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Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

Chromatin remodeling plays a key role in the establishment and maintenance of gene expression patterns essential for plant development and responses to environmental factors. Post-translational modification of histones, including acetylation, is one of the most relevant chromatin remodeling mechanisms that operate in eukaryotic cells. Histone acetylation is an evolutionarily conserved chromatin signature commonly associated with transcriptional activation. Histone acetylation levels are tightly regulated through the antagonistic activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In plants, different families of HATs are present, including the MYST family, which comprises homologs of the catalytic subunit of the Nucleosome Acetyltransferase of H4 (NuA4) complex in yeast. This complex mediates acetylation of histones H4, H2A, and H2A.Z, and is involved in transcriptional regulation, heterochromatin silencing, cell cycle progression, and DNA repair in yeast. In Arabidopsis and, other plant species, homologs for most of the yeast NuA4 subunits are present and although the existence of this complex has not been demonstrated yet, compelling evidence supports the notion that this type of HAT complex functions from mosses to angiosperms. Recent proteomic studies show that several Arabidopsis homologs of NuA4 components, including the assembly platform proteins and the catalytic subunit, are associated in vivo with additional members of this complex suggesting that a NuA4-like HAT complex is present in plants. Furthermore, the functional characterization of some Arabidopsis NuA4 subunits has uncovered the involvement of these proteins in the regulation of different plant biological processes. Interestingly, for most of the mutant plants deficient in subunits of this complex characterized so far, conspicuous defects in flowering time are observed, suggesting a role for NuA4 in the control of this plant developmental program. Moreover, the particip

Many tree species from Mediterranean regions have started to show increased rates of crown defoliation, reduced growth, and dieback associated with the increase in temperatures and changes in the frequency and intensity of drought events experienced during the last decades. In this regard, Quercus ilex L. subsp. ballota [Desf.] (Holm oak), despite being a drought-tolerant species widely distributed in the Mediterranean basin, it has recently started to show acute signs of decline, extended areas from Spain being affected. However, few studies have assessed the role of climatic variability (i.e., temperature, precipitation, and drought) on the decline and resilience of Holm oak. Here, we measured secondary growth of seventy Holm oaks from a coppice stand located in central Spain. Sampled trees had different stages of decline, so they were classified into four vigour groups considering their crown foliar lost: healthy (0%), low defoliated (<25%), highly defoliated (25–70%), and dying (70–100%). Our results showed that during the study period (1980–2009) the highly defoliated and dying Holm oaks grew significantly less than their healthy and low defoliated neighbours, suggesting permanent growth reduction in the less vigorous individuals. Despite these differences, all four vigour groups showed similar responses to climatic variations, especially during winter and late spring – early summer seasons, and similar resilience after severe drought events, managing to significantly recover to pre-drought growth rates after only two years. Our findings, hence, illustrate that tree vigour influences secondary growth but not responsiveness to climatic variability in Holm oak. Still, as reduced growth rates are frequently associated with the process of tree mortality, we conclude that the less vigorous Holm oaks might not be able to cope with future water stress conditions, leading to increased mortality rates among this emblematic Mediterranean species.

Many tree species from Mediterranean regions have started to show increased rates of crown defoliation, reduced growth, and dieback associated with the increase in temperatures and changes in the frequency and intensity of drought events experienced during the last decades. In this regard, Quercus ilex L. subsp. ballota [Desf.] (Holm oak), despite being a drought-tolerant species widely distributed in the Mediterranean basin, it has recently started to show acute signs of decline, extended areas from Spain being affected. However, few studies have assessed the role of climatic variability (i.e., temperature, precipitation, and drought) on the decline and resilience of Holm oak. Here, we measured secondary growth of seventy Holm oaks from a coppice stand located in central Spain. Sampled trees had different stages of decline, so they were classified into four vigour groups considering their crown foliar lost: healthy (0%), low defoliated (<25%), highly defoliated (25–70%), and dying (70–100%). Our results showed that during the study period (1980–2009) the highly defoliated and dying Holm oaks grew significantly less than their healthy and low defoliated neighbours, suggesting permanent growth reduction in the less vigorous individuals. Despite these differences, all four vigour groups showed similar responses to climatic variations, especially during winter and late spring – early summer seasons, and similar resilience after severe drought events, managing to significantly recover to pre-drought growth rates after only two years. Our findings, hence, illustrate that tree vigour influences secondary growth but not responsiveness to climatic variability in Holm oak. Still, as reduced growth rates are frequently associated with the process of tree mortality, we conclude that the less vigorous Holm oaks might not be able to cope with future water stress conditions, leading to increased mortality rates among this emblematic Mediterranean species.

