Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms leading to mortality and the associated changes in tree growth rates are still ...limited. We compiled a new pan‐continental tree‐ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the mortality events. The extent and duration of these reductions were highly variable (1–100 years in 96% of events) due to the complex interactions among study species and the source(s) of mortality. Strong and long‐lasting declines were found for gymnosperms, shade‐ and drought‐tolerant species, and trees that died from competition. Angiosperms and trees that died due to biotic attacks (especially bark‐beetles) typically showed relatively small and short‐term growth reductions. Our analysis did not highlight any universal trade‐off between early growth and tree longevity within a species, although this result may also reflect high variability in sampling design among sites. The intersite and interspecific variability in growth patterns before mortality provides valuable information on the nature of the mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality. Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or bark‐beetle attack, while long‐term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth‐based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark‐beetle outbreaks.
• The extent to which water availability can be used to predict the enlargement and final dimensions of xylem conduits remains an open issue.
• We reconstructed the time course of tracheid ...enlargement in Pinus sylvestris trees in central Spain by repeated measurements of tracheid diameter on microcores sampled weekly during a 2 yr period. We analyzed the role of water availability in these dynamics empirically through time-series correlation analysis and mechanistically by building a model that simulates daily tracheid enlargement rate and duration based on Lockhart’s equation and water potential as the sole input.
• Tracheid enlargement followed a sigmoid-like time course, which varied intra- and interannually. Our empirical analysis showed that final tracheid diameter was strongly related to water availability during tracheid enlargement. The mechanistic model was calibrated and successfully validated (R² = 0.92) against the observed tracheid enlargement time course. The model was also able to reproduce the seasonal variations of tracheid enlargement rate, duration and final diameter (R² = 0.84–0.99).
• Our results support the hypothesis that tracheid enlargement and final dimensions can be modeled based on the direct effect of water potential on turgor-driven cell expansion. We argue that such a mechanism is consistent with other reported patterns of tracheid dimension variation.
Forest disturbances such as drought, fire, and logging affect the forest carbon dynamics and the terrestrial carbon sink. Forest mortality after disturbances creates uncertainties that need to be ...accounted for to understand forest dynamics and their associated C‐sink. We combined data from permanent resampling plots and biomass oriented dendroecological plots to estimate time series of annual woody biomass growth (ABI) in several forests. ABI time series were used to benchmark a vegetation model to analyze dynamics in forest productivity and carbon allocation forced by environmental variability. The model implements source and sink limitations explicitly by dynamically constraining carbon allocation of assimilated photosynthates as a function of temperature and moisture. Bias in tree‐ring reconstructed ABI increased back in time from data collection and with increasing disturbance intensity. ABI bias ranged from zero, in open stands without recorded mortality, to over 100% in stands with major disturbances such as thinning or snowstorms. Stand leaf area was still lower than in control plots decades after heavy thinning. Disturbances, species life‐history strategy and climatic variability affected carbon‐partitioning patterns in trees. Resprouting broadleaves reached maximum biomass growth at earlier ages than nonresprouting conifers. Environmental variability and leaf area explained much variability in woody biomass allocation. Effects of stand competition on C‐allocation were mediated by changes in stand leaf area except after major disturbances. Divergence between tree‐ring estimated and simulated ABI were caused by unaccounted changes in allocation or misrepresentation of some functional process independently of the model calibration approach. Higher disturbance intensity produced greater modifications of the C‐allocation pattern, increasing error in reconstructed biomass dynamics. Legacy effects from disturbances decreased model performance and reduce the potential use of ABI as a proxy to net primary productivity. Trait‐based dynamics of C‐allocation in response to environmental variability need to be refined in vegetation models.
Forest disturbances affect carbon dynamics. We used time series of woody biomass growth (ABI) to benchmark a vegetation model where carbon allocation of assimilated photosynthates is dynamically calculated as a function of temperature and moisture. Bias in tree‐ring reconstructed ABI increases back in time and with increasing disturbance intensity. Disturbances, species life‐history strategy and climatic variability modify carbon‐partitioning patterns in trees. Environmental variability explained much variability in woody biomass allocation. Effects of stand competition on C‐allocation were mediated by changes in leaf area except after major disturbances. Divergence between tree‐ring estimated and simulated ABI was independent of the model calibration approach. Higher disturbance intensity produced greater modifications of the C‐allocation pattern, increasing error in reconstructed biomass dynamics. Legacy effects from disturbances reduce the potential use of ABI as a proxy to net primary productivity. Trait‐based dynamics of C‐allocation in response to environmental variability need to be refined in vegetation models.
Spasticity, perceived by patients as muscle rigidity and spasms, is a common symptom in multiple sclerosis (MS). It is associated with functional impairment that can exacerbate other MS symptoms and ...reduce quality of life. Pharmacological treatment options are limited and frequently ineffective. Treatment adherence is a key issue to address in these patients. The efficacy and safety of 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray for treatment of MS spasticity were demonstrated in four Phase III trials. Observational studies and registry data subsequently confirmed the effectiveness and tolerability of THC:CBD oromucosal spray under everyday practice conditions. Among patients who respond to treatment, THC:CBD oromucosal spray has been shown to produce positive improvements in gait parameters and to normalize muscle fibers.
