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There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate cancer progression. Additionally, optimized machine learning classifier analysis reveals proteomic signatures capable of detecting the disease prior to biopsy, performing on par with an accepted clinical risk calculator benchmark.
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Biomarcadores de Tumor , Neoplasias de la Próstata , Proteómica , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/sangre , Biomarcadores de Tumor/sangre , Proteómica/métodos , Espectrometría de Movilidad Iónica/métodos , Antígeno Prostático Específico/sangre , Anciano , Aprendizaje Automático , Persona de Mediana EdadRESUMEN
Graphene holds great potential for superconductivity due to its pure 2D nature, the ability to tune its carrier density through electrostatic gating, and its unique, relativistic-like electronic properties. At present, still far from controlling and understanding graphene superconductivity, mainly because the selective introduction of superconducting properties to graphene is experimentally very challenging. Here, a method is developed that enables shaping at will graphene superconductivity through a precise control of graphene-superconductor junctions. The method combines the proximity effect with scanning tunnelling microscope (STM) manipulation capabilities. Pb nano-islands are first grown that locally induce superconductivity in graphene. Using a STM, Pb nano-islands can be selectively displaced, over different types of graphene surfaces, with nanometre scale precision, in any direction, over distances of hundreds of nanometres. This opens an exciting playground where a large number of predefined graphene-superconductor hybrid structures can be investigated with atomic scale precision. To illustrate the potential, a series of experiments are performed, rationalized by the quasi-classical theory of superconductivity, going from the fundamental understanding of superconductor-graphene-superconductor heterostructures to the construction of superconductor nanocorrals, further used as "portable" experimental probes of local magnetic moments in graphene.
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AIM: To identify clusters of nurses in relation to the utilisation and attitude towards nursing diagnosis and to compare their profiles considering demographics, professional characteristics and nursing practice environments. BACKGROUND: Nursing diagnosis has benefits for both patients and nurses, and the attitude of nurses towards nursing diagnosis has been proposed as a determinant of its use. Therefore, an adequate understanding of nurses' attitude and utilisation profiles regarding nursing diagnosis is essential for the nursing managers who want to adopt nursing diagnosis as a practice framework. METHODS: A cross-sectional survey design was used. A sample of 239 nurses working in the Catalan primary health care system were categorised into clusters with similar attitude and utilisation profiles, which were compared with each other a posteriori. RESULTS: Nursing managers were grouped into more positive attitude clusters than clinical nurses. Nurses working in supportive nursing practice environments were classified into more positive attitude and higher utilisation clusters. CONCLUSION: The field of work and nursing practice environments were found as differential factors in profiles of nurses with different attitudes towards and/or utilisation of nursing diagnosis. IMPLICATIONS FOR NURSING MANAGEMENT: The promotion of supportive nursing practice environments could enhance the implementation and maintenance of nursing diagnosis as a practice framework in primary health care.
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Conocimientos, Actitudes y Práctica en Salud , Diagnóstico de Enfermería/estadística & datos numéricos , Adulto , Estudios Transversales , Femenino , Humanos , Satisfacción en el Trabajo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Diagnóstico de Enfermería/métodos , España , Estadísticas no Paramétricas , Encuestas y CuestionariosRESUMEN
Polyamines (putrescine, spermidine and spermine) are traditionally implicated in the response of plants to environmental cues. Free spermine accumulation has been suggested as a particular feature of long-term salt stress, and in the model plant Arabidopsis thaliana the spermine synthase gene (AtSPMS) has been reported as inducible by abscisic acid (ABA) and acute salt stress treatments. With the aim to unravel the physiological role of free spermine during salinity, we analyzed polyamine metabolism in A. thaliana salt-hypersensitive sos mutants (salt overlay sensitive; sos1-1, sos2-1 and sos3-1), and studied the salt stress tolerance of the mutants in spermine and thermospermine synthesis (acl5-1, spms-1 and acl5-1/spms-1). Results presented here indicate that induction in polyamine metabolism is a SOS-independent response to salinity and is globally over-induced in a sensitive background. In addition, under long-term salinity, the mutants in the synthesis of spermine and thermospermine (acl5-1, spms-1 and double acl5-1/spms-1) accumulated more Na(+) and performed worst than WT in survival experiments. Therefore, support is given to a role for these higher polyamines in salt tolerance mechanisms.
