Thermal, water, and land cover factors led to contrasting urban and rural vegetation resilience to extreme hot months.

With continuing global warming and urbanization, it is increasingly important to understand the resilience of urban vegetation to extreme high temperatures, but few studies have examined urban vegetation at large scale or both concurrent and delayed responses. In this study, we performed an urban-rural comparison using the Enhanced Vegetation Index and months that exceed the historical 90th percentile in mean temperature (referred to as "hot months") across 85 major cities in the contiguous United States. We found that hot months initially enhanced vegetation greenness but could cause a decline afterwards, especially for persistent (≥4 months) and intense (≥+2 °C) episodes in summer. The urban responses were more positive than rural in the western United States or in winter, but more negative during spring-autumn in the eastern United States. The east-west difference can be attributed to the higher optimal growth temperatures and lower water stress levels of the western urban vegetation than the rural. The urban responses also had smaller magnitudes than the rural responses, especially in deciduous forest biomes, and least in evergreen forest biomes. Within each biome, analysis at 1 km pixel level showed that impervious fraction and vegetation cover, local urban heat island intensity, and water stress were the key drivers of urban-rural differences. These findings advance our understanding of how prolonged exposure to warm extremes, particularly within urban environments, affects vegetation greenness and vitality. Urban planners and ecosystem managers should prioritize the long and intense events and the key drivers in fostering urban vegetation resilience to heat waves.

Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.

cGAS-STING signalling regulates microglial chemotaxis in genome instability.

Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-ß treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system.

Alzheimer's disease-associated R47H TREM2 increases, but wild-type TREM2 decreases, microglial phagocytosis of synaptosomes and neuronal loss.

Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems. Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F.

Quantification of human contribution to soil moisture-based terrestrial aridity.

Current knowledge of the spatiotemporal patterns of changes in soil moisture-based terrestrial aridity has considerable uncertainty. Using Standardized Soil Moisture Index (SSI) calculated from multi-source merged data sets, we find widespread drying in the global midlatitudes, and wetting in the northern subtropics and in spring between 45°N-65°N, during 1971-2016. Formal detection and attribution analysis shows that human forcings, especially greenhouse gases, contribute significantly to the changes in 0-10 cm SSI during August-November, and 0-100 cm during September-April. We further develop and apply an emergent constraint method on the future SSI's signal-to-noise (S/N) ratios and trends under the Shared Socioeconomic Pathway 5-8.5. The results show continued significant presence of human forcings and more rapid drying in 0-10 cm than 0-100 cm. Our findings highlight the predominant human contributions to spatiotemporally heterogenous terrestrial aridification, providing a basis for drought and flood risk management.

Gridded daily weather data for North America with comprehensive uncertainty quantification.

Access to daily high-resolution gridded surface weather data based on direct observations and over long time periods is essential for many studies and applications including vegetation, wildlife, soil health, hydrological modelling, and as driver data in Earth system models. We present Daymet V4, a 40-year daily meteorological dataset on a 1 km grid for North America, Hawaii, and Puerto Rico, providing temperature, precipitation, shortwave radiation, vapor pressure, snow water equivalent, and day length. The dataset includes an objective quantification of uncertainty based on strict cross-validation analysis for temperature and precipitation results. The dataset represents several improvements from a previous version, and this data descriptor provides complete documentation for updated methods. Improvements include: reductions in the timing bias of input reporting weather station measurements; improvement to the three-dimensional regression model techniques in the core algorithm; and a novel approach to handling high elevation temperature measurement biases. We show cross-validation analyses with the underlying weather station data to demonstrate the technical validity of new dataset generation methods, and to quantify improved accuracy.

Seasonal changes in GPP/SIF ratios and their climatic determinants across the Northern Hemisphere.

