CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin's lymphoma.

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20- normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions.

Mapping the root systems of individual trees in a natural community using genotyping-by-sequencing.

The architecture of root systems is an important driver of plant fitness, competition and ecosystem processes. However, the methodological difficulty of mapping roots hampers the study of these processes. Existing approaches to match individual plants to belowground samples are low throughput and species specific. Here, we developed a scalable sequencing-based method to map the root systems of individual trees across multiple species. We successfully applied it to a tropical dry forest community in the Brazilian Caatinga containing 14 species. We sequenced all 42 individual shrubs and trees in a 14 × 14 m plot using double-digest restriction site-associated sequencing (ddRADseq). We identified species-specific markers and individual-specific haplotypes from the data. We matched these markers to the ddRADseq data from 100 mixed root samples from across the centre (10 × 10 m) of the plot at four different depths using a newly developed R package. We identified individual root samples for all species and all but one individual. There was a strong significant correlation between belowground and aboveground size measurements, and we also detected significant species-level root-depth preference for two species. The method is more scalable and less labour intensive than the current techniques and is broadly applicable to ecology, forestry and agricultural biology.

Wood Nutrient-Water-Density Linkages Are Influenced by Both Species and Environment.

Tropical trees store a large amount of nutrients in their woody tissues, thus triggering the question of what the functional association of these elements with other wood traits is. Given the osmotic activity of mineral elements such as potassium, sodium, and calcium, these elements should be strong candidates in mediating the water storing capacity in tropical trees. We investigated the role of wood nutrients in facilitating wood water storage in trees by using branch samples from 48 tropical tree species in South America and examined their associations with wood density (ρ). Wood density varied from 316 kg/m3 in Peru plots, where the soil nutrient status is relatively higher, to 908 kg/m3 in Brazil plots, where the nutrient availability is lower. Phosphorus content in wood varied significantly between plots with lowest values found in French Guiana (1.2 mol/m3) and plots with highest values found in Peru (43.6 mol/m3). Conversely, potassium in woody tissues showed a significant cross-species variation with Minquartia guianensis in Brazil showing the lowest values (8.8 mol/m3) and with Neea divaricata in Peru having the highest values (114 mol/m3). We found that lower wood density trees store more water in their woody tissues with cations, especially potassium, having a positive association with water storage. Specific relationships between wood cation concentrations and stem water storage potential nevertheless depend on both species' identity and growing location. Tropical trees with increased water storage capacity show lower wood density and have an increased reliance on cations to regulate this reservoir. Our study highlights that cations play a more important role in tropical tree water relations than has previously been thought, with potassium being particularly important.

Tree mode of death and mortality risk factors across Amazon forests.

The carbon sink capacity of tropical forests is substantially affected by tree mortality. However, the main drivers of tropical tree death remain largely unknown. Here we present a pan-Amazonian assessment of how and why trees die, analysing over 120,000 trees representing > 3800 species from 189 long-term RAINFOR forest plots. While tree mortality rates vary greatly Amazon-wide, on average trees are as likely to die standing as they are broken or uprooted-modes of death with different ecological consequences. Species-level growth rate is the single most important predictor of tree death in Amazonia, with faster-growing species being at higher risk. Within species, however, the slowest-growing trees are at greatest risk while the effect of tree size varies across the basin. In the driest Amazonian region species-level bioclimatic distributional patterns also predict the risk of death, suggesting that these forests are experiencing climatic conditions beyond their adaptative limits. These results provide not only a holistic pan-Amazonian picture of tree death but large-scale evidence for the overarching importance of the growth-survival trade-off in driving tropical tree mortality.

Functional Trait Variation Among and Within Species and Plant Functional Types in Mountainous Mediterranean Forests.

