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During recent decades, tree mortality and dieback have been reported in forest ecosystems across global biomes. Although numerous forest species, including those of the genus Quercus, have been affected by hotter and drier conditions in the Mediterranean Basin during the last decades, there is scarce information regarding the interactive role of past management and climate across large areas of south-western Europe. Here, we examined the influence of several climatic factors (mean annual temperature, annual precipitation) over the last 3 decades, latitude, land management and site conditions on the cork oak (Quercus suber L.) population dynamics given their high ecological and economic relevance. We sampled 20 plots across contrasting environmental conditions in SW Iberian Peninsula with different land property (public vs. private) to characterize cork oak tree size, stand density, mortality ratio and regeneration. We observed widespread effects of latitude (8.9% at northern vs. 15.6% at southern plots) and land property (6.9% in private properties vs. 13.9% in public ones) on tree mortality. Tree density and basal area differed with latitude, with higher values (307.2 trees ha-1 and 38.4 m2 ha-1, respectively) at northern populations. In addition, the more intense cork-focused productive management resulted in higher tree sizes in private (mean DBH = 47.3 cm) than in public (mean DBH = 37.8 cm) plots. Tree regeneration was higher in northern forests (94.9 ± 25.2 vs. 26.0 ± 6.1 saplings ha-1 for the southern location), being this difference more pronounced in public plots. These findings highlight the importance of sustainable forest management in public and private forests for further reduction of mortality processes, as well as for enhancing the regeneration aimed to the conservation of cork oak under forecasted drier conditions of these economically invaluable Mediterranean forests.

Drought- and heat-driven tree mortality, along with associated insect outbreaks, have been observed globally in recent decades and are expected to increase in future climates. Despite its potential to profoundly alter ecosystem carbon and water cycles, how tree mortality scales up to ecosystem functions and fluxes is uncertain. We describe a framework for this scaling where the effects of mortality are a function of the mortality attributes, such as spatial clustering and functional role of the trees killed, and ecosystem properties, such as productivity and diversity. We draw upon remote-sensing data and ecosystem flux data to illustrate this framework and place climate-driven tree mortality in the context of other major disturbances. We find that emerging evidence suggests that climate-driven tree mortality impacts may be relatively small and recovery times are remarkably fast (~4 years for net ecosystem production). We review the key processes in ecosystem models necessary to simulate the effects of mortality on ecosystem fluxes and highlight key research gaps in modeling. Overall, our results highlight the key axes of variation needed for better monitoring and modeling of the impacts of tree mortality and provide a foundation for including climate-driven tree mortality in a disturbance framework.

We used Species Distribution Modeling to predict the probability of Iberian pine (Pinus nigra subsp. salzmannii [Dunal] Franco) occurrences in southern Spain in response to environmental variables and to forecast the effects of climate change on their predicted geographical distribution. The ensemble modeling approach “biomod2” was used, together with present Iberian pine data, to predict the current potential distribution based on bioclimatic explanatory variables (200 m resolution) and to forecast future suitability by studying three periods (2040, 2070, and 2100), considering the Global Circulation Models BCM2, CNCM3, and ECHAM5, and the regional model EGMAM, for different scenarios (SRAB1, SRA2, SRB1). Model evaluation was performed using Kappa, True Skills Statistic (TSS), and Area Under the Curve (AUC) values. The biomod2 approach highlighted the average number of days with a minimum temperature equal to or below 0°C, annual precipitation, and aridity index as the most important variables to describe the P. nigra occurrence probability. Model performances were generally satisfactory and the highest AUC values and high stability of the results were given by GAM and GLM, but MaxEnt and the SRE model were scarcely accurate according to all our statistics. The ensemble Species Distribution Modeling of P. nigra in Andalusia predicted the highest probability of species occurrence in the eastern areas, Sierra de Cazorla being the area with the highest occurrence of P. nigra in Andalusia. In the future habitat, the general probability of P. nigra occurrence in Andalusia will decrease widely; the species is expected to lose habitat suitability at moderate altitudes and its occurrence probability will have decreased by nearly 70% on average by 2100, affected by the selected scenario. Populations in Sierra de Cazorla are those most suitable for P. nigra growth, even under the most pessimistic scenarios. It is likely that the natural southern populations of P. nigra will be very sensitive to changes in climate.

We explored the effects of tree-fall gaps caused by Heterobasidion annosum-induced tree death on the regeneration of the relict Abies pinsapo in southern Spain. We analyzed the structure and regeneration of A. pinsapo in 44 circular closed-canopy plots and 11 gaps (mean size 75 m2) located in H. annosum infection foci. We measured adult density, basal area, and height of all tree species with a diameter at breast height greater than 7.5 cm and quantified regeneration abundance. Diameter structures were analyzed using Weibull functions. A. pinsapo comprised 49-81% of total adult tree density (358-1418 trees ha-1) and total basal area (15.70-39.22 m2 ha-1). Density of A. pinsapo juveniles ranged from 129 to 416 individuals ha-1, while that of juveniles of other tree species such as Quercus ilex was much lower. A. pinsapo saplings and seedlings were more abundant within gaps than in closed-canopy sites. A. pinsapo regeneration was related to the tree species composition of the stands adjacent to gaps. The main potential species replacing A. pinsapo in H. annosum-induced gaps were, in decreasing order of importance, Quercus ilex, Q. faginea, and Juniperus oxycedrus. The current stand structure and gap-infilling processes suggest that A. pinsapo regenerates adequately within H. annosum-induced gaps. However, the relative proportion of other coexisting tree species within H. annosum-related gaps will increase substantially over time as compared with closed-canopy areas.

Continental Mediterranean forests face drought but also cold spells and both climate extremes can impair the resilience capacity of these forests. Climate warming could amplify the negative effects of cold spells by inducing premature dehardening. Here we capitalize on a winter drought-induced dieback triggered by a cold spell which occurred in December 2001 affecting Scots pine forests in eastern Spain. We assessed post-dieback recovery by quantifying and comparing radial growth and xylem anatomy of non-declining (ND, crown cover >50%) and declining (D, crown cover ≤50%) trees in two sites (VP, Villarroya de los Pinares; TO, Torrijas). We also characterized xylogenesis in both sites and aboveground productivity in site VP. Dieback caused legacy effects since needle loss, a 60% reduction in litter fall and radial-growth decline characterized D-trees 3 years after dieback symptoms started appearing in spring 2002. D-trees formed collapsed tracheids in the 2002-ring, particularly in the most affected VP site where xylogenesis differences between ND and D trees were most noticeable. The lower growth rates of D-trees were caused by a shorter duration of their major xylogenesis phases. In site VP the radial-enlargement and wall-thickening of tracheids were significantly reduced in D-trees as compared to ND-trees because these xylogenesis phases tended to start earlier and end later in ND-trees. Gompertz models fitted to tracheid production predicted that maximum growth rates occurred 11-12 days earlier in ND than in D-trees. The formation of radially-enlarging tracheids was enhanced by longer days in both study sites and also by wetter conditions in the driest TO site, but xylogenesis sensitivity to climate was reduced in D-trees. Winter-drought dieback impairs xylem anatomy and phenology, aboveground productivity, xylogenesis and growth in Mediterranean Scots pine populations. Affected stands show a costly post-dieback recovery challenging their resilience ability. [ABSTRACT FROM AUTHOR]