Satellite-derived sun-induced chlorophyll fluorescence (SIF) has been increasingly used for estimating gross primary production (GPP). However, the relationship between SIF and GPP has not been well defined, impeding the translation of satellite observed SIF to GPP. Previous studies have generally assumed a linear relationship between SIF and GPP at daily and longer time scales, but support for this assumption is lacking. Here, we used the GPP/SIF ratio to investigate seasonal variations in the relationship between SIF and GPP over the Northern Hemisphere (NH). Based on multiple SIF products and MODIS and FLUXCOM GPP data, we found strong seasonal hump-shaped patterns for the GPP/SIF ratio over northern latitudes, with higher values in the summer than in the spring or autumn. This hump-shaped GPP/SIF seasonal variation was confirmed by examining different SIF products and was evident for most vegetation types except evergreen broadleaf forests. The seasonal amplitude of the GPP/SIF ratio decreased from the boreal/arctic region to drylands and the tropics. For most of the NH, the lowest GPP/SIF values occurred in October or September, while the maximum GPP/SIF values were evident in June and July. The most pronounced seasonal amplitude of GPP/SIF occurred in intermediate temperature and precipitation ranges. GPP/SIF was positively related to temperature in the early and late parts of the growing season, but not during the peak growing months. These shifting relationships between temperature and GPP/SIF across different months appeared to play a key role in the seasonal dynamics of GPP/SIF. Several mechanisms may explain the patterns we observed, and future research encompassing a broad range of climate and vegetation settings is needed to improve our understanding of the spatial and temporal relationships between SIF and GPP. Nonetheless, the strong seasonal variation in GPP/SIF we identified highlights the importance of incorporating this behavior into SIF-based GPP estimations.

CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer's disease-protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion.

CD33 is a Siglec (sialic acid-binding immunoglobulin-type lectin) receptor on microglia. Human CD33 can be alternatively spliced into two isoforms: the long isoform (CD33M) and a shorter isoform (CD33m) that lacks the sialic acid-binding site. CD33m appears to protect against Alzheimer's disease; however, it remains unclear how. To investigate potential mechanisms by which CD33m may confer protection, we expressed the CD33m and CD33M isoforms of human CD33 in mouse BV-2 and human CHME3 microglial cells and assessed microglia functions. In the BV-2 cells, CD33M inhibited microglial phagocytosis of beads, synapses, debris and dead cells, while CD33m increased phagocytosis of beads, debris and cells. RNAi knockdown of the endogenous mouse CD33 increased phagocytosis and prevented CD33m's (but not CD33M's) effect on phagocytosis. CD33M increased cell attachment but inhibited cell proliferation, while CD33m did the opposite. We also found that CD33M inhibited cell migration. In human CHME3 cells, CD33M increased cell attachment, but inhibited phagocytosis, proliferation and migration, whereas CD33m did the opposite. We conclude that CD33M inhibits microglial phagocytosis, inhibits migration and increases adhesion, while CD33m increases phagocytosis, proliferation and inhibits adhesion. Thus, CD33m might protect against Alzheimer's disease by increasing microglial proliferation, movement and phagocytosis of debris and dead cells.

Moisture availability mediates the relationship between terrestrial gross primary production and solar-induced chlorophyll fluorescence: Insights from global-scale variations.

Effective use of solar-induced chlorophyll fluorescence (SIF) to estimate and monitor gross primary production (GPP) in terrestrial ecosystems requires a comprehensive understanding and quantification of the relationship between SIF and GPP. To date, this understanding is incomplete and somewhat controversial in the literature. Here we derived the GPP/SIF ratio from multiple data sources as a diagnostic metric to explore its global-scale patterns of spatial variation and potential climatic dependence. We found that the growing season GPP/SIF ratio varied substantially across global land surfaces, with the highest ratios consistently found in boreal regions. Spatial variation in GPP/SIF was strongly modulated by climate variables. The most striking pattern was a consistent decrease in GPP/SIF from cold-and-wet climates to hot-and-dry climates. We propose that the reduction in GPP/SIF with decreasing moisture availability may be related to stomatal responses to aridity. Furthermore, we show that GPP/SIF can be empirically modeled from climate variables using a machine learning (random forest) framework, which can improve the modeling of ecosystem production and quantify its uncertainty in global terrestrial biosphere models. Our results point to the need for targeted field and experimental studies to better understand the patterns observed and to improve the modeling of the relationship between SIF and GPP over broad scales.

Characterization and preclinical evaluation of a protease activated receptor 2 (PAR2) monoclonal antibody as a preventive therapy for migraine.