Plant structural and biochemical traits are frequently used to characterise the life history of plants. Although some common patterns of trait covariation have been identified, recent studies suggest these patterns of covariation may differ with growing location and/or plant functional type (PFT). Mediterranean forest tree/shrub species are often divided into three PFTs based on their leaf habit and form, being classified as either needleleaf evergreen (Ne), broadleaf evergreen (Be), or broadleaf deciduous (Bd). Working across 61 mountainous Mediterranean forest sites of contrasting climate and soil type, we sampled and analysed 626 individuals in order to evaluate differences in key foliage trait covariation as modulated by growing conditions both within and between the Ne, Be, and Bd functional types. We found significant differences between PFTs for most traits. When considered across PFTs and by ignoring intraspecific variation, three independent functional dimensions supporting the Leaf-Height-Seed framework were identified. Some traits illustrated a common scaling relationship across and within PFTs, but others scaled differently when considered across PFTs or even within PFTs. For most traits much of the observed variation was attributable to PFT identity and not to growing location, although for some traits there was a strong environmental component and considerable intraspecific and residual variation. Nevertheless, environmental conditions as related to water availability during the dry season and to a smaller extend to soil nutrient status and soil texture, clearly influenced trait values. When compared across species, about half of the trait-environment relationships were species-specific. Our study highlights the importance of the ecological scale within which trait covariation is considered and suggests that at regional to local scales, common trait-by-trait scaling relationships should be treated with caution. PFT definitions by themselves can potentially be an important predictor variable when inferring one trait from another. These findings have important implications for local scale dynamic vegetation models.

Tropical Tree Branch-Leaf Nutrient Scaling Relationships Vary With Sampling Location.

Bivariate relationships between plant tissue nutrient concentration have largely been studied across broad environmental scales regardless of their covariation with soil and climate. Comparing leaf and branch wood concentrations of C, Ca, K, Mg, N, Na, and P for trees growing in tropical forests in Amazonia and Australia we found that the concentrations of most elements varied with sampling location, but with foliar and branch woody tissues varying from site to site in different ways. Using a Mixed Effect Model (MEM) approach it was further found that relationships between branch and leaf concentrations within individual plots differed in terms of both slope and/or significance to the ordinary least squares (OLS) estimates for most elements. Specifically, using MEM we found that within plots only K and Mg were correlated across organs, but with the K cross-organ intercept estimates varying significantly between sites. MEM analyses further showed that within-plot wood density variations were also negatively related to wood K and Na, suggesting a potentially important role for these cations in water transport and/or storage in woody tissues. The OLS method could not detect significant correlations in any of the above cases. By contrast, although Ca, N, and P leaf and wood tissue concentrations showed similar patterns when individual elements were compared across sites, MEM analyses suggested no consistent association within sites. Thus, for all these three elements, strong within-tree scaling relationships were inferred when data were analyzed across sites using OLS, even though there was no relationship within individual sites. Thus (as for Ca, N, and P) not only can a pooling of data across sites result in trait (co)variations attributable to the environment potentially being incorrectly attributed solely to the species and/or individual (the so-called "ecological fallacy"), but in some cases (as was found here for K and Na) the opposite can also sometimes occur with significant within-site covariations being obscured by large site-site variations. We refer to the latter phenomenon as "environmental obfuscation."

Seeking Resistance in Coral Reef Ecosystems: The Interplay of Biophysical Factors and Bleaching Resistance under a Changing Climate: The Interplay of a Reef's Biophysical Factors Can Mitigate the Coral Bleaching Response.

If we are to ensure the persistence of species in an increasingly warm world, of interest is the identification of drivers that affect the ability of an organism to resist thermal stress. Underpinning any organism's capacity for resistance is a complex interplay between biological and physical factors occurring over multiple scales. Tropical coral reefs are a unique system, in that their function is dependent upon the maintenance of a coral-algal symbiosis that is directly disrupted by increases in water temperature. A number of physical factors have been identified as affecting the biological responses of the coral organism under broadscale thermal anomalies. One such factor is water flow, which is capable of modulating both organismal metabolic functioning and thermal environments. Understanding the physiological and hydrodynamic drivers of organism response to thermal stress improves predictive capabilities and informs targeted management responses, thereby increasing the resilience of reefs into the future.

Compositional response of Amazon forests to climate change.