• The P. nigra growth was enhanced by high spring precipitation. • Temperature explained a higher proportion of the BAI variance than precipitation. • Growth projections forecast a decline in BAI across all ecological regions. • The growth decline was lower in EN populations compared to the other populations. Droughts chronically alter resource availability in forest ecosystems. The increased frequency and severity of such extreme climate events challenge the acclimation potential of tree species especially across the drought-prone Mediterranean region. Pinus nigra is a widely distributed tree species in the Mediterranean region and considered vulnerable to extreme droughts. We used a 1000 km latitudinal gradient from northern Morocco to north-eastern Spain incorporating four regions (Edge-South, Core-South, Core-North and Edge-North) and including different P. nigra provenances. We aim to identify the climate and forest structure related drivers that influence tree radial growth (BAI, basal area increment). We developed statistical models for BAI by incorporating the potential effects of climate and forest structure (diameter and age distributions). Then, we forecasted the future growth of P. nigra forests during the 21st century considering the emission scenario A2 with an expected increase of +2.7 °C at the end of this century. Our results showed large variability across P. nigra populations in terms of environmental conditions, forest structure, and growth. The northernmost P. nigra populations, subjected to wetter and cooler conditions were those presenting the lowest BAI (4.9 cm2), whereas the southernmost P. nigra populations subjected to drier and warmer conditions presented the highest BAI values (11.5 cm2). Pinus nigra growth was enhanced by high spring precipitation, but this positive effect was probably modulated by forest structure. Temperature explained a higher proportion of the BAI variance than precipitation, with warmer summer conditions decreasing growth. Growth projections forecasted a decline in BAI (from 9.6 to 7.0 cm2) across all ecological regions starting around the mid-21st century but being lower in Edge-North populations compared to the other populations. Our study provides quantitative knowledge related to how P. nigra populations have been growing across four distinctive ecological regions. We also provide a forecasting tool that incorporates both climate and stand structure related information to project dynamics in tree populations. [ABSTRACT FROM AUTHOR]

The intent of this study is to illustrate cultural differences in the amount of perceived burden for primary caregivers of persons with Alzheimer's Disease. Caregivers in Guatemala and Rhode Island were given a questionnaire exploring: caregiver well-being, available supports, traditional ideology, and perceived burden. The data indicate that Guatemalans have less institutional and more informal supports available, as compared with USA caregivers. Guatemalan caregivers brought patients to a doctor sooner after the appearance of their first symptoms (0.9+/-1.0 years versus 1.6+/-1.8 years) and had poorer perceived health than USA subjects, suggesting a higher level of caregiver burden. Cultural response bias however may account for the difference in perceived health. [ABSTRACT FROM AUTHOR]

We analyzed the impacts of drought severity on a variety of sectors in a topographically complex basin (the upper Aragón basin 2181 km2) in the Central Spanish Pyrenees. Using diverse data sources including meteorological and hydrological observations, remote sensing and tree rings, we analyze the possible hydrological implications of drought occurrence and severity on water availability in various sectors, including downstream impacts on irrigation water supply for crop production. Results suggest varying responses in forest activity, secondary growth, plant phenology, and crop yield to drought impacts. Specifically, meteorological droughts have distinct impacts downstream, mainly due to water partitioning between streamflow and irrigation channels that transport water to crop producing areas. This implies that drought severity can extend beyond the physical boundaries of the basin, with impacts on crop productivity. This complex response to drought impacts makes it difficult to develop objective basin-scale operational definitions for monitoring drought severity. Moreover, given the high spatial variability in responses to drought across sectors, it is difficult to establish reliable drought thresholds from indices that are relevant across all socio-economic sectors. The anthropogenic impacts (e.g. water regulation projects, ecosystem services, land cover and land use changes) pose further challenges to assessing the response of different systems to drought severity. This study stresses the need to consider the seasonality of drought impacts and appropriate drought time scales to adequately assess and understand their complexity. Unlabelled Image • Strong spatial and temporal complexity when assessing drought impacts. • Different responses not only as a function of hydrological subsystems, vegetation metrics and vegetation types • Diverse impacts seasonally, over different drought time-scales, and water resources management policies. [ABSTRACT FROM AUTHOR]

Cardiogenic shock complicating acute myocardial infarction (AMI-CS) remains a critical condition with high morbimortality. Despite advances, gender disparities persist in the management of this condition. Our aim was to evaluate gender differences in the utilization and outcomes of mechanical circulatory support (MCS) in AMI-CS. In addition, we addressed the management strategies for AMI-CS stratified by race/ethnicity. We performed a retrospective study using the National Inpatient Sample from 2016 to 2019, including admissions with AMI-CS. The use of MCS and outcomes were compared between genders using inverse probability of treatment weighting. Odds ratios (OR) with their 95% confidence interval (CI) were estimated. A total of 151,560 admissions for AMI-CS were analyzed, including 98,855 male and 52,705 female patients. After the inverse probability of treatment weighting adjustment, females were significantly less likely to receive MCS (OR 0.77, 95% CI 0.73 to 0.81, p <0.001) and had higher in-hospital mortality rates (OR 1.09, 95% CI 1.00 to 1.18, p = 0.045) than males. No significant gender differences were observed in major bleeding, renal replacement therapy, or mechanical ventilation. Racial disparities were also evident, with female patients across all racial groups being less likely to receive MCS compared with their male counterparts. In conclusion, significant gender disparities exist in the utilization and outcomes of MCS in patients with AMI-CS. Female patients are less likely to receive MCS and have higher in-hospital mortality rates compared with male patients. Racial minorities, including Black and Hispanic patients, experience lower utilization of MCS compared with White patients. These findings underscore the complex interplay between gender, race/ethnicity, and health care access and outcomes., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