Many tree species from Mediterranean regions have started to show increased rates of crown defoliation, reduced growth, and dieback associated with the increase in temperatures and changes in the frequency and intensity of drought events experienced during the last decades. In this regard, Quercus ilex L. subsp. ballota [Desf.] (Holm oak), despite being a drought-tolerant species widely distributed in the Mediterranean basin, it has recently started to show acute signs of decline, extended areas from Spain being affected. However, few studies have assessed the role of climatic variability (i.e., temperature, precipitation, and drought) on the decline and resilience of Holm oak. Here, we measured secondary growth of seventy Holm oaks from a coppice stand located in central Spain. Sampled trees had different stages of decline, so they were classified into four vigour groups considering their crown foliar lost: healthy (0%), low defoliated (<25%), highly defoliated (25–70%), and dying (70–100%). Our results showed that during the study period (1980–2009) the highly defoliated and dying Holm oaks grew significantly less than their healthy and low defoliated neighbours, suggesting permanent growth reduction in the less vigorous individuals. Despite these differences, all four vigour groups showed similar responses to climatic variations, especially during winter and late spring – early summer seasons, and similar resilience after severe drought events, managing to significantly recover to pre-drought growth rates after only two years. Our findings, hence, illustrate that tree vigour influences secondary growth but not responsiveness to climatic variability in Holm oak. Still, as reduced growth rates are frequently associated with the process of tree mortality, we conclude that the less vigorous Holm oaks might not be able to cope with future water stress conditions, leading to increased mortality rates among this emblematic Mediterranean species.

Many tree species from Mediterranean regions have started to show increased rates of crown defoliation, reduced growth, and dieback associated with the increase in temperatures and changes in the frequency and intensity of drought events experienced during the last decades. In this regard, Quercus ilex L. subsp. ballota [Desf.] (Holm oak), despite being a drought-tolerant species widely distributed in the Mediterranean basin, it has recently started to show acute signs of decline, extended areas from Spain being affected. However, few studies have assessed the role of climatic variability (i.e., temperature, precipitation, and drought) on the decline and resilience of Holm oak. Here, we measured secondary growth of seventy Holm oaks from a coppice stand located in central Spain. Sampled trees had different stages of decline, so they were classified into four vigour groups considering their crown foliar lost: healthy (0%), low defoliated (<25%), highly defoliated (25–70%), and dying (70–100%). Our results showed that during the study period (1980–2009) the highly defoliated and dying Holm oaks grew significantly less than their healthy and low defoliated neighbours, suggesting permanent growth reduction in the less vigorous individuals. Despite these differences, all four vigour groups showed similar responses to climatic variations, especially during winter and late spring – early summer seasons, and similar resilience after severe drought events, managing to significantly recover to pre-drought growth rates after only two years. Our findings, hence, illustrate that tree vigour influences secondary growth but not responsiveness to climatic variability in Holm oak. Still, as reduced growth rates are frequently associated with the process of tree mortality, we conclude that the less vigorous Holm oaks might not be able to cope with future water stress conditions, leading to increased mortality rates among this emblematic Mediterranean species.

Many tree species from Mediterranean regions have started to show increased rates of crown defoliation, reduced growth, and dieback associated with the increase in temperatures and changes in the frequency and intensity of drought events experienced during the last decades. In this regard, Quercus ilex L. subsp. ballota [Desf.] (Holm oak), despite being a drought-tolerant species widely distributed in the Mediterranean basin, it has recently started to show acute signs of decline, extended areas from Spain being affected. However, few studies have assessed the role of climatic variability (i.e., temperature, precipitation, and drought) on the decline and resilience of Holm oak. Here, we measured secondary growth of seventy Holm oaks from a coppice stand located in central Spain. Sampled trees had different stages of decline, so they were classified into four vigour groups considering their crown foliar lost: healthy (0%), low defoliated (<25%), highly defoliated (25–70%), and dying (70–100%). Our results showed that during the study period (1980–2009) the highly defoliated and dying Holm oaks grew significantly less than their healthy and low defoliated neighbours, suggesting permanent growth reduction in the less vigorous individuals. Despite these differences, all four vigour groups showed similar responses to climatic variations, especially during winter and late spring – early summer seasons, and similar resilience after severe drought events, managing to significantly recover to pre-drought growth rates after only two years. Our findings, hence, illustrate that tree vigour influences secondary growth but not responsiveness to climatic variability in Holm oak. Still, as reduced growth rates are frequently associated with the process of tree mortality, we conclude that the less vigorous Holm oaks might not be able to cope with future water stress conditions, leading to increased mortality rates among this emblematic Mediterranean species.

The effect of population size on population genetic diversity and structure has rarely been studied jointly with other factors such as the position of a population within the species’ distribution range or the presence of mutualistic partners influencing dispersal. Understanding these determining factors for genetic variation is critical for conservation of relict plants that are generally suffering from genetic deterioration. Working with 16 populations of the vulnerable relict shrub Cneorum tricoccon throughout the majority of its western Mediterranean distribution range, and using nine polymorphic microsatellite markers, we examined the effects of periphery (peripheral vs. central), population size (large vs. small), and seed disperser (introduced carnivores vs. endemic lizards) on the genetic diversity and population structure of the species. Contrasting genetic variation (H: 0.04–0.476) was found across populations. Peripheral populations showed lower genetic diversity, but this was dependent on population size. Large peripheral populations showed high levels of genetic diversity, whereas small central populations were less diverse. Significant isolation by distance was detected, indicating that the effect of long-distance gene flow is limited relative to that of genetic drift, probably due to high selfing rates (F = 0.155–0.887), restricted pollen flow, and ineffective seed dispersal. Bayesian clustering also supported the strong population differentiation and highly fragmented structure. Contrary to expectations, the type of disperser showed no significant effect on either population genetic diversity or structure. Our results challenge the idea of an effect of periphery per se that can be mainly explained by population size, drawing attention to the need of integrative approaches considering different determinants of genetic variation. Furthermore, the very low genetic diversity observed in several small populations and the strong among-population differenti

Demographic and genetic connectivity of fragmented plant populations will depend on effective propagule flow across the landscape. We analyze functional connectivity in a holm oak (Quercus ilex) fragmented landscape by considering three important stages driving recruitment: effective pollination, acorn production and acorn dispersal. We used a network approach to (1) determine if pollen-mediated gene exchange across the landscape was spatially structured; (2) estimate the effects of limited acorn dispersal on functional connectivity; (3) identify which landscape traits could drive source–sink dynamics of gene flow. Although long distance dispersal was relatively frequent, most effective pollen flow occurred over short distances (<100 m). This resulted in a significantly modular structure of the mating network, yielding higher gene flow among nearby fragments. Limited mouse acorn hoarding activity had a strong impact on landscape connectivity, decreasing male gametic immigration rates into forest patches by one order of magnitude Besides, our results show that big forest fragments (>10 ha) are the main pollen sources, while small ones (<1 ha) are important pollen sinks. Thus, big fragments are critical to maintain functional connectivity, while small forest fragments may provide acorn crops better representing regional genetic diversity. In addition to area effects, less isolated and more central fragments showed higher migration rates and exchanged effective pollen with more fragments. Hence, we expected that landscapes with uniform or clumped distribution of big forest fragments would show optimal connectivity traits. However, despite that simulated gene flow was more evenly distributed across the landscape, connectance and migration rates decreased. Our results call for caution before translating patch-level management guidelines to the landscape scale. They also show that the level of functional connectivity may change throughout the recruitment process, suggesti