Most of the planet's diversity is concentrated in the tropics, which includes many regions undergoing rapid climate change. Yet, while climate-induced biodiversity changes are widely documented elsewhere, few studies have addressed this issue for lowland tropical ecosystems. Here we investigate whether the floristic and functional composition of intact lowland Amazonian forests have been changing by evaluating records from 106 long-term inventory plots spanning 30 years. We analyse three traits that have been hypothesized to respond to different environmental drivers (increase in moisture stress and atmospheric CO2 concentrations): maximum tree size, biogeographic water-deficit affiliation and wood density. Tree communities have become increasingly dominated by large-statured taxa, but to date there has been no detectable change in mean wood density or water deficit affiliation at the community level, despite most forest plots having experienced an intensification of the dry season. However, among newly recruited trees, dry-affiliated genera have become more abundant, while the mortality of wet-affiliated genera has increased in those plots where the dry season has intensified most. Thus, a slow shift to a more dry-affiliated Amazonia is underway, with changes in compositional dynamics (recruits and mortality) consistent with climate-change drivers, but yet to significantly impact whole-community composition. The Amazon observational record suggests that the increase in atmospheric CO2 is driving a shift within tree communities to large-statured species and that climate changes to date will impact forest composition, but long generation times of tropical trees mean that biodiversity change is lagging behind climate change.

Field methods for sampling tree height for tropical forest biomass estimation.

Quantifying the relationship between tree diameter and height is a key component of efforts to estimate biomass and carbon stocks in tropical forests. Although substantial site-to-site variation in height-diameter allometries has been documented, the time consuming nature of measuring all tree heights in an inventory plot means that most studies do not include height, or else use generic pan-tropical or regional allometric equations to estimate height.Using a pan-tropical dataset of 73 plots where at least 150 trees had in-field ground-based height measurements, we examined how the number of trees sampled affects the performance of locally derived height-diameter allometries, and evaluated the performance of different methods for sampling trees for height measurement.Using cross-validation, we found that allometries constructed with just 20 locally measured values could often predict tree height with lower error than regional or climate-based allometries (mean reduction in prediction error = 0.46 m). The predictive performance of locally derived allometries improved with sample size, but with diminishing returns in performance gains when more than 40 trees were sampled. Estimates of stand-level biomass produced using local allometries to estimate tree height show no over- or under-estimation bias when compared with biomass estimates using field measured heights. We evaluated five strategies to sample trees for height measurement, and found that sampling strategies that included measuring the heights of the ten largest diameter trees in a plot outperformed (in terms of resulting in local height-diameter models with low height prediction error) entirely random or diameter size-class stratified approaches.Our results indicate that even limited sampling of heights can be used to refine height-diameter allometries. We recommend aiming for a conservative threshold of sampling 50 trees per location for height measurement, and including the ten trees with the largest diameter in this sample.

A Single Center Evaluation of the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging against Transperineal Prostate Mapping Biopsy: An Analysis of Men with Benign Histology and Insignificant Cancer following Transrectal Ultrasound Biopsy.