With ongoing global warming, increasing water deficits promote physiological stress on forest ecosystems with negative impacts on tree growth, vitality, and survival. How individual tree species will react to increased drought stress is therefore a key research question to address for carbon accounting and the development of climate change mitigation strategies. Recent tree-ring studies have shown that trees at higher latitudes will benefit from warmer temperatures, yet this is likely highly species-dependent and less well-known for more temperate tree species. Using a unique pan-European tree-ring network of 26,430 European beech (Fagus sylvatica L.) trees from 2118 sites, we applied a linear mixed-effects modeling framework to (i) explain variation in climate-dependent growth and (ii) project growth for the near future (2021-2050) across the entire distribution of beech. We modeled the spatial pattern of radial growth responses to annually varying climate as a function of mean climate conditions (mean annual temperature, mean annual climatic water balance, and continentality). Over the calibration period (1952-2011), the model yielded high regional explanatory power (R 2  = 0.38-0.72). Considering a moderate climate change scenario (CMIP6 SSP2-4.5), beech growth is projected to decrease in the future across most of its distribution range. In particular, projected growth decreases by 12%-18% (interquartile range) in northwestern Central Europe and by 11%-21% in the Mediterranean region. In contrast, climate-driven growth increases are limited to around 13% of the current occurrence, where the historical mean annual temperature was below ~6°C. More specifically, the model predicts a 3%-24% growth increase in the high-elevation clusters of the Alps and Carpathian Arc. Notably, we find little potential for future growth increases (-10 to +2%) at the poleward leading edge in southern Scandinavia. Because in this region beech growth is found to be primarily water-limited, a northward shift in its distributional range will be constrained by water availability., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare no conflicts of interest.

A sense of belonging in school is fostered when students feel included. School nurses can establish an inclusive school atmosphere where students feel safe, supported, accepted, and valued. The language choices of school nurses play a key role in fostering such an environment. Through consciously using language that promotes respect, acceptance, justice, and equity, nurses can support student well-being. Nurses may be using embedded terminologies and outdated language that promotes exclusion but can learn and model inclusive language practices such as cultural humility, calling in, and respecting pronouns. Making intentional choices to embrace and employ these practices is imperative to supporting student health today.

Competing Interests: The authors declare no conflicts of interest.

Snail1 is a transcriptional factor required for cancer-associated fibroblast (CAF) activation, and mainly detected in CAFs in human tumors. In the mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) model of murine mammary gland tumors, Snai1 gene deletion, besides increasing tumor-free lifespan, altered macrophage differentiation, with fewer expressing low levels of MHC class II. Snail1 was not expressed in macrophages, and in vitro polarization with interleukin-4 (IL4) or interferon-γ (IFNγ) was not altered by Snai1 gene depletion. We verified that CAF activation modified polarization of naïve bone-marrow-derived macrophages (BMDMΦs). When BMDMΦs were incubated with Snail1-expressing (active) CAFs or with conditioned medium derived from these cells, they exhibited a lower cytotoxic capability than when incubated with Snail1-deleted (inactive) CAFs. Gene expression analysis of BMDMΦs polarized by conditioned medium from wild-type or Snai1-deleted CAFs revealed that active CAFs differentially stimulated a complex combination of genes comprising genes that are normally induced by IL4, downregulated by IFNγ, or not altered during the two canonical differentiations. Levels of RNAs relating to this CAF-induced alternative polarization were sensitive to inhibitors of factors specifically released by active CAFs, such as prostaglandin E 2 and TGFβ. Finally, CAF-polarized macrophages promoted the activation of the immunosuppressive regulatory T cells (T-regs). Our results imply that an active CAF-rich tumor microenvironment induces the polarization of macrophages to an immunosuppressive phenotype, preventing the macrophage cytotoxic activity on tumor cells and enhancing the activation of T-reg cells., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Ongoing climatic change is threatening the survival of drought-sensitive tree species, such as silver fir ( Abies alba ). Drought-induced dieback had been previously explored in this conifer, although the role played by tree-level genetic diversity and its relationship with growth patterns and soil microsite conditions remained elusive. We used double digest restriction-site-associated DNA sequencing (ddRADseq) to describe different genetic characteristics of five silver fir forests in the Spanish Pyrenees, including declining and non-declining trees. Single nucleotide polymorphisms (SNPs) were used to investigate the relationships between genetics, dieback, intraspecific trait variation (functional dendrophenotypic traits and leaf traits), local bioclimatic conditions, and rhizosphere soil properties. While there were no noticeable genetic differences between declining and non-declining trees, genome-environment associations with selection signatures were abundant, suggesting a strong influence of climate, soil physicochemical properties, and soil microbial diversity on local adaptation. These results provide novel insights into how genetics and diverse environmental factors are interrelated and highlight the need to incorporate genetic data into silver fir forest dieback studies to gain a better understanding of local adaptation.