The regulation of CONSTANS (CO) gene expression is crucial to accurately measure changes in daylength, which influences flowering time in Arabidopsis thaliana. CO expression is under both transcriptional and posttranslational control mechanisms. We previously showed that the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1) physically interacts with CO in Arabidopsis. This interaction is required to precisely modulate the timing of CO accumulation and, consequently, to maintain low levels of FLOWERING LOCUS T expression during the first part of the day. The data presented here demonstrate that HOS1 is involved in the red light-mediated degradation of CO that takes place in the early stages of the daylight period. Our results show that phytochrome B (phyB) is able to regulate flowering time, acting in the phloem companion cells, as previously described for CO and HOS1. Moreover, we reveal that phyB physically interacts with HOS1 and CO, indicating that the three proteins may be present in a complex in planta that is required to coordinate a correct photoperiodic response in Arabidopsis. © 2015 American Society of Plant Biologists.

[Background] Different superparamagnetic iron oxide nanoparticles have been tested for their potential use in cancer treatment, as they enter into cells with high effectiveness, do not induce cytotoxicity, and are retained for relatively long periods of time inside the cells. We have analyzed the interaction, internalization and biocompatibility of dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles with an average diameter of 15 nm and negative surface charge in MCF-7 breast cancer cells., [Results] Cells were incubated with dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles for different time intervals, ranging from 0.5 to 72 h. These nanoparticles showed efficient internalization and relatively slow clearance. Time-dependent uptake studies demonstrated the maximum accumulation of dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles after 24 h of incubation, and afterwards they were slowly removed from cells. Superparamagnetic iron oxide nanoparticles were internalized by energy dependent endocytosis and localized in endosomes. Transmission electron microscopy studies showed macropinocytosis uptake and clathrin-mediated internalization depending on the nanoparticles aggregate size. MCF-7 cells accumulated these nanoparticles without any significant effect on cell morphology, cytoskeleton organization, cell cycle distribution, reactive oxygen species generation and cell viability, showing a similar behavior to untreated control cells., [Conclusions] All these findings indicate that dimercaptosuccinic acid-coated superparamagnetic iron oxide nanoparticles have excellent properties in terms of efficiency and biocompatibility for application to target breast cancer cells.

1. Interannual variability in climatic conditions should be taken into account in climate change studies in semi-arid ecosystems. It may determine differentiation in phenotypic plasticity among populations, with populations experiencing higher environmental heterogeneity showing higher levels of plasticity., 2. The ability of populations to evolve key functional traits and plasticity may determine the survival of plant populations under the drier and more variable climate expected for semi-arid ecosystems., 3. Working with populations of the semi-arid Chilean shrub Senna candolleana along its entire distribution range, we assessed inter- and intra-population variation in functional traits as well as in their plasticity in response to water availability. We measured morphological and physiological traits related to drought resistance in both field conditions and in a greenhouse experiment, where drought response was evaluated under two water availability treatments., 4. All populations responded plastically, but higher precipitation heterogeneity in dry-edge populations seemed to have selected for more plastic genotypes compared to populations growing at mesic sites and with more homogeneous environmental conditions., 5. Synthesis. Our results suggest adaptive plasticity since higher levels of phenotypic plasticity were positively associated with plant performance. However, we did not find evidence for genetic variation for plasticity within populations. To the extent that phenotypic plasticity may play a key role in future persistence, populations at mesic sites may be more vulnerable to climate change due to their lower plasticity and their current limitations to evolve novel norms of reaction. Conversely, although Senna candolleana populations at the dry edge are exposed to higher levels of stress, they may be less susceptible to climate change in view of their greater plasticity. We highlight the need to consider population differentiation in both mean traits and their plasticity to model realistic scenarios of species distribution under climate change.

Plants can respond to climate change by either migrating, adapting to the new conditions or going extinct. Relict plant species of limited distribution can be especially vulnerable as they are usually composed of small and isolated populations, which may reduce their ability to cope with rapidly changing environmental conditions. The aim of this study was to assess the vulnerability of Cneorum tricoccon L. (Cneoraceae), a Mediterranean relict shrub of limited distribution, to a future drier climate. We evaluated population differentiation in functional traits related to drought tolerance across seven representative populations of the species’ range. We measured morphological and physiological traits in both the field and the greenhouse under three water availability levels. Large phenotypic differences among populations were found under field conditions. All populations responded plastically to simulated drought, but they differed in mean trait values as well as in the slope of the phenotypic response. Particularly, dry-edge populations exhibited multiple functional traits that favored drought tolerance, such as more sclerophyllous leaves, strong stomatal control but high photosynthetic rates, which increases water use efficiency (iWUE), and an enhanced ability to accumulate sugars as osmolytes. Although drought decreased RGR in all populations, this reduction was smaller for populations from the dry edge. Our results suggest that dry-edge populations of this relict species are well adapted to drought, which could potentially mitigate the species’ extinction risk under drier scenarios. Dry-edge populations not only have a great conservation value but can also change expectations from current species’ distribution models.

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón. Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los individuos con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón en a) individuos sin EPOC ni cáncer de pulmón, b) individuos con EPOC, c) individuos con adenocarcinoma, d) individuos con EPOC y adenocarcinoma, o e) individuos con EPOC y carcinoma escamoso. La presente invención describe además un kit de diagnóstico, así como un dispositivo y sus usos para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón según se ha indicado anteriormente.

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón. Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los individuos con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón en a) individuos sin EPOC ni cáncer de pulmón, b) individuos con EPOC, c) individuos con adenocarcinoma, d) individuos con EPOC y adenocarcinoma, o e) individuos con EPOC y carcinoma escamoso. La presente invención describe además un kit de diagnóstico, así como un dispositivo y sus usos para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón según se ha indicado anteriormente.

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los individuos con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón en a) individuos sin EPOC ni cáncer de pulmón, b) individuos con EPOC, c) individuos con adenocarcinoma, d) individuos con EPOC y adenocarcinoma, o e) individuos con EPOC y carcinoma escamoso. La presente invención describe además un kit de diagnóstico, así como un dispositivo y sus usos para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón según se ha indicado anteriormente

Método de obtención de datos útiles para el diagnóstico, pronóstico y clasificación de los individuos con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón en a) individuos sin EPOC ni cáncer de pulmón, b) individuos con EPOC, c) individuos con adenocarcinoma, d) individuos con EPOC y adenocarcinoma, o e) individuos con EPOC y carcinoma escamoso. La presente invención describe además un kit de diagnóstico, así como un dispositivo y sus usos para el diagnóstico, pronóstico y clasificación de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) y/o cáncer de pulmón según se ha indicado anteriormente

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Plants have evolved different strategies to cope with drought, involving alternative ecophysiologies and different levels of plasticity. These strategies are critical for species of limited distribution, which are especially vulnerable to the current rates of rapid environmental change. The aim of this study was to assess the water strategy of two species with limited distribution, Cneorum tricoccon L. and Rhamnus ludovici-salvatoris Chodat., and evaluate their interpopulation variability along an aridity gradient to estimate their vulnerability to a drier climate. We measured different ecophysiological traits influenced by drought - stomatal conductance, maximum photochemical efficiency of photosynthesis II, carbon isotope ratio and chlorophyll concentration - in two climatically contrasting years, before and during summer drought. Both species were vulnerable to drought at the aridity limit of the gradient, but showed contrasting water strategies: while C. tricoccon was consistent in its water conservation strategy across the aridity gradient, R. ludovici-salvatoris was not, displaying higher and more variable stomatal conductances and being able to increase water-use efficiency at the most xeric sites. Changes in length and intensity of drought events may favor one species' strategy to the detriment of the other: C. tricoccon is more vulnerable to chronic and prolonged droughts, whereas short but acute droughts might have a stronger effect on R. ludovici-salvatoris. In those communities where these two species coexist, such different strategies might lead to changes in community structure under climate change scenarios, with unknown cascade effects on ecosystem functioning. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The invention describes a method for obtaining data that are useful for the diagnosis, prognosis and classification of individuals with chronic obstructive pulmonary disease (COPD) and/or lung cancer, a diagnostic kit, a device and the uses thereof for the diagnosis, prognosis and classification of patients as a) individuals without COPD or lung cancer, b) individuals with COPD, c) individuals with adenocarcinoma, d) individuals with COPD and adenocarcinoma, or e) individuals with COPD and squamous cell carcinoma.

The correct understanding of tumour development relies on the comprehensive study of proteins. They are the main orchestrators of vital processes, such as signalling pathways, which drive the carcinogenic process. Proteomic technologies can be applied to cancer research to detect differential protein expression and to assess different responses to treatment. Lung cancer is the number one cause of cancer-related death in the world. Mostly diagnosed at late stages of the disease, lung cancer has one of the lowest 5-year survival rates at 15 %. The use of different proteomic techniques such as two-dimensional gel electrophoresis (2D-PAGE), isotope labelling (ICAT, SILAC, iTRAQ) and mass spectrometry may yield new knowledge on the underlying biology of lung cancer and also allow the development of new early detection tests and the identification of changes in the cancer protein network that are associated with prognosis and drug resistance.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Premise of the study: The main aim of this study was to isolate and characterize microsatellite loci in Cneorum tricoccon (Cneoraceae), a Mediterranean shrub relict of the early Tertiary, which inhabits western Mediterranean islands and coasts. Microsatellites will be useful for investigating biogeography and landscape genetics across the species distribution range, including current or past gene flow. Methods and Results: Seventeen microsatellite loci were characterized, of which 10 were polymorphic and amplified for a total of 56 alleles in three populations of C. tricoccon. The markers revealed average coefficients of expected heterozygosity (H e = 0.425), observed heterozygosity (H o = 0.282), and inbreeding coefficient value per population (F IS = 0.408). Conclusions: These microsatellite primers will potentially be useful in the study of population and landscape genetics, conservation status of isolated populations, island-continental distribution, current or historical movements between populations, and in the investigation of the consequences of dispersal mechanisms of these plants. © 2012 Botanical Society of America.

The Arabidopsis thaliana early in short days6 (esd6) mutant was isolated in a screen for mutations that accelerate flowering time. Among other developmental alterations, esd6 displays early flowering in both long- and short-day conditions. Fine mapping of the mutation showed that the esd6 phenotype is caused by a lesion in the HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1) locus, which encodes a RING finger–containing E3 ubiquitin ligase. The esd6/hos1 mutation causes decreased FLOWERING LOCUS C expression and requires CONSTANS (CO) protein for its early flowering phenotype under long days. Moreover, CO and HOS1 physically interact in vitro and in planta, and HOS1 regulates CO abundance, particularly during the daylight period. Accordingly, hos1 causes a shift in the regular long-day pattern of expression of FLOWERING LOCUS T (FT) transcript, starting to rise 4 h after dawn in the mutant. In addition, HOS1 interacts synergistically with CONSTITUTIVE PHOTOMORPHOGENIC1, another regulator of CO protein stability, in the regulation of flowering time. Taken together, these results indicate that HOS1 is involved in the control of CO abundance, ensuring that CO activation of FT occurs only when the light period reaches a certain length and preventing precocious flowering in Arabidopsis.

The rotation of the earth results in periodic changes in environmental factors such as daylength and temperature; the circadian clock is the endogenous mechanism responsible for day-length measurement, and allows plants to anticipate these fluctuations and modulate their developmental programs to maximize adaptation to those environmental cues. Flowering represents the transition from a vegetative to reproductive phase and is controlled by complex and highly regulated genetic pathways. In many plants, the time of flowering is strongly influenced by photoperiod, which synchronizes the floral transition with the favourable season of the year. Over the last decade, genetic approaches have aided the discovery of many signalling components involved in the photoperiod pathway and here, we highlight the significant progress made in identifying the molecular mechanisms that measure daylength and control flowering initiation in Arabidopsis, a long day (LD) plant, and in rice, a short day (SD) plant. Some components of the Arabidopsis regulatory network are conserved in other species, but the difference in the function of particular genes may contribute to the opposite photoperiodic flowering response observed between LD and SD plants. The specific regulatory mechanisms involved in controlling CONSTANS (CO) expression and stability by the circadian clock and the different photoreceptors will be described. In addition, the role of FLOWERING LOCUS T (FT), as part of the florigen, and several other light signalling and circadian-dependent components in photoperiodic flowering will be also discussed.

Mutations affecting the Arabidopsis SWC6 gene encoding a putative orthologue of a component of the SWR1 chromatin remodelling complex in plants have been characterized. swc6 mutations cause early flowering, shortened inflorescence internodes, and altered leaf and flower development. These phenotypic defects resemble those of the photoperiod independent early flowering 1 (pie1) and early in short days 1 (esd1) mutants, also affected in homologues of the SWR1 complex subunits. SWC6 is a ubiquitously expressed nuclear HIT-Zn finger-containing protein, with the highest levels found in pollen. Double mutant analyses suggest that swc6 abolishes the FLC-mediated late-flowering phenotype of plants carrying active alleles of FRI and of mutants of the autonomous pathway. It was found that SWC6 is required for the expression of the FLC repressor to levels that inhibit flowering. However, the effect of swc6 in an flc null background and the down-regulation of other FLC-like/MAF genes in swc6 mutants suggest that flowering inhibition mediated by SWC6 occurs through both FLC- and FLC-like gene-dependent pathways. Both genetic and physical interactions between SWC6 and ESD1 have been demonstrated, suggesting that both proteins act in the same complex. Using chromatin immunoprecipitation, it has been determined that SWC6, as previously shown for ESD1, is required for both histone H3 acetylation and H3K4 trimethylation of the FLC chromatin. Altogether, these results suggest that SWC6 and ESD1 are part of an Arabidopsis SWR1 chromatin remodelling complex involved in the regulation of diverse aspects of plant development, including floral repression through the activation of FLC and FLC-like genes. © 2008 The Author(s).

We have characterized Arabidopsis esd1 mutations, which cause early flowering independently of photoperiod, moderate increase of hypocotyl length, shortened inflorescence internodes, and altered leaf and flower development. Phenotypic analyses of double mutants with mutations at different loci of the flowering inductive pathways suggest that esd1 abolishes the FLC-mediated late flowering phenotype of plants carrying active alleles of FRI and of mutants of the autonomous pathway. We found that ESD1 is required for the expression of the FLC repressor to levels that inhibit flowering. However, the effect of esd1 in a flc-3 null genetic background and the downregulation of other members of the FLC-like/MAF gene family in esd1 mutants suggest that flowering inhibition mediated by ESD1 occurs through both FLC-and FLC-like gene-dependent pathways. The ESD1 locus was identified through a map-based cloning approach. ESD1 encodes ARP6, a homolog of the actin-related protein family that shares moderate sequence homology with conventional actins. Using chromatin immunoprecipitation (ChIP) experiments, we have determined that ARP6 is required for both histone acetylation and methylation of the FLC chromatin in Arabidopsis.