Cardiac allograft vasculopathy (CAV), the major cause of late allograft loss after cardiac transplantation, results from donor-directed cellular and humoral alloimmune responses. Graft vascular ...endothelial cells (EC) are primary targets of these destructive responses, suggesting that factors associated with endothelial injury and repair could serve as biomarkers of CAV.
Using a protein profiler array platform, we measured the levels of 55 angiogenesis-related proteins in sera from 33 adult heart transplant recipients, including 17 with angiographically documented CAV and 16 age- and gender-matched controls without CAV. All patients were >2 years after heart transplant.
The study population was 75% male with a mean age of 62 ± 11 years. On average, patients were 12 ± 5 years after heart transplantation. We found that vascular endothelial growth factor (VEGF)-C, VEGF-A, angiopoietin-2, artemin, urokinase-type plasminogen activator and vasohibin were strongly associated with established CAV (all p < 0.01). Multivariable modeling identified VEGF-C, VEGF-A and platelet factor-4 (PF-4) as significant independent biomarkers of CAV. Furthermore, receiver-operating characteristic curve analysis demonstrated that the combination of all 3 molecules provided outstanding performance for the diagnosis of CAV (area under the curve AUC = 0.98; p < 0.001).
Serum levels of VEGF-C, VEGF-A and PF-4 demonstrate strong associations with established CAV and, together with related angiogenesis factors, may serve as a reliable, non-invasive diagnostic test for CAV in cardiac transplant recipients.
Many threatened species depend on climatic microrefugia, but places with harsh climates for predators may also play a refugial role. Feral cats threaten many native species in arid Australia. ...Although cats can persist in regions with no free water, their abundance should depend on the availability of microclimates that protect them from harsh environmental conditions. We developed a biophysical model of feral cat heat stress and used it to explore how behavior and microhabitat features influence water requirements and activity. Tests of model predictions against fine‐scale GPS and microclimate data highlight the importance of refuges, particularly rabbit burrows. Continent‐wide simulations show large but temporally varying areas of the arid zone that would be lethal for cats without access to deep or shaded burrows. Our approach can identify locations that may act as natural refuges for native prey, and where habitat management strategies may be effective in controlling cat abundance.
Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping ...activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc-but not with a vasodilator-strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.
The spatial organization of cell fates during development involves the interpretation of morphogen gradients by cellular signaling cascades and transcriptional networks. Recent studies use ...biophysical models, genetics, and quantitative imaging to unravel how tissue-level morphogen behavior arises from subcellular events. Moreover, data from several systems show that morphogen gradients, downstream signaling, and the activity of cell-intrinsic transcriptional networks change dynamically during pattern formation. Studies from Drosophila and now also vertebrates suggest that transcriptional network dynamics are central to the generation of gene expression patterns. Together, this leads to the view that pattern formation is an emergent behavior that results from the coordination of events occurring across molecular, cellular, and tissue scales. The development of novel approaches to study this complex process remains a challenge.
How climate impacts organisms depends not only on their physiology, but also whether they can buffer themselves against climate variability via their behaviour. One of the way species can withstand ...hot temperatures is by seeking out cool microclimates, but only if their habitat provides such refugia. Here, we describe a novel thermoregulatory strategy in an arboreal mammal, the koala Phascolarctos cinereus. During hot weather, koalas enhanced conductive heat loss by seeking out and resting against tree trunks that were substantially cooler than ambient air temperature. Using a biophysical model of heat exchange, we show that this behaviour greatly reduces the amount of heat that must be lost via evaporative cooling, potentially increasing koala survival during extreme heat events. While it has long been known that internal temperatures of trees differ from ambient air temperatures, the relevance of this for arboreal and semi-arboreal mammals has not previously been explored. Our results highlight the important role of tree trunks as aboveground ‘heat sinks’, providing cool local microenvironments not only for koalas, but also for all tree-dwelling species.
Knowing where species occur is fundamental to many ecological and environmental applications. Species distribution models (SDMs) are typically based on correlations between species occurrence data ...and environmental predictors, with ecological processes captured only implicitly. However, there is a growing interest in approaches that explicitly model processes such as physiology, dispersal, demography and biotic interactions. These models are believed to offer more robust predictions, particularly when extrapolating to novel conditions. Many process–explicit approaches are now available, but it is not clear how we can best draw on this expanded modelling toolbox to address ecological problems and inform management decisions. Here, we review a range of process–explicit models to determine their strengths and limitations, as well as their current use. Focusing on four common applications of SDMs – regulatory planning, extinction risk, climate refugia and invasive species – we then explore which models best meet management needs. We identify barriers to more widespread and effective use of process‐explicit models and outline how these might be overcome. As well as technical and data challenges, there is a pressing need for more thorough evaluation of model predictions to guide investment in method development and ensure the promise of these new approaches is fully realised.