The analysis of climate variability and development of reconstructions based on tree-ring records in tropical forests have been increasing in recent decades. In the Amazon region, ring width and stable isotope long-term chronologies have been used for climatic studies, however little is known about the potential of wood traits such as density and chemical concentrations. In this study, we used well-dated rings of Cedrela fissilis Vell. from the drought-prone southern Amazon basin to assess the potential of using inter-annual variations of annually-resolved ring width, wood density, stable oxygen isotope (δ 18 O TR ) measured in tree-ring cellulose and concentration of Sulfur (S TR ) and Calcium (Ca TR ) in xylem cells to study climate variability. During wet years, Cedrela fissilis produced wider and denser rings with higher Ca TR and lower S TR , as well as depleted δ 18 O TR values. During dry years, a wider range of responses was observed in growth, density and S TR , while lower Ca TR and enriched δ 18 O TR values were found. The annual centennial chronologies spanning from 1835 to 2018 showed good calibration skills for reconstructing local precipitation, evapotranspiration (P-PET), Amazon-wide rainfall, as well as climate modes related to sea surface temperature (SST) anomalies such as El Niño South Oscillation (ENSO), Tropical Northern Atlantic (TNA), and the Western Hemisphere Warm Pool (WHWP) oscillations. Ca TR explained 42 % of the variance of local precipitation (1975-2018), RW explained 30 % of the P-PET variance (1975-2018), while δ 18 O TR explained 60 % and 57 % of the variance of Amazon rainfall (1960-2018) and El Niño 3.4 (1920-2018), respectively. Our results show that a multi-proxy tropical tree-ring approach can be used for high-reliable reconstructions of climate variability over Amazon basin at inter-annual and multidecadal time scales., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems., Trial Design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment., Clinical Trial Registration: www.soltihope.com, identifier NCT04497285., Competing Interests: ElS reports having obtained travel/accommodation paid by Gilead and Daiichi Sankyo and honoraria from Novartis. JC reports personal fees from NOVARTIS and Pfizer. Mafalda Oliveira reports financial relationships with AstraZeneca, Guardant Health, Roche, MSD, Pfizer, SeaGen, iTEOS, Eisai, Novartis, Relay Therapeutics and Gilead. PT reports honoraria and consulting fees from AstraZeneca, Daiichi-Sankyo, Novartis, Seagen, Pfizer and Lilly and travel and accommodation paid by AstraZeneca and Pfizer. MV reports honoraria and consulting fees from Roche, Novartis and Daiichi Sankyo- AstraZeneca. MaM reports honoraries received from Lilly and Prosenestar; and research agreements with Pfizer, Lilly, Prosenestar, PharmaMar and Circle Pharma. JG reports grants and personal fees from Novartis, grants and personal fees from Pfizer, grants, and personal fees from Roche, outside the submitted work. CS has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, AX’s Consulting, Byondis BV, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann - La Roche Ltd, Exact Sciences, Exeter Pharma, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, Pint Pharma, prIME Oncology, Puma Biotechnology, Seagen, Synthon, Sanofi Aventis and Zymeworks. SP reports advisor/consultant role for AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer, SeaGen, Polyphor, Roche, Gebro Pharma, Pierre Fabre, and conference travel and accommodation paid by Gilead and Pfizer. RL reports grants and personal fees from Roche, grants and personal fees from Merck, personal fees from AstraZeneca, personal fees from Bayer, personal fees, and non-financial support from BMS, personal fees from Pharmamar, personal fees from Leo, personal fees and non-financial support from Novartis, outside the submitted work. MiM has declared advisor role or consulting from Novartis, Pfizer, Lilly, Gilead, PiereFabre and MSD; research funding from Pfizer and travel expences from Pfizer and Gilead. JB reports personal fees from Astra Zeneca and Pfizer. MoM declares the following competing interests: expert testimony honoraria from Novartis, Roche, and Eisai; advisory board honoraria from Pierre Fabre, and Seagen; and conference travel grants from Roche, Pfizer, Gilead and Lilly. IB reports honoraria and consulting fees from AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen and Veracyte; and grant/Research Support to the Institution from AstraZeneca, Lilly and Roche and travel and accommodation paid by Roche, Lilly and Pierre-Fabre, outside the submitted work. VB reports consultant or Advisory Role fees from Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart, Lilly; Janssen; personal fees Nanobiotix NANORAY-312/and Honoraria from Eli Lilly; MSD; SOLTI; TACTICS; Getthi; Gedefo. Travel/inscription/accommodation: Bayer ESMO GI and Institutional financial support for clinical trials from: Abbvie; ACEO; Adaptaimmune; Amcure; AMGEN; Amunix, AstraZeneca; Bycicle; BMS Cytomx; GSK; Genentech/Roche; Genmab; Incyte; Ipsen; Janssen; Kura; Lilly; Loxo; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; PUMA; Ryvu; Ribbon; Sanofi; Taiho; Tesaro; BeiGene; Transgene; Takeda; Incyte; Innovio; MSD; PsiOxus; Seattle Genetics; Mersana; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax; DebioPharm; Boehringer Ingelheim; Regeneron; Rigontec; Millennium; Seagen; Synthon; Spectrum; Urogen; Zenith. EC reports personal fees from Roche, Lilly, Novartis, Pfizer, during the conduct of the study. EG reports advisory or consultant role from Roche, AstraZeneca, Seattle Genetics, Gilead, Pfizer and Eisai and travel grants from Pfizer, AstraZeneca and Roche. RS-B reports personal honoraria from Novartis, AstraZeneca, MSD Oncology, Lilly Oncology, Glaxo Smith Kline, Clovis, and Seagen. SC reports advisory or consultant role from Pfizer, Daiichi Sankyo, and Seagen and travel grants from Pfizer and AstraZeneca. MH reports consulting fees from AstraZeneca. AlP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche and Novartis, consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA and Daiichi Sankyo, Inc. outside the submitted work. AC reports honoraria and consulting fees from Pfizer, Novartis, and AstraZeneca. TP reports having received Fees for Non-CME Services Received Directly from Commercial Interest or their Agents e.g., speakers’ bureaus from AstraZeneca, Consulting Fees e.g., advisory boards from Novartis, and Fees for Non-CME Services Received Directly from Commercial Interest or their Agents e.g., speakers’ bureaus from Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Olivera-Salguero, Seguí, Cejalvo, Oliveira, Tolosa, Vidal, Malumbres, Gavilá, Saura, Pernas, López, Margelí, Balmaña, Muñoz, Blancas, Boni, Ciruelos, Galve, Perelló, Sánchez-Bayona, de la Cruz, de la Hoya, Galván, Sanfeliu, Gonzalez-Farre, Sirenko, Blanch-Torras, Canes, Masanas, Olmos, Forns, Prat, Casas and Pascual.)

The frequency and intensity of drought events are increasing worldwide, challenging the adaptive capacity of several tree species. Here, we evaluate tree growth patterns and climate sensitivity to precipitation, temperature, and drought in the relict Moroccan fir Abies marocana . We selected two study sites, formerly stated as harboring contrasting A. marocana taxa ( A. marocana and A. tazaotana , respectively). For each tree, dendrochronological methods were applied to quantify growth patterns and climate-growth sensitivity. Further, ddRAD-seq was performed on the same trees and close saplings to obtain single nucleotide polymorphisms (SNPs) and related genotype-phenotype associations. Genetic differentiation between the two studied remnant populations of A. marocana was weak. Growth patterns and climate-growth relationships were almost similar at the two sites studied, supporting a negative effect of warming. Growth trends and tree size showed associations with SNPs, although there were no relationships with phenotypes related to climatic sensitivity. We found significant differences in the SNPs subjected to selection in the saplings compared to the old trees, suggesting that relict tree populations might be subjected to genetic differentiation and local adaptation to climate dryness. Our results illustrate the potential of tree rings and genome-wide analysis to improve our understanding of the adaptive capacity of drought-sensitive forests to cope with ongoing climate change.

Long-term records of tree-ring width (TRW), latewood maximum density (MXD) and blue intensity (BI) measurements on conifers have been largely used to develop high-resolution temperature reconstructions in cool temperate forests. However, the potential of latewood blue intensity (LWBI), less commonly used earlywood blue intensity (EWBI), and delta (difference between EWBI and LWBI, dBI) blue intensity in Mediterranean tree species is still unexplored. Here we developed BI chronologies in moist-elevation limits of the most southwestern European distribution of Pinus nigra subsp. salzmanii Arnold. We tested whether BI variables derived from tree rings of black pine are better proxies than ring-width variables to reconstruct long-term changes in climatic factors and water availability. For this we applied correlations and regression analyses with daily and monthly climate data, a spatial and temporal drought index (Standardized Precipitation-Evapotranspiration Index-SPEI) and Vapour Pressure Deficit (VPD), as well as atmospheric circulation patterns: North Atlantic Oscillation (NAO), Southern Oscillation Index (SOI) and Western Mediterranean Oscillation (WeMO). We found a positive relation between black pine growth (RW) and temperature during the winter preceding the growing season. Among all variables LWBI and dBI were found to be more sensitive than TRW to SPEI at low-elevation site, with EWBI series containing an opposite climatic signal. LWBI and dBI were significantly related to June and September precipitation at high-elevation site. Winter VPD was related with higher EWI and LWI series, whereas dBI and EWBI were related with January SOI and February NAO. We confirm the potential of long-term dBI series to reconstruct climate in drought-prone regions. This novel study in combination with other wood anatomical measurements has wide implications for further use of BI to understand and reconstruct environmental changes in Mediterranean conifer forests., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Rear-edge populations at the xeric distribution limit of tree species are particularly vulnerable to forest dieback triggered by drought. This is the case of silver fir (Abies alba) forests located in Southwestern Europe. While silver fir drought-induced dieback patterns have been previously explored, information on the role played by nutritional impairment is lacking despite its potential interactions with tree carbon-water balances. We performed a comparative analysis of radial growth, intrinsic water-use efficiency (iWUE), oxygen isotopes (δ 18 O) and nutrient concentrations in leaves of declining (DD) and non-declining (ND) trees in silver fir in four forests in the Spanish Pyrenees. We also evaluated the relationships among dieback predisposition, intraspecific trait variation (wood density and leaf traits) and rhizosphere soil physical-chemical properties. The onset of growth decline in DD trees occurred more than two decades ago, and they subsequently showed low growth resilience against droughts. The DD trees presented consistently lower foliar concentrations of nutrients such as P, K, Cu and Ni than ND trees. The strong effects of foliar nutrient status on growth resilience indices support the key role played by mineral nutrition in tree functioning and growth before, during and after drought. In contrast, variability in wood density and leaf morphological traits, as well as soil properties, showed weak relationships with tree nutritional status and drought performance. At the low elevation, warmer sites, DD trees showed stronger climate-growth relationships and lower δ 18 O than ND trees. The uncoupling between iWUE and δ 18 O, together with the positive correlations between P and K leaf concentrations and δ 18 O, point to deeper soil/bedrock water sources and vertical decoupling between nutrient and water uptake in DD trees. This study provides novel insights into the mechanisms driving silver fir dieback and highlights the need to incorporate tree nutrition into forest dieback studies., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Tree-ring data has been widely used to inform about tree growth responses to drought at the individual scale, but less is known about how tree growth sensitivity to drought scales up driving changes in forest dynamics. Here, we related tree-ring growth chronologies and stand-level forest changes in basal area from two independent data sets to test if tree-ring responses to drought match stand forest dynamics (stand basal area growth, ingrowth, and mortality). We assessed if tree growth and changes in forest basal area covary as a function of spatial scale and tree taxa (gymnosperm or angiosperm). To this end, we compared a tree-ring network with stand data from the Spanish National Forest Inventory. We focused on the cumulative impact of drought on tree growth and demography in the period 1981-2005. Drought years were identified by the Standardized Precipitation Evapotranspiration Index, and their impacts on tree growth by quantifying tree-ring width reductions. We hypothesized that forests with greater drought impacts on tree growth will also show reduced stand basal area growth and ingrowth and enhanced mortality. This is expected to occur in forests dominated by gymnosperms on drought-prone regions. Cumulative growth reductions during dry years were higher in forests dominated by gymnosperms and presented a greater magnitude and spatial autocorrelation than for angiosperms. Cumulative drought-induced tree growth reductions and changes in forest basal area were related, but initial stand density and basal area were the main factors driving changes in basal area. In drought-prone gymnosperm forests, we observed that sites with greater growth reductions had lower stand basal area growth and greater mortality. Consequently, stand basal area, forest growth, and ingrowth in regions with large drought impacts was significantly lower than in regions less impacted by drought. Tree growth sensitivity to drought can be used as a predictor of gymnosperm demographic rates in terms of stand basal area growth and ingrowth at regional scales, but further studies may try to disentangle how initial stand density modulates such relationships. Drought-induced growth reductions and their cumulative impacts have strong potential to be used as early-warning indicators of regional forest vulnerability., (© 2022 The Ecological Society of America.)

The mechanistic pathways connecting ocean-atmosphere variability and terrestrial productivity are well-established theoretically, but remain challenging to quantify empirically. Such quantification will greatly improve the assessment and prediction of changes in terrestrial carbon sequestration in response to dynamically induced climatic extremes. The jet stream latitude (JSL) over the North Atlantic-European domain provides a synthetic and robust physical framework that integrates climate variability not accounted for by atmospheric circulation patterns alone. Surface climate impacts of north-south summer JSL displacements are not uniform across Europe, but rather create a northwestern-southeastern dipole in forest productivity and radial-growth anomalies. Summer JSL variability over the eastern North Atlantic-European domain (5-40E) exerts the strongest impact on European beech, inducing anomalies of up to 30% in modelled gross primary productivity and 50% in radial tree growth. The net effects of JSL movements on terrestrial carbon fluxes depend on forest density, carbon stocks, and productivity imbalances across biogeographic regions., (© 2022. The Author(s).)

Forests are being impacted by climate and land-use changes which have altered their productivity and growth. Understanding how tree growth responds to climate in natural and planted stands may provide valuable information to prepare management in sight of climate change. Plantations are expected to show higher sensitivity to climate and lower post-drought resilience than natural stands, due to their lower compositional and structural diversity. We reconstructed and compared the radial growth of six conifers with contrasting ecological and climatic niches (Abies pinsapo, Cedrus atlantica, Pinus sylvestris, Pinus nigra, Pinus pinea, Pinus pinaster) in natural and planted stands subjected to seasonal drought in 40 sites. We quantified the relationships between individual growth variability and climate variables (temperature, precipitation and the SPEI drought index), as well as post-drought resilience. Elevated precipitation during the previous autumn-winter and current spring to early summer enhanced growth in both natural and planted stands of all species. Temperature effects on growth were less consistent: only plantations of A. pinsapo, C. atlantica, P. nigra, P. pinea, P. sylvetris and a natural stand of P. nigra showed negative impacts of summer temperature on growth. Drought reduced growth of all species in both plantations and natural stands, with variations in the temporal scale of the response. Drought constrained growth more severely in natural stands than in plantations of C. atlantica, P. pinaster and P. nigra, whereas the inverse pattern was found for A. pinsapo. Resilience to drought varied between species: natural stands of A. pinsapo, C. atlantica and P. pinaster recovered faster than plantations, while P. pinea plantations recovered faster than natural stands. Overall, plantations did not consistently show a higher sensitivity to climate and a lower capacity to recover after drought. Therefore, plantations are potential tools for mitigating climate warming., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Climate warming is expected to positively alter upward and poleward treelines which are controlled by low temperature and a short growing season. Despite the importance of treelines as a bioassay of climate change, a global field assessment and posterior forecasting of tree growth at annual scales is lacking. Using annually resolved tree-ring data located across Eurasia and the Americas, we quantified and modeled the relationship between temperature and radial growth at treeline during the 20th century. We then tested whether this temperature-growth association will remain stable during the 21st century using a forward model under two climate scenarios (RCP 4.5 and 8.5). During the 20th century, growth enhancements were common in most sites, and temperature and growth showed positive trends. Interestingly, the relationship between temperature and growth trends was contingent on tree age suggesting biogeographic patterns in treeline growth are contingent on local factors besides climate warming. Simulations forecast temperature-growth decoupling during the 21st century. The growing season at treeline is projected to lengthen and growth rates would increase and become less dependent on temperature rise. These forecasts illustrate how growth may decouple from climate warming in cold regions and near the margins of tree existence. Such projected temperature-growth decoupling could impact ecosystem processes in mountain and polar biomes, with feedbacks on climate warming., (© 2021 John Wiley & Sons Ltd.)

Understanding how climate warming and land-use changes determine the vulnerability of forests to drought is critical. However, we still lack: (i) robust quantifications of long-term growth changes during aridification processes, (ii) links between growth decline, changes in forest cover, stand structure and soil conditions, and (iii) forecasts of growth variability to projected climate warming. We investigated tree-ring records over the past 400-700 years, quantified changes in grazing area and forest cover during the 20th century, sampled current stand structure, and analyzed soil organic carbon δ 13 C and total nitrogen δ 15 N of Atlas cedar (Cedrus atlantica (Endl.) Manetti ex Carrière) Moroccan forests to characterize their dieback. Atlas cedar forests experienced massive dieback after the 1970s, particularly in the xeric High Atlas region. Forest cover increased in the less xeric regions (Middle Atlas and Rif) by almost 20%, while it decreased about 18% in the High Atlas, where soil δ 13 C and δ 15 N showed evidences of grazing. Growth declined and became more variable in response to recent droughts. The relative growth reduction (54%) was higher in the Middle Atlas than elsewhere (Rif, 32%; High Atlas, 36%). Growth synchrony between forests located within the Middle and High Atlas regions increased after the 1970s. Simulations based on a worst-case emission scenario and rapid warming forecast a stronger limitation of growth by low soil moisture in all regions, but particularly in the Middle Atlas and after the mid-21st century. Climate warming is expected to strengthen growth synchronization preceding dieback of conifer forests in xeric regions. The likelihood of similar dieback episodes is further exacerbated by historical degradation of these forests., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM., Methods: TRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls., Results: Sixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%)., Conclusion: TRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction., Competing Interests: Competing interests: JS-M, JPO, IG-D, IJC-R, MNC, DG-G, AL, LS and MO-G are employees of Health in Code SL. LM is a stakeholder and CEO of Health in Code SL., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Global climate change is expected to further raise the frequency and severity of extreme events, such as droughts. The effects of extreme droughts on trees are difficult to disentangle given the inherent complexity of drought events (frequency, severity, duration, and timing during the growing season). Besides, drought effects might be modulated by trees' phenotypic variability, which is, in turn, affected by long-term local selective pressures and management legacies. Here we investigated the magnitude and the temporal changes of tree-level resilience (i.e., resistance, recovery, and resilience) to extreme droughts. Moreover, we assessed the tree-, site-, and drought-related factors and their interactions driving the tree-level resilience to extreme droughts. We used a tree-ring network of the widely distributed Scots pine (Pinus sylvestris) along a 2,800 km latitudinal gradient from southern Spain to northern Germany. We found that the resilience to extreme drought decreased in mid-elevation and low productivity sites from 1980-1999 to 2000-2011 likely due to more frequent and severe droughts in the later period. Our study showed that the impact of drought on tree-level resilience was not dependent on its latitudinal location, but rather on the type of sites trees were growing at and on their growth performances (i.e., magnitude and variability of growth) during the predrought period. We found significant interactive effects between drought duration and tree growth prior to drought, suggesting that Scots pine trees with higher magnitude and variability of growth in the long term are more vulnerable to long and severe droughts. Moreover, our results indicate that Scots pine trees that experienced more frequent droughts over the long-term were less resistant to extreme droughts. We, therefore, conclude that the physiological resilience to extreme droughts might be constrained by their growth prior to drought, and that more frequent and longer drought periods may overstrain their potential for acclimation., (© 2020 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Drought-induced dieback episodes have been globally reported. However, few studies have jointly examined the role played by drought on growth of co-occurring shrub and tree species showing different dieback and mortality. Here, we focused on dieback events affecting Mediterranean shrublands dominated by the Phoenician juniper (Juniperus phoenicea) since the middle 2000s in three sites across a wide geographical and climatic gradient in Spain. We compared their growth responses to climate and drought with coexisting tree species (Pinus pinea, Pinus pinaster and Quercus faginea), which did not show dieback in response to drought. We characterized the major climatic constraints of radial growth for trees, surviving and dead junipers by quantifying climate-growth relationships. Then, we simulated growth responses to temperature and soil moisture using the process-based VS-Lite growth model. Growth of shrubs and trees was strongly reduced during extreme droughts but the highest negative growth responsiveness to climate and drought was observed in trees followed by dead junipers from the most xeric and cold sites. Growth of dead junipers responded more negatively to droughts prior to the dieback than co-occurring, living junipers. Growth was particularly depressed in the dead junipers from the warmest site after the warm and dry 1990s. The growth model showed how a steep precipitation reduction in the 1980s triggered soil moisture limitation at the driest sites, affecting growth, particularly in the case of dead junipers and mainly in warm and dry sites. The asynchrony in the simulated seasonal timing of drought events caused contrasting effects on growth of co-occurring shrubs and tree species, compromising their future coexistence. Junipers were particularly vulnerable to hotter droughts during the early growing season. The presented projections indicate that de-shrubification events in response to hotter droughts will be common but conditioned by site conditions. Our modelling approach provides tools to evaluate vulnerability thresholds of growth under similar drought-induced dieback and mortality processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The effects of climate change on forest growth are not homogeneous across tree species distribution ranges because of inter-population variability and spatial heterogeneity. Although latitudinal and thermal gradients in growth patterns have been widely investigated, changes in these patterns along longitudinal gradients due to the different timing and severity of regional droughts are less studied. Here, we investigated these responses in Mediterranean Black pine (Pinus nigra Arn.). We built a tree-ring width dataset comprising 77 forests (1202 trees) across the Mediterranean Basin. The biogeographical patterns in growth patterns and the relationships between growth and mean temperature, precipitation, drought and atmospheric circulations patterns (NAO -North Atlantic Oscillation-, SOI -Southern Oscillation Index- and MOI -Mediterranean Oscillation index-) were analyzed. Then, we evaluated the spatial and temporal growth synchrony between and within east and west populations. We found different growth and climate patterns in west vs. east Black pine populations, although in both regions growth was driven by similar temperature and precipitation variables. MOI significantly influenced tree growth, whilst NAO and SOI showed weaker effects. Growth of east and west Black pine populations desynchronized after the 1970s when several and uncoupled regional droughts occurred across the Mediterranean Basin. We detected a climate shift from the 1970s to the 1980s affecting growth patterns, changing growth-climate relationships, and reducing forest growth from west to east Black pine forests. Afterwards, climate and growth of east and west populations became increasingly more divergent. Our findings imply that integral bioclimatic and biogeographical analyses across the species distribution area must be considered to adequately assess the impact of climate change on tree growth under warming and more arid conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Drought-induced forest dieback is causing reductions in productivity, increasing tree mortality and impairing terrestrial carbon uptake worldwide. However, the role played by long-term nutrient imbalances during drought-induced dieback is still unknown. To improve our knowledge on the relationships between dieback and nutrient imbalances, we analysed wood anatomical traits (tree-ring width and wood density), soil properties and long-term chemical information in tree-ring wood (1900-2010) by non-destructive Micro X-ray fluorescence (μXRF) and destructive (ICP-OES) techniques. We studied two major European conifers with ongoing drought-induced dieback in mesic (Abies alba, silver fir) and xeric (Pinus sylvestris, Scots pine) sites. In each site we compared coexisting declining (D) and non-declining (ND) trees. We used dendrochronology and generalized additive and linear mixed models to analyse trends in tree-ring nutrients and their relationships with wood traits. The D trees presented lower growth and higher minimum wood density than ND trees, corresponding to a smaller lumen area of earlywood tracheids and thus a lower theoretical hydraulic conductivity. These differences in growth and wood-anatomy were more marked in silver fir than in Scots pine. Moreover, most of the chemical elements showed higher concentrations in D than in ND trees during the last two-five decades (e.g., Mn, K and Mg), while Ca and Na increased in the sapwood of ND trees. The Mn concentrations, and related ratios (Ca:Mn, Mn:Al and P:Mn) showed the highest differences between D and ND trees for both tree species. These findings suggest that a reduced hydraulic conductivity, consistent with hydraulic impairment, is affecting the use of P in D trees, making them more prone to drought-induced damage. The retrospective quantifications of Mn ratios may be used as early-warning signals of impending dieback., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation-contraction (EC) coupling., Methods: We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram., Results: Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho)., Conclusions: Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

In cancer cells, epithelial-to-mesenchymal transition (EMT) is controlled by Snail1, a transcriptional factor also required for the activation of cancer-associated fibroblasts (CAF). Snail1 is short-lived in normal epithelial cells as a consequence of its coordinated and continuous ubiquitination by several F-box-specific E3 ligases, but its degradation is prevented in cancer cells and in activated fibroblasts. Here, we performed an siRNA screen and identified USP27X as a deubiquitinase that increases Snail1 stability. Expression of USP27X in breast and pancreatic cancer cell lines and tumors positively correlated with Snail1 expression levels. Accordingly, downregulation of USP27X decreased Snail1 protein in several tumor cell lines. USP27X depletion impaired Snail1-dependent cell migration and invasion and metastasis formation and increased cellular sensitivity to cisplatin. USP27X was upregulated by TGFβ during EMT and was required for TGFβ-induced expression of Snail1 and other mesenchymal markers in epithelial cells and CAF. In agreement with this, depletion of USP27X prevented TGFβ-induced EMT and fibroblast activation. Collectively, these results indicate that USP27X is an essential protein controlling Snail1 expression and function and may serve as a target for inhibition of Snail1-dependent tumoral invasion and chemoresistance. SIGNIFICANCE: These findings show that inhibition of USP27X destabilizes Snail1 to impair EMT and renders tumor cells sensitive to chemotherapy, thus opening new strategies for the inhibition of Snail1 expression and its protumoral actions. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/1/33/F1.large.jpg., (©2018 American Association for Cancer Research.)

Climate change can impair ecosystem functions and services in extensive dry forests worldwide. However, attribution of climate change impacts on tree growth and forest productivity is challenging due to multiple inter-annual patterns of climatic variability associated with atmospheric and oceanic circulations. Moreover, growth responses to rising atmospheric CO 2 , namely carbon fertilization, as well as size ontogenetic changes can obscure the climate change signature as well. Here we apply Structural Equation Models (SEM) to investigate the relative role of climate change on tree growth in an extreme Mediterranean environment (i.e., extreme in terms of the combination of sandy-unconsolidated soils and climatic aridity). Specifically, we analyzed potential direct and indirect pathways by which different sources of climatic variability (i.e. warming and precipitation trends, the North Atlantic Oscillation, [NAO]; the Mediterranean Oscillation, [MOI]; the Atlantic Mediterranean Oscillation, [AMO]) affect aridity through their control on local climate (in terms of mean annual temperature and total annual precipitation), and subsequently tree productivity, in terms of basal area increments (BAI). Our results support the predominant role of Diameter at Breast Height (DHB) as the main growth driver. In terms of climate, NAO and AMO are the most important drivers of tree growth through their control of aridity (via effects of precipitation and temperature, respectively). Furthermore and contrary to current expectations, our findings also support a net positive role of climate warming on growth over the last 50 years and suggest that impacts of climate warming should be evaluated considering multi-annual and multi-decadal periods of local climate defined by atmospheric and oceanic circulation in the North Atlantic., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Changes in the anatomical relationship between left phrenic nerve and coronary veins may occur due to the reverse remodelling observed in super-responders to cardiac resynchronization therapy (CRT) and might be the underlying mechanism in patients developing late-onset phrenic nerve stimulation (PNS) without evidence of lead dislodgement (LD). In this study, we sought to evaluate the role of super-response (SR) to CRT as a potential predictor of late-onset PNS., Methods and Results: Consecutive patients implanted with a left ventricular (LV) lead in a single centre were retrospectively analysed. Phrenic nerve stimulation was classified as 'early' when it occurred within 3 months of implantation and 'late' for occurrences thereafter. 'Late' PNS was considered related to LD (LD-PNS) when LV threshold differed by > 1 V or impedance >250 Ω from baseline values or in case of radiological displacement. Cases not meeting the former criteria were classified as 'non-LD-PNS'. Super-response was defined as a decrease ≥30% of the left ventricluar end-systolic volume at 1-year echocardiography. At 32 ± 7 months follow-up, PNS occurred in 20 of 139 patients. Late non-LD-PNS incidence was significantly higher in the SR group (8/61; 13.1%) when compared with the non-SR (1/78; 1.3%) (P = 0.010). Super-response remained the only predictor of non-LD-PNS at multivariate analysis (odds ratio: 11.62, 95% confidence interval 1.41-95.68, P = 0.023)., Conclusion: Incidence of late non-LD-PNS is higher among SR to CRT, suggesting a potential role of the changes in the anatomical relationship between left phrenic nerve and coronary veins.