AIM: Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models. METHODS: Flow cytometry, immunocytochemistry, calcium imaging, Homogeneous Time Resolved Technology (HTRF) epitope competition assay and serum pharmacokinetic (PK) assay in rats were performed to confirm the activity, specificity and in vivo stability of PAR650097, a novel anti- protease activated receptor 2 monoclonal antibody. In vivo assessment was performed in female C57BL/6J mice by evaluation of PAR650097 in preventing cutaneous allodynia elicited by (a) supradural injection of the protease activated receptor 2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-amide trifluoroacetate (SLIGRL), or calcitonin gene-related (CGRP) peptide, and (b) induction of latent sensitization by priming with three daily episodes of restraint stress followed by challenge with a subthreshold inhalational exposure to umbellulone (UMB), a transient receptor potential ankyrin 1 (TRPA1) agonist. PAR650097 was administered as a pretreatment prior to the first restraint stress, umbellulone exposure, SLIGRL or calcitonin gene-related peptide injection. Additionally, fremanezumab, a calcitonin gene-related peptide antibody was administered as pre-treatment prior to supradural administration of calcitonin gene-related peptide or SLIGRL. RESULTS: In vitro, PAR650097 demonstrated rapid interaction with protease activated receptor 2, enabling it to fully inhibit protease-induced protease activated receptor 2 activation, in human and mouse cells, with high potency. Furthermore, PAR650097 was highly selective for protease activated receptor 2, demonstrating no affinity for protease activated receptor 1 protein and no functional effect on the activation of cellular protease activated receptor 1 with thrombin. In addition, PAR650097 had an acceptable PK profile, compatible with testing the effects of selective protease activated receptor 2 inhibition in vivo. In vivo, PAR650097 blocked cutaneous allodynia induced by either supradural SLIGRL or calcitonin gene-related peptide. Fremanezumab abolished cutaneous allodynia induced by supradural CGRP, and partially attenuated cutaneous allodynia induced by SLIGRL. Administration of PAR650097, before the first restraint stress episode, did not prevent the acute stress-induced cutaneous allodynia or restraint stress priming revealed by cutaneous allodynia induced by inhalational umbellulone. In contrast, PAR650097 prevented expression of cutaneous allodynia when given before the umbellulone challenge in restraint stress-primed animals. CONCLUSION: PAR650097 specifically inhibits endogenously expressed protease activated receptor 2 in human and mouse cells with high potency. This antibody has an acceptable PK profile in rodents and effectively blocked SLIGR-induced cutaneous allodynia. PAR650097 additionally prevented cutaneous allodynia induced by supradural calcitonin gene-related peptide, indicating that the protease activated receptor 2 receptor is a downstream consequence of calcitonin gene-related peptide actions. Fremanezumab effectively blocked calcitonin gene-related peptide-induced cutaneous allodynia and only partially reduced cutaneous allodynia induced by a protease activated receptor 2 activator, suggesting both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine pain. While PAR650097 did not prevent stress-induced cutaneous allodynia or priming, it effectively prevented cutaneous allodynia induced by a TRPA1 agonist in animals with latent sensitization. Activation of protease activated receptor 2, therefore, contributes to both calcitonin gene-related peptide-dependent and -independent mechanisms in promoting migraine-like pain. Therapeutic targeting of protease activated receptor 2 receptors may represent an anti-migraine pain strategy with a potentially broad efficacy profile.

Quantifying the drivers and predictability of seasonal changes in African fire.

Africa contains some of the most vulnerable ecosystems to fires. Successful seasonal prediction of fire activity over these fire-prone regions remains a challenge and relies heavily on in-depth understanding of various driving mechanisms underlying fire evolution. Here, we assess the seasonal environmental drivers and predictability of African fire using the analytical framework of Stepwise Generalized Equilibrium Feedback Assessment (SGEFA) and machine learning techniques (MLTs). The impacts of sea-surface temperature, soil moisture, and leaf area index are quantified and found to dominate the fire seasonal variability by regulating regional burning condition and fuel supply. Compared with previously-identified atmospheric and socioeconomic predictors, these slowly evolving oceanic and terrestrial predictors are further identified to determine the seasonal predictability of fire activity in Africa. Our combined SGEFA-MLT approach achieves skillful prediction of African fire one month in advance and can be generalized to provide seasonal estimates of regional and global fire risk.

Representing the function and sensitivity of coastal interfaces in Earth system models.

Between the land and ocean, diverse coastal ecosystems transform, store, and transport material. Across these interfaces, the dynamic exchange of energy and matter is driven by hydrological and hydrodynamic processes such as river and groundwater discharge, tides, waves, and storms. These dynamics regulate ecosystem functions and Earth's climate, yet global models lack representation of coastal processes and related feedbacks, impeding their predictions of coastal and global responses to change. Here, we assess existing coastal monitoring networks and regional models, existing challenges in these efforts, and recommend a path towards development of global models that more robustly reflect the coastal interface.

Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study.

The specific targeting of protein-protein interactions by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine-masking approach was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine-containing molecules. Ultimately, this will facilitate the discovery of phosphoserine-containing small-molecule therapeutics.

Urban warming advances spring phenology but reduces the response of phenology to temperature in the conterminous United States.

Urbanization has caused environmental changes, such as urban heat islands (UHIs), that affect terrestrial ecosystems. However, how and to what extent urbanization affects plant phenology remains relatively unexplored. Here, we investigated the changes in the satellite-derived start of season (SOS) and the covariation between SOS and temperature (RT ) in 85 large cities across the conterminous United States for the period 2001-2014. We found that 1) the SOS came significantly earlier (6.1 ± 6.3 d) in 74 cities and RT was significantly weaker (0.03 ± 0.07) in 43 cities when compared with their surrounding rural areas (P < 0.05); 2) the decreased magnitude in RT mainly occurred in cities in relatively cold regions with an annual mean temperature <17.3 °C (e.g., Minnesota, Michigan, and Pennsylvania); and 3) the magnitude of urban-rural difference in both SOS and RT was primarily correlated with the intensity of UHI. Simulations of two phenology models further suggested that more and faster heat accumulation contributed to the earlier SOS, while a decrease in required chilling led to a decline in RT magnitude in urban areas. These findings provide observational evidence of a reduced covariation between temperature and SOS in major US cities, implying the response of spring phenology to warming conditions in nonurban environments may decline in the warming future.

Alder Distribution and Expansion Across a Tundra Hillslope: Implications for Local N Cycling.

Increases in the availability of nitrogen (N) may have consequences for plant growth and nutrient cycling in N-limited tundra plant communities. We investigated the impact alder (Alnus viridis spp. fruticosa), an N-fixing deciduous shrub, has on tundra N cycling at a hillslope located on Alaska's Seward Peninsula. We quantified N fixation using 15N2 incubations within two distinct alder communities at this site: alder shrublands located on well-drained, rocky outcroppings in the uplands and alder savannas located in water tracks along the moist toeslope of the hill. Annual N fixation rates in alder shrublands were 1.95 ± 0.68 g N m-2 year-1, leading to elevated N levels in adjacent soils and plants. Alder savannas had lower N fixation rates (0.53 ± 0.19 g N m-2 year-1), perhaps due to low phosphorus availability and poor drainage in these highly organic soil profiles underlain by permafrost. In addition to supporting higher rates of N fixation, tall-statured alder shrublands had different foliar traits than relatively short-statured alder in savannas, providing an opportunity to link N fixation to remotely-sensed variables. We were able to generate a map of the alder shrubland distribution at this site using a multi-sensor fusion approach. The change in alder shrubland distribution through time was also determined from historic aerial and satellite imagery. Analysis of historic imagery showed that the area of alder shrublands at this site has increased by 40% from 1956 to 2014. We estimate this increase in alder shrublands was associated with a 22% increase in N fixation. Our results suggest that expansion of alder shrublands has the potential to substantially alter N cycling, increase plant productivity, and redistribute C storage in upland tundra regions. An improved understanding of the consequences of N fixation within N-limited tundra plant communities will therefore be crucial for predicting the biogeochemistry of these warming ecosystems.

Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain.

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely because of the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb or by systemic delivery of an anti-P2X4 bispecific mAb with enhanced blood-spinal cord barrier permeability produced long-lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.

The sensitivity of the forest carbon budget shifts across processes along with stand development and climate change.

The future trajectory of atmospheric CO2 concentration depends on the development of the terrestrial carbon sink, which in turn is influenced by forest dynamics under changing environmental conditions. An in-depth understanding of model sensitivities and uncertainties in non-steady-state conditions is necessary for reliable and robust projections of forest development and under scenarios of global warming and CO2 enrichment. Here, we systematically assessed if a biogeochemical process-based model (3D-CMCC-CNR), which embeds similarities with many other vegetation models, applied in simulating net primary productivity (NPP) and standing woody biomass (SWB), maintained a consistent sensitivity to its 55 input parameters through time, during forest ageing and structuring as well as under climate change scenarios. Overall, the model applied at three contrasting European forests showed low sensitivity to the majority of its parameters. Interestingly, model sensitivity to parameters varied through the course of >100 yr of simulations. In particular, the model showed a large responsiveness to the allometric parameters used for initialize forest carbon and nitrogen pools early in forest simulation (i.e., for NPP up to ~37%, 256 g C·m-2 ·yr-1 and for SWB up to ~90%, 65 Mg C/ha, when compared to standard simulation), with this sensitivity decreasing sharply during forest development. At medium to longer time scales, and under climate change scenarios, the model became increasingly more sensitive to additional and/or different parameters controlling biomass accumulation and autotrophic respiration (i.e., for NPP up to ~30%, 167 g C·m-2 ·yr-1 and for SWB up to ~24%, 64 Mg C/ha, when compared to standard simulation). Interestingly, model outputs were shown to be more sensitive to parameters and processes controlling stand development rather than to climate change (i.e., warming and changes in atmospheric CO2 concentration) itself although model sensitivities were generally higher under climate change scenarios. Our results suggest the need for sensitivity and uncertainty analyses that cover multiple temporal scales along forest developmental stages to better assess the potential of future forests to act as a global terrestrial carbon sink.

Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

Interleukin (IL)-33 is an IL-1 family alarmin released from damaged epithelial and endothelial barriers to elicit immune responses and allergic inflammation via its receptor ST2. Serine proteases released from neutrophils, mast cells and cytotoxic lymphocytes have been proposed to process the N-terminus of IL-33 to enhance its activity. Here we report that processing of full length IL-33 can occur in mice deficient in these immune cell protease activities. We sought alternative mechanisms for the proteolytic activation of IL-33 and discovered that exogenous allergen proteases and endogenous calpains, from damaged airway epithelial cells, can process full length IL-33 and increase its alarmin activity up to ~60-fold. Processed forms of IL-33 of apparent molecular weights ~18, 20, 22 and 23 kDa, were detected in human lungs consistent with some, but not all, proposed processing sites. Furthermore, allergen proteases degraded processed forms of IL-33 after cysteine residue oxidation. We suggest that IL-33 can sense the proteolytic and oxidative microenvironment during tissue injury that facilitate its rapid activation and inactivation to regulate the duration of its alarmin function.

Central inhibition of granulocyte-macrophage colony-stimulating factor is analgesic in experimental neuropathic pain.

With less than 50% of patients responding to the current standard of care and poor efficacy and selectivity of current treatments, neuropathic pain continues to be an area of considerable unmet medical need. Biological therapeutics such as monoclonal antibodies (mAbs) provide better intrinsic selectivity; however, delivery to the central nervous system (CNS) remains a challenge. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is well described in inflammation-induced pain, and early-phase clinical trials evaluating its antagonism have exemplified its importance as a peripheral pain target. Here, we investigate the role of this cytokine in a murine model of traumatic nerve injury and show that deletion of the GM-CSF receptor or treatment with an antagonizing mAb alleviates pain. We also demonstrate enhanced analgesic efficacy using an engineered construct that has greater capacity to penetrate the CNS. Despite observing GM-CSF receptor expression in microglia and astrocytes, the gliosis response in the dorsal horn was not altered in nerve injured knockout mice compared with wild-type littermate controls as evaluated by ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein, respectively. Functional analysis of glial cells revealed that pretreatment with GM-CSF potentiated lipopolysaccharide-induced release of proinflammatory cytokines. In summary, our data indicate that GM-CSF is a proinflammatory cytokine that contributes to nociceptive signalling through driving spinal glial cell secretion of proinflammatory mediators. In addition, we report a successful approach to accessing CNS pain targets, providing promise for central compartment delivery of analgesics.

Mapping local and global variability in plant trait distributions.

Our ability to understand and predict the response of ecosystems to a changing environment depends on quantifying vegetation functional diversity. However, representing this diversity at the global scale is challenging. Typically, in Earth system models, characterization of plant diversity has been limited to grouping related species into plant functional types (PFTs), with all trait variation in a PFT collapsed into a single mean value that is applied globally. Using the largest global plant trait database and state of the art Bayesian modeling, we created fine-grained global maps of plant trait distributions that can be applied to Earth system models. Focusing on a set of plant traits closely coupled to photosynthesis and foliar respiration-specific leaf area (SLA) and dry mass-based concentrations of leaf nitrogen ([Formula: see text]) and phosphorus ([Formula: see text]), we characterize how traits vary within and among over 50,000 [Formula: see text]-km cells across the entire vegetated land surface. We do this in several ways-without defining the PFT of each grid cell and using 4 or 14 PFTs; each model's predictions are evaluated against out-of-sample data. This endeavor advances prior trait mapping by generating global maps that preserve variability across scales by using modern Bayesian spatial statistical modeling in combination with a database over three times larger than that in previous analyses. Our maps reveal that the most diverse grid cells possess trait variability close to the range of global PFT means.