Endothermic organisms typically maintain high and relatively constant body temperatures in the face of environmental variation by regulating their metabolic and water loss rates in conjunction with ...behavioural and postural adjustments. A mechanistic understanding of these processes provides a perspective of the fundamental niches of endotherms by quantifying their energy and water requirements, restrictions on habitat use and survival limits.
Here we introduce and document the endotherm model of NicheMapR, an R package that includes a suite of programs for the mechanistic modelling of energy and mass exchange between organisms and their environments. The NicheMapR endotherm model is based on a Fortran program that simultaneously solves for the metabolic rate, water loss rate, fur/feather temperature and skin temperature required to balance the heat budget in a given microclimate. These calculations are a function of traits relating to insulation, shape, physiological and behavioural responses. The program contains algorithms for computing heat transfer through a porous insulative layer (fur/feathers), including solar and infrared radiation fluxes as well as convective and conductive exchange, and can handle differing dorsal and ventral traits and environments.
Here we configure the program to be called from R as part of the NicheMapR package and describe the model in detail. We break the program into a set of modules that can be run in isolation, or jointly, and combined in different ways to capture species‐specific thermoregulatory responses. We explain the theory and underlying subroutines, and the default thermoregulatory settings. We discuss how the model can be adapted to incorporate species‐specific behaviours and extended to incorporate multiple body parts. We also compare the endotherm modelling setup with the ectotherm model of the NicheMapR package and discuss how the different modelling strategies they require reflect fundamental biological issues.
Semaphorin 3F (SEMA3F) provides neuronal guidance cues via its ability to bind neuropilin 2 (NRP2) and Plexin A family molecules. Recent studies indicate that SEMA3F has biological effects in other ...cell types, however its mechanism(s) of function is poorly understood. Here, we analyze SEMA3F-NRP2 signaling responses in human endothelial, T cell and tumor cells using phosphokinase arrays, immunoprecipitation and Western blot analyses. Consistently, SEMA3F inhibits PI-3K and Akt activity, and responses are associated with the disruption of mTOR/rictor assembly and mTOR-dependent activation of the RhoA GTPase. We also find that the expression of vascular endothelial growth factor, as well as mTOR-inducible cellular activation responses and cytoskeleton stability are inhibited by SEMA3F-NRP2 interactions in vitro. In vivo, local and systemic overproduction of SEMA3F reduces tumor growth in NRP2-expressing xenografts. Taken together, SEMA3F regulates mTOR signaling in diverse human cell types, suggesting that it has broad therapeutic implications.
Aim: Body size often varies clinally, with dominant explanations centred on how body size influences heat exchange (e.g. Bergmann's rule). However, for endotherms, pelage properties can also ...dramatically alter heat exchange - a point emphasized by Scholander in the 1950s but which has received little attention in biogeographical analyses. Here, we investigate how geographical variation in both body size and fur properties of the koala (Phascolarctos cinereus) is related to climate. Location: Eastern Australia. Methods: We measured head length and fur depths of koala museum specimens from across its geographical range, and quantified the relationship between fur depth and insulation. We used linear regression and regression tree analyses to test for associations between morphological traits and climate variables relating to four hypotheses: heat conservation (Bergmann's rule), heat dissipation, fasting endurance/survival of extremes, and productivity. Results: Both body size and fur depth of koalas decrease substantially towards the tropics. Consistent with Scholander's view, fur properties showed stronger associations with climate than body size. Males, the larger sex, had shorter fur than females in hot environments but not in more temperate regions, suggesting that shorter fur compensates for sexual size dimorphism. While fur depth and male body size were more strongly associated with variables relating to heat dissipation, female body size was most strongly associated with minimum temperatures. Main conclusions: Body size interacts strongly with other traits, such as fur properties, to influence how animals experience climate. Our results emphasize how the consideration of geographical variation in suites of functionally related traits can provide important insight into how species persist across broad environmental gradients.
We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II ...trial could be corroborated in a rigorous, multicenter, phase III trial.
Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point.
Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86–1.32, P = 0.55, overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79–1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82–1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin.
The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further.
Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.
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