Dendrochemical studies in old forests are still underdeveloped. Old trees growing in remote high-elevation areas far from direct human influence constitute a promising biological proxy for the long-term reconstructions of environmental changes using tree-rings. Furthermore, centennial-long chronologies of multi-elemental chemistry at inter- and intra-annual resolution are scarce. Here, we use a novel non-destructive method by applying Micro X-ray fluorescence (μXRF) to wood samples of old Pinus uncinata trees from two Pyrenean high-elevation forests growing on acidic and basic soils. To disentangle ontogenetic (changes in tree age and diameter) from environmental influences (e.g., climate warming) we compared element patterns in sapwood (SW) and heartwood (HW) during the pre-industrial (1700-1849) and industrial (1850-2008) periods. We quantified tree-ring growth, wood density and relative element concentrations at annual (TRW, tree-ring) to seasonal resolution (EW, earlywood; LW, latewood) and related them to climate variables (temperature and precipitation) and volcanic eruptions in the 18th and 19th centuries. We detected differences for most studied elements between SW and HW along the stem and also between EW and LW within rings. Long-term positive and negative trends were observed for Ca and K, respectively. Cl, P and S showed positive trends during the industrial period. However, differences between sites were also notable. Higher values of Mg, Al, Si and the Ca/Mn ratio were observed at the site with acidic soil. Growing-season temperatures were positively related to growth, maximum wood density and to the concentration of most elements. Peaks in S, Fe, Cl, Zn and Ca were linked to major volcanic eruptions (e.g., Tambora in 1815). Our results reveal the potential of long-term wood-chemistry studies based on the μXRF non-destructive technique to reconstruct environmental changes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Forecasted increase drought frequency and severity may drive worldwide declines in forest productivity. Species-level responses to a drier world are likely to be influenced by their functional traits. Here, we analyse forest resilience to drought using an extensive network of tree-ring width data and satellite imagery. We compiled proxies of forest growth and productivity (TRWi, absolutely dated ring-width indices; NDVI, Normalized Difference Vegetation Index) for 11 tree species and 502 forests in Spain corresponding to Mediterranean, temperate, and continental biomes. Four different components of forest resilience to drought were calculated based on TRWi and NDVI data before, during, and after four major droughts (1986, 1994-1995, 1999, and 2005), and pointed out that TRWi data were more sensitive metrics of forest resilience to drought than NDVI data. Resilience was related to both drought severity and forest composition. Evergreen gymnosperms dominating semi-arid Mediterranean forests showed the lowest resistance to drought, but higher recovery than deciduous angiosperms dominating humid temperate forests. Moreover, semi-arid gymnosperm forests presented a negative temporal trend in the resistance to drought, but this pattern was absent in continental and temperate forests. Although gymnosperms in dry Mediterranean forests showed a faster recovery after drought, their recovery potential could be constrained if droughts become more frequent. Conversely, angiosperms and gymnosperms inhabiting temperate and continental sites might have problems to recover after more intense droughts since they resist drought but are less able to recover afterwards., (© 2018 John Wiley & Sons Ltd.)

Mitral valve prolapse (MVP) is a common and benign condition. However, some anatomic forms have been recently associated with life-threatening ventricular arrhythmias and sudden cardiac death. Imaging MVP holds the promise of individualized MVP risk assessment. Noninvasive imaging techniques available today are playing an increasingly important role in the diagnosis, prognosis and monitoring of MVP. In this article, we will review the current evidence on arrhythmogenic MVP, with special focus on the utility of echocardiography and CMR for identifying benign and "malignant" forms of MVP. The clinical relevance of this manuscript lies in the value of imaging technology to improve MVP risk prediction, including those arrhythmic-MVP cases with a higher risk of sudden cardiac death.

Warmer and drier climatic conditions are projected for the 21st century; however, the role played by extreme climatic events on forest vulnerability is still little understood. For example, more severe droughts and heat waves could threaten quaternary relict tree refugia such as Circum-Mediterranean fir forests (CMFF). Using tree-ring data and a process-based model, we characterized the major climate constraints of recent (1950-2010) CMFF growth to project their vulnerability to 21st-century climate. Simulations predict a 30% growth reduction in some fir species with the 2050s business-as-usual emission scenario, whereas growth would increase in moist refugia due to a longer and warmer growing season. Fir populations currently subjected to warm and dry conditions will be the most vulnerable in the late 21st century when climatic conditions will be analogous to the most severe dry/heat spells causing dieback in the late 20th century. Quantification of growth trends based on climate scenarios could allow defining vulnerability thresholds in tree populations. The presented predictions call for conservation strategies to safeguard relict tree populations and anticipate how many refugia could be threatened by 21st-century dry spells., Competing Interests: The authors declare no conflict of interest.

Growth models can be used to assess forest vulnerability to climate warming. If global warming amplifies water deficit in drought-prone areas, tree populations located at the driest and southernmost distribution limits (rear-edges) should be particularly threatened. Here, we address these statements by analyzing and projecting growth responses to climate of three major tree species (silver fir, Abies alba; Scots pine, Pinus sylvestris; and mountain pine, Pinus uncinata) in mountainous areas of NE Spain. This region is subjected to Mediterranean continental conditions, it encompasses wide climatic, topographic and environmental gradients, and, more importantly, it includes rear-edges of the continuous distributions of these tree species. We used tree-ring width data from a network of 110 forests in combination with the process-based Vaganov-Shashkin-Lite growth model and climate-growth analyses to forecast changes in tree growth during the 21st century. Climatic projections were based on four ensembles CO 2 emission scenarios. Warm and dry conditions during the growing season constrain silver fir and Scots pine growth, particularly at the species rear-edge. By contrast, growth of high-elevation mountain pine forests is enhanced by climate warming. The emission scenario (RCP 8.5) corresponding to the most pronounced warming (+1.4 to 4.8 °C) forecasted mean growth reductions of -10.7% and -16.4% in silver fir and Scots pine, respectively, after 2050. This indicates that rising temperatures could amplify drought stress and thus constrain the growth of silver fir and Scots pine rear-edge populations growing at xeric sites. Contrastingly, mountain pine growth is expected to increase by +12.5% due to a longer and warmer growing season. The projections of growth reduction in silver fir and Scots pine portend dieback and a contraction of their species distribution areas through potential local extinctions of the most vulnerable driest rear-edge stands. Our modeling approach provides accessible tools to evaluate forest vulnerability to warmer conditions., (© 2016 John Wiley & Sons Ltd.)