the importance of individual plant water stress on forest response to changes in climate highlight the need for additional studies into these two important, but relatively understudied, properties of tropical forests. With regard to soil hydraulic properties, recent studies suggest that the relationship between a soil’s texture and its hydraulic properties may differ significantly between tropical and temperate soils (31, 32). However, the impact of these differences on plant water availability remains uncertain. With regard to plant hydraulic architecture, although some measurements exist on rooting properties and vascular architecture of tropical trees (33–36), the above- and below-ground hydraulic attributes of tropical trees remain poorly characterized, especially compared with the hydraulic attributes of their temperate counterparts.In some areas, particularly those areas with long dry seasons, increasing water stress is likely to be accompanied by increases in fire frequency, which may act to generate more rapid transitions from a higher biomass forested state to a more savannah-like biome (26, 27). Because these two mechanisms have distinct impacts on forest composition, structure, and function, both must be considered when predicting future responses to changes in climate. The potential impacts of fire on patterns of ecosystem change are discussed in SI Appendix, section S1. Recent modeling studies indicate that CO₂ fertilization may mitigate the impact of increasing water stress (37); however, experimental studies are needed to quantify the impact of elevated CO₂ concentrations better on the physiological functioning of Amazon trees.Although regional patterns of Amazonian AGB are complex, reflecting the impact of multiple factors, our results suggest that plant-level responses to soil texture heterogeneity and changes in DSL are important in explaining the observed basin-wide pattern of variation in Amazonian AGB, providing a mechanistic explanation for the observed correlations between DSL, AGB, and changes in stand structure and composition (16, 17). These conclusions may also apply to African and Asian tropical forests; however, important differences exist in the future climate predictions for these regions (38) and their soil edaphic and nutrient characteristics and historical fire regimes (39–41).The response of forests to changes in their climate forcing is an emergent ecosystem-level response that is ultimately driven by individual trees responding to changes in their local environments. Nonlinearities in the performance of individual plants, such as their rates of photosynthetic assimilation and mortality, as environmental conditions change imply that terrestrial biosphere models need to represent these differential responses of individuals to capture emergent ecosystem properties accurately (42). This analysis demonstrates that the conventional approach of modeling average plants in average environments within climatological grid cells underestimates the direct, near-term response of tropical forests to climatological change but overestimates the direct impacts of larger scale changes in forcing. Consequently, accurate predictions for the timing and nature of forest responses to changes in climate require consideration of how climate and soils affect the performance of individuals within plant canopies. As we have shown here, models that incorporate plant-level dynamics are able to characterize observed extant patterns of variation in the structure, composition, and dynamics of Amazonian ecosystems more accurately, and accounting for these patterns has important implications for the sensitivity and ecological resilience of Amazon forests to different levels of climatological perturbation.