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in ...astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
To determine the concordance and statistical precision in gait velocity in people with multiple sclerosis (pwMS), measured with FeetMe® (insoles with pressure and motion sensors) compared with ...GAITRite® (classic reference system of gait analysis) in the timed 25-Feet Walk test (T25WT).
This observational, cross-sectional, prospective, single center study was conducted between September-2018 and April-2019 in pwMS aged 18-55 years, with Expanded Disability Status Scale (EDSS) 0-6.5 and relapse free ≥30 days at baseline. Primary endpoint was gait velocity. Secondary endpoints were ambulation time, cadence, and stride length assessment, while the correlation between gait variables and the clinical parameters of MS subjects was assessed as an exploratory endpoint.
A total of 207 MS subjects were enrolled, of whom, 205 were considered in primary analysis. Most subjects were women (66.8%) and had relapsing-remitting MS (RRMS) (82.9%), with overall mean (standard deviation SD) age of 41.5 (8.0) year and EDSS 3.1 (2.0). There was a statistically significant (p<0.0001) and strong agreement (intra-class correlation coefficient (ICC) >0.830) in gait velocity, ambulation time and cadence assessment between FeetMe® and GAITRite®.
Agreement between devices was strong (ICC≥0.800). FeetMe® is the first validated wearable medical device that allows gait monitoring in MS subjects, being potentially able to assess disease activity, progression, and treatment response.
Climate change may reduce forest growth and increase forest mortality, which is connected to high carbon costs through reductions in gross primary production and net ecosystem exchange. Yet, the ...spatiotemporal patterns of vulnerability to both short‐term extreme events and gradual environmental changes are quite uncertain across the species’ limits of tolerance to dryness. Such information is fundamental for defining ecologically relevant upper limits of species tolerance to drought and, hence, to predict the risk of increased forest mortality and shifts in species composition. We investigate here to what extent the impact of short‐ and long‐term environmental changes determines vulnerability to climate change of three evergreen conifers (Scots pine, silver fir, Norway spruce) and two deciduous hardwoods (European beech, sessile oak) tree species at their southernmost limits of distribution in the Mediterranean Basin. Finally, we simulated future forest growth under RCP 2.6 and 8.5 emission scenarios using a multispecies generalized linear mixed model. Our analysis provides four key insights into the patterns of species’ vulnerability to climate change. First, site climatic marginality was significantly linked to the growth trends: increasing growth was related to less climatically limited sites. Second, estimated species‐specific vulnerability did not match their a priori rank in drought tolerance: Scots pine and beech seem to be the most vulnerable species among those studied despite their contrasting physiologies. Third, adaptation to site conditions prevails over species‐specific determinism in forest response to climate change. And fourth, regional differences in forests vulnerability to climate change across the Mediterranean Basin are linked to the influence of summer atmospheric circulation patterns, which are not correctly represented in global climate models. Thus, projections of forest performance should reconsider the traditional classification of tree species in functional types and critically evaluate the fine‐scale limitations of the climate data generated by global climate models.
Current and forecasted trends in tree growth from temperate and boreal tree species growing at the southernmost limit of their natural distribution in Europe. The tree growth projections by 2100 revealed a generalized decrease in growth under the climatic conditions derived from the RCP 8.5 emission scenario.
Forest decline under environmental stress is expressed by regeneration failure and accelerated mortality in all ontogenic stages at the population level. Characterizing functional traits and ...mechanisms that best capture species decline and mortality is essential to assess forest dynamics.
We analysed sensitivity to increasing water stress in two species with different water‐use strategies on a mixed Quercus pyrenaica–Pinus sylvestris forest where adult pines express vulnerability to climate change but oaks do not. We compared the dynamics of radial growth, wood δ13C and sapwood non‐structural carbohydrates (NSCs) in response to drought at different time‐scales in both species and two age cohorts in pine.
Both species were very sensitive to water stress, which influenced trait phenotypic plasticity at short‐ and long time‐scales. Water‐use strategy in pines of both ages was more conservative than in the more drought‐tolerant oak. Both species showed negative growth trends despite increasing intrinsic water‐use efficiency. Recent growth of pines is slower than it was in the past. Carbon isotope discrimination trends in young pines suggested increasing leaf gas exchange constraints. NSCs were far from depletion in both species and all pine ages. Intra‐ and inter‐annual NSC variability was higher in oaks than in pines and in soluble sugars (SS) than in starch. SS were lowest in young pines. Sensitivity of NSCs to contrasting climatic years was low in pines, and NSC levels mostly remained homeostatic for this species. The sensitivity to climate expressed suggests different C allocation strategies, with less coupling between radial growth and current‐year photosynthesis in young pines.
Synthesis. Pines expressed negative responses to increased water stress regardless of age, showing rising gas exchange constraints through tighter stomatal control of water losses than oaks. Young pines showed similar functional responses to water stress than old pines in decline, which suggests species‐level vulnerability and could be regarded as early warning signals anticipating mortality in pines. Yet, given the high sensitivity to drought also expressed by the non‐declining oak, it would have been difficult to unequivocally disentangle species decline based only on the functional traits analysed.
Resumen
La ausencia de regeneración y la mortalidad acelerada por estrés ambiental en todas las escalas ontogénicas y a nivel poblacional indican decaimiento forestal.
En este trabajo analizamos la sensibilidad al aumento del estrés hídrico en un bosque mixto de Quercus pyrenaica y Pinus sylvestris, dos especies con diferentes estrategias en el uso del agua. En esta masa los pinos adultos muestran síntomas de decaimiento pero los robles no. Comparamos las respuestas a la sequía del crecimiento radial, el δ13C de la madera y los carbohidratos no estructurales de la albura (NSC) a diferentes escalas temporales en las dos especies y en pinos de dos clases de edad.
Ambas especies mostraron una alta sensibilidad al estrés hídrico, el cual mostró una estrecha relación con la plasticidad fenotípica en escalas temporales cortas y largas. Los pinos de todas las edades estudiadas mostraron estrategias más conservadoras en el uso del agua que la especie más tolerante a la sequía, el roble. Las dos especies mostraron tendencias de crecimiento negativas, pese a mostrar tendencias positivas en iWUE. El crecimiento radial de los pinos es menor actualmente que a la misma edad en el pasado. Las tendencias de la discriminación isotópica del carbono en los pinos jóvenes sugieren un incremento de las limitaciones en el intercambio gaseoso foliar. Tanto la variabilidad intranual como la interanual en los NSC fueron mayores en los robles que en los pinos y en azúcares solubles (SS) que en almidón. Los pinos mostraron los valores más bajos de SS. La sensibilidad de los NSC a dos años climáticamente contrastados fue muy baja en pinos, cuyos niveles de NSC permanecieron homeostáticos en consecuencia. La sensibilidad al clima mostrada por los diferentes rasgos funcionales analizados sugiere diferencias en la redistribución del carbono dentro de la planta, con menor acoplamiento entre crecimiento radial y fotosíntesis en pinos jóvenes.
Síntesis. Los pinos respondieron negativamente al incremento del estrés hídrico independientemente de su edad, aumentando sus limitaciones en el intercambio gaseoso mediante un mayor control estomático que los robles. Los pinos jóvenes y viejos tuvieron una respuesta functional ante el estrés hídrico parecida. Esto sugiere vulnerabilidad a nivel de especie y podría considerarse como una señal de aviso temprano previa a futuros aumentos en la mortalidad en pinos. A pesar de ello, dada la alta sensibilidad a la sequía de los robles, que no están en decaimiento, hubiera sido difícil deducir solamente mediante el análisis de los caracteres funcionales estudiados si las especies están en decaimiento o no.
Pines expressed negative responses to increased water stress regardless of age, showing rising gas exchange constraints through tighter stomatal control of water losses than oaks. Young pines showed similar functional responses to water stress than old pines in decline, which suggests species‐level vulnerability and could be regarded as early‐warning signals anticipating mortality in pines.
Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising ...option and can be readily obtained using minimally invasive procedures.
In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded.
Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy.
Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.
Fingolimod approval was based mainly on two clinical trials, FREEDOMS and TRANSFORMS, which demonstrated the efficacy and safety of fingolimod in patients with multiple sclerosis (MS). We present an ...observational study that validates these trials findings in a real-world setting, whereby the effectiveness and safety of fingolimod was assessed in Seville's' (Spain) clinical practice. This retrospective study in MS patients assessed effectiveness (relapses, EDSS, gadolinium-enhancing T1 and new/enlarged T2-weighted lesions): total cohort (n = 249) and stratified according to prior treatment (glatiramer acetate/interferon beta-1 immunomodulator, natalizumab, naïve), gender, basal EDSS score, basal Gd+ lesions, ARR prior to treatment, age at treatment initiation and number of prior treatments. A multivariante model was used to assess the ARR with baseline characteristics. The safety profile (adverse events AEs) was also described. Fingolimod reduced the annualized relapse rate (ARR) by 75%, 67% and 85% in the total cohort, patients previously treated with immunomodulatory and naïve patients (p<0.0001 all cases). However, patients previously treated with natalizumab kept a constant ARR. The ARR results and the consequent increase in the proportion of relapse-free patients were independent of the age at treatment initiation, number of prior treatments, gender and basal Gd+ lesions. Although fingolimod was effective regardless the basal EDSS score and ARR prior to fingolimod treatment, better outcomes were observed in patients with basal EDSS score <3 (0.2 vs. 0.4; p = 0.0244) and ARR ≥ 2 prior to fingolimod treatment (p = 0.0338). Only the basal EDSS score was association with ARR in the first 24 months of fingolimod treatment in the multivariante model (p = 0.0439). The cumulative probability of disability progression was 20% (month-24) in the total cohort, and was independent from prior treatment, age at treatment initiation, number of prior treatments, gender, basal EDSS score, basal Gd+ lesions and ARR prior to treatment. The real-world fingolimod benefits observed in this study seem to be similar than those observed in previous clinical trials.
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