PURPOSE: In this study we evaluated the diagnostic performance of transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging to detect prostate cancer against transperineal prostate mapping biopsy as the reference test. MATERIALS AND METHODS: Transrectal ultrasound guided biopsy, multiparametric magnetic resonance imaging and transperineal prostate mapping biopsy were performed in 426 patients between April 2012 and January 2016. Patients initially underwent systematic 12 core transrectal ultrasound guided biopsy followed 3 months later by 1.5 Tesla, high resolution T2, diffusion-weighted, dynamic contrast enhanced multiparametric magnetic resonance imaging. Two specialist uroradiologists blinded to the results of transperineal prostate mapping biopsy allocated a PI-RADS™ (Prostate Imaging-Reporting and Data System) score to each multiparametric magnetic resonance imaging study. Transperineal prostate mapping biopsy with 5 mm interval sampling, which was performed within 6 months of multiparametric magnetic resonance imaging, served as the reference test. RESULTS: Transrectal ultrasound guided biopsy identified 247 of 426 patients with prostate cancer and 179 of 426 with benign histology. Transperineal prostate mapping biopsy detected prostate cancer in 321 of 426 patients. On transperineal prostate mapping biopsy 94 of 179 patients with benign transrectal ultrasound guided biopsy had prostate cancer and 95 of 247 with prostate cancer on transrectal ultrasound guided biopsy were identified with cancer of higher grade. Using a multiparametric magnetic resonance imaging PI-RADS score of 3 or greater to detect significant prostate cancer, defined as any core containing Gleason 4 + 3 or greater prostate cancer on transperineal prostate mapping biopsy, the ROC AUC was 0.754 (95% CI 0.677-0.819) with 87.0% sensitivity (95% CI 77.3-97.0), 55.3% specificity (95% CI 50.2-60.4) and 97.1% negative predictive value (95% CI 94.8-99.4). CONCLUSIONS: Multiparametric magnetic resonance imaging is a more accurate diagnostic test than transrectal ultrasound guided biopsy. However, a significant proportion of ISUP (International Society of Urological Pathology) Grade Group 2 prostate cancer remained undetected following multiparametric magnetic resonance imaging. Although multiparametric magnetic resonance imaging could avoid unnecessary biopsy in many patients with ISUP Grade Group 3 or greater prostate cancer, at less stringent definitions of significant cancer a substantial proportion of prostate cancer would remain undetected after multiparametric magnetic resonance imaging.

On the relationship between fire regime and vegetation structure in the tropics.

We assessed data from 11 experiments examining the effects of the timing and/or frequency of fire on tropical forest and/or savanna vegetation structure over one decade or more. The initial 'control treatment' in many such cases consisted of previously cleared land. This is as opposed to natural vegetation subject to some sort of endogenous fire regime before the imposition of fire treatments. Effects of fire on fractional foliar cover are up to 10-fold greater when clearing pre-treatments are imposed. Moreover, because many of the 'classic' fire trials were initialised with applied management questions in mind, most have also used burning regimes much more frequent and/or severe than those occurring in the absence of human activity. Once these factors are taken into account, our modelling analysis shows that nonanthropogenic fire regimes serve to reduce canopy vegetative cover to a much lower extent than has previously been argued to be the case. These results call into question the notion that fire effects on tropical vegetation can be of a sufficient magnitude to maintain open-type savanna ecosystems under climatic/soil regimes otherwise sufficient to give rise to a more luxurious forest-type vegetation cover.

Rainforest trees respond to drought by modifying their hydraulic architecture.

Increased drought is forecasted for tropical regions, with severe implications for the health and function of forest ecosystems. How mature forest trees will respond to water deficit is poorly known. We investigated wood anatomy and leaf traits in lowland tropical forest trees after 24 months of experimental rainfall exclusion. Sampling sun-exposed young canopy branches from target species, we found species-specific systematic variation in hydraulic-related wood anatomy and leaf traits in response to drought stress. Relative to controls, drought-affected individuals of different tree species variously exhibited trait measures consistent with increasing hydraulic safety. These included narrower or less vessels, reduced vessel groupings, lower theoretical water conductivities, less water storage tissue and more abundant fiber in their wood, and more occluded vessels. Drought-affected individuals also had thinner leaves, and more negative pre-dawn or mid-day leaf water potentials. Future studies examining both wood and leaf hydraulic traits should improve the representation of plant hydraulics within terrestrial ecosystem and biosphere models, and help fine-tune predictions of how future climate changes will affect tropical forests globally.

Supporting the library and information needs of UWE health and social care students on placement.

OBJECTIVE: The aim of this research was to explore the library and information needs of health and social care students whilst on placement. METHODS: Both desk and primary research were conducted and included an online questionnaire to students and semi-structured interviews. RESULTS: The questionnaire was completed by 252 students from a variety of programmes, equivalent to a 10% response rate. The results indicate a wide range of factors impacting on the library and information experiences of students. Whilst differences in the availability of a physical library in hospital or community locations still exist, these are mitigated by technology and a preference for home study. A significant result is that 77% (n = 193) of students on placement study at home, using a variety of Internet-connected devices. This highlights a marked change in practice and underlines the need for mobile-compliant e-resources and accessible at-a-distance services. CONCLUSION: As a result of this research, practical recommendations on how library support can be improved were developed including enhanced collaboration and learning with NHS colleagues, and knowledge sharing with other departments within the University who support our students.

Leaf-level photosynthetic capacity in lowland Amazonian and high-elevation Andean tropical moist forests of Peru.

We examined whether variations in photosynthetic capacity are linked to variations in the environment and/or associated leaf traits for tropical moist forests (TMFs) in the Andes/western Amazon regions of Peru. We compared photosynthetic capacity (maximal rate of carboxylation of Rubisco (Vcmax ), and the maximum rate of electron transport (Jmax )), leaf mass, nitrogen (N) and phosphorus (P) per unit leaf area (Ma , Na and Pa , respectively), and chlorophyll from 210 species at 18 field sites along a 3300-m elevation gradient. Western blots were used to quantify the abundance of the CO2 -fixing enzyme Rubisco. Area- and N-based rates of photosynthetic capacity at 25°C were higher in upland than lowland TMFs, underpinned by greater investment of N in photosynthesis in high-elevation trees. Soil [P] and leaf Pa were key explanatory factors for models of area-based Vcmax and Jmax but did not account for variations in photosynthetic N-use efficiency. At any given Na and Pa , the fraction of N allocated to photosynthesis was higher in upland than lowland species. For a small subset of lowland TMF trees examined, a substantial fraction of Rubisco was inactive. These results highlight the importance of soil- and leaf-P in defining the photosynthetic capacity of TMFs, with variations in N allocation and Rubisco activation state further influencing photosynthetic rates and N-use efficiency of these critically important forests.

Evolutionary heritage influences Amazon tree ecology.

Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change.

Separating species and environmental determinants of leaf functional traits in temperate rainforest plants along a soil-development chronosequence.

We measured a diverse range of foliar characteristics in shrub and tree species in temperate rainforest communities along a soil chronosequence (six sites from 8 to 120000 years) and used multilevel model analysis to attribute the proportion of variance for each trait into genetic (G, here meaning species-level), environmental (E) and residual error components. We hypothesised that differences in leaf traits would be driven primarily by changes in soil nutrient availability during ecosystem progression and retrogression. Several leaf structural, chemical and gas-exchange traits were more strongly driven by G than E effects. For leaf mass per unit area (MA), foliar [N], net CO2 assimilation and dark respiration rates and foliar carbohydrate concentration, the G component accounted for 60-87% of the total variance, with the variability associated with plot, the E effect, much less important. Other traits, such as foliar [P] and N:P, displayed strong E and residual effects. Analyses revealed significant reductions in the slopes of G-only bivariate relationships when compared with raw relationships, indicating that a large proportion of trait-trait relationships is species based, and not a response to environment per se. This should be accounted for when assessing the mechanistic basis for using such relationships in order to make predictions of responses of plants to short-term environmental change.

Biome-specific effects of nitrogen and phosphorus on the photosynthetic characteristics of trees at a forest-savanna boundary in Cameroon.

Photosynthesis/nutrient relationships of proximally growing forest and savanna trees were determined in an ecotonal region of Cameroon (Africa). Although area-based foliar N concentrations were typically lower for savanna trees, there was no difference in photosynthetic rates between the two vegetation formation types. Opposite to N, area-based P concentrations were-on average-slightly lower for forest trees; a dependency of photosynthetic characteristics on foliar P was only evident for savanna trees. Thus savanna trees use N more efficiently than their forest counterparts, but only in the presence of relatively high foliar P. Along with some other recent studies, these results suggest that both N and P are important modulators of woody tropical plant photosynthetic capacities, influencing photosynthetic metabolism in different ways that are also biome specific. Attempts to find simple unifying equations to describe woody tropical vegetation photosynthesis-nutrient relationships are likely to meet with failure, with ecophysiological distinctions between forest and savanna requiring acknowledgement.