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Arabidopsis/metabolismo , Tolerancia a la Sal/fisiología , Espermina/metabolismo , Arabidopsis/genética , Poliaminas Biogénicas/metabolismo , Regulación de la Expresión Génica de las Plantas , Genes de Plantas/efectos de los fármacos , Variación Genética , Reguladores del Crecimiento de las Plantas/metabolismo , Salinidad , Tolerancia a la Sal/genética , Cloruro de Sodio/metabolismo , Espermina/análogos & derivados , Espermina/biosíntesis , Espermina Sintasa/genética , Espermina Sintasa/metabolismoRESUMEN
Temperature is one of the most important environmental factors limiting the geographical distribution of plants and accounts for significant reductions in the yield of agriculturally important crops. Low temperature damages many plant species, especially those adapted to tropical climates. In contrast, some species from temperate regions are able to develop freezing tolerance in response to low-non-freezing temperature, an adaptive process named cold acclimation. Numerous molecular, biochemical and physiological changes occur during cold acclimation, most of them being associated with significant changes in gene expression and metabolite profiles. During recent years, transcriptomic and metabolomic approaches have allowed the identification of cold-responsive genes and main metabolites which accumulate in plants exposed to cold. The obtained data support the previously held idea that polyamines (PAs) are involved in plant responses to cold, although their specific role is still not well understood. In this review, we synthesize published data regarding PA-responses to cold stress and integrate them with global transcriptional and metabolic changes. The potential of PA genetic engineering for the development of plants resistant to cold and freezing temperatures, and their plausible mechanisms of action are also discussed.
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Aclimatación/fisiología , Frío , Regulación de la Expresión Génica de las Plantas/fisiología , Poliaminas/metabolismo , Aclimatación/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Modelos BiológicosRESUMEN
Polyamines have been globally associated to plant responses to abiotic stress. Particularly, putrescine has been related to a better response to cold and dehydration stresses. It is known that this polyamine is involved in cold tolerance, since Arabidopsis thaliana plants mutated in the key enzyme responsible for putrescine synthesis (arginine decarboxilase, ADC; EC 4.1.1.19) are more sensitive than the wild type to this stress. Although it is speculated that the over-expression of ADC genes may confer tolerance, this is hampered by pleiotropic effects arising from the constitutive expression of enzymes from the polyamine metabolism. Here, we present our work using A. thaliana transgenic plants harboring the ADC gene from oat under the control of a stress-inducible promoter (pRD29A) instead of a constitutive promoter. The transgenic lines presented in this work were more resistant to both cold and dehydration stresses, associated with a concomitant increment in endogenous putrescine levels under stress. Furthermore, the increment in putrescine upon cold treatment correlated with the induction of known stress-responsive genes, and suggested that putrescine may be directly or indirectly involved in ABA metabolism and gene expression.
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Aclimatación , Arabidopsis/metabolismo , Deshidratación , Congelación , Putrescina/metabolismo , Ácido Abscísico/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Dioxigenasas/metabolismo , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Estrés FisiológicoRESUMEN
Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day-night cycle. Post-transcriptional regulation is emerging as an important component of circadian networks, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones and Sm spliceosomal proteins, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5'-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions.
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Empalme Alternativo/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiología , Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Proteína Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Animales , Arabidopsis/enzimología , Arabidopsis/genética , Arabidopsis/efectos de la radiación , Proteínas de Arabidopsis/genética , Secuencia de Bases , Relojes Circadianos/genética , Ritmo Circadiano/genética , Oscuridad , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimología , Drosophila melanogaster/genética , Drosophila melanogaster/efectos de la radiación , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Luz , Metilación , Mutación , Proteínas Circadianas Period/genética , Fenotipo , Proteína Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/genética , Precursores del ARN/genética , Precursores del ARN/metabolismo , Sitios de Empalme de ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Empalmosomas/metabolismo , Factores de Transcripción/genéticaRESUMEN
The levels of endogenous polyamines have been shown to increase in plant cells challenged with low temperature; however, the functions of polyamines in the regulation of cold stress responses are unknown. Here, we show that the accumulation of putrescine under cold stress is essential for proper cold acclimation and survival at freezing temperatures because Arabidopsis (Arabidopsis thaliana) mutants defective in putrescine biosynthesis (adc1, adc2) display reduced freezing tolerance compared to wild-type plants. Genes ADC1 and ADC2 show different transcriptional profiles upon cold treatment; however, they show similar and redundant contributions to cold responses in terms of putrescine accumulation kinetics and freezing sensitivity. Our data also demonstrate that detrimental consequences of putrescine depletion during cold stress are due, at least in part, to alterations in the levels of abscisic acid (ABA). Reduced expression of NCED3, a key gene involved in ABA biosynthesis, and down-regulation of ABA-regulated genes are detected in both adc1 and adc2 mutant plants under cold stress. Complementation analysis of adc mutants with ABA and reciprocal complementation tests of the aba2-3 mutant with putrescine support the conclusion that putrescine controls the levels of ABA in response to low temperature by modulating ABA biosynthesis and gene expression.
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Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Frío , Regulación de la Expresión Génica de las Plantas , Putrescina/metabolismo , Ácido Abscísico/farmacología , Aclimatación , Análisis de Varianza , Arabidopsis/efectos de los fármacos , Arabidopsis/genética , Arabidopsis/fisiología , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , ADN Bacteriano/genética , Congelación , Perfilación de la Expresión Génica , Genes de Plantas , Mutagénesis Insercional , Mutación , Putrescina/farmacología , ARN de Planta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Environmental stresses are the major cause of crop loss worldwide. Polyamines are involved in plant stress responses. However, the precise role(s) of polyamine metabolism in these processes remain ill-defined. Transgenic approaches demonstrate that polyamines play essential roles in stress tolerance and open up the possibility to exploit this strategy to improve plant tolerance to multiple environmental stresses. The use of Arabidopsis as a model plant enables us to carry out global expression studies of the polyamine metabolic genes under different stress conditions, as well as genome-wide expression analyses of insertional-mutants and plants over-expressing these genes. These studies are essential to dissect the polyamine mechanism of action in order to design new strategies to increase plant survival in adverse environments.
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Arabidopsis/fisiología , Regulación de la Expresión Génica de las Plantas , Poliaminas/química , Poliaminas/metabolismo , Biotecnología/métodos , Ambiente , Perfilación de la Expresión Génica , Genómica , Modelos Biológicos , Modelos Genéticos , Mutación , Fenómenos Fisiológicos de las Plantas , Plantas Modificadas GenéticamenteRESUMEN
We have obtained Arabidopsis thaliana transgenic plants constitutively overexpressing ADC2, one of the two genes encoding arginine decarboxylase (ADC) in Arabidopsis. These plants contained very high levels of putrescine (Put) but no changes were observed in spermidine and spermine contents. The results obtained from quantification of free and conjugated polyamines suggest that conjugation may be a limiting step for control of Put homeostasis within a non-toxic range for plant survival. Transgenic plants with increased levels of ADC2 transcript and elevated Put content showed dwarfism and late-flowering, and the phenotype was rescued by gibberellin A3 (GA3) application. The contents of bioactive GA4 and GA1, and of GA9 (a precursor of GA4), as well as the levels of AtGA20ox1, AtGA3ox1 and AtGA3ox3 transcripts (quantified by real-time PCR) were lower in the ADC2 overexpressor plants than in the wild type. No change in the expression of genes encoding earlier enzymes in the GA biosynthesis pathway was detected by microarray analysis. These results suggest that Put accumulation affects GA metabolism through the repression of biosynthetic steps catalyzed by GA 20-oxidase and GA 3-oxidase.
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Arabidopsis/genética , Carboxiliasas/genética , Flores/genética , Giberelinas/biosíntesis , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Carboxiliasas/metabolismo , Flores/crecimiento & desarrollo , Flores/metabolismo , Regulación de la Expresión Génica de las Plantas , Fenotipo , Plantas Modificadas Genéticamente , Análisis por Matrices de Proteínas , Putrescina/metabolismo , Espermidina/metabolismo , Espermina/metabolismoRESUMEN
In recent years, there has been a growing interest in NADPH-oxidases which are involved in the active generation of reactive oxygen species (ROS), owing to their role in oxidative burst, signalling and oxidative damage derived from biotic and abiotic stresses. NADPH oxidase activity is enhanced by some environmental cues, such as zinc deficiency and chilling stress, where zinc and polyamines have been suggested to be involved in the modulation of ROS generation. In order to further characterise NADPH oxidation activity during oxidative stress we exposed Lotus glaber Mill. (narrow-leaf trefoil; syn. L. tenuis Waldst. et Kit. ex Wild var. Miller) plants to the herbicide methyl viologen (MV) and evaluated zinc and polyamines as oxidative stress regulatory compounds. For this purpose we conducted in vitro and in vivo experiments, observing that zinc and the higher polyamines spermidine and spermine inhibited the NADPH oxidation activity in vitro while preventing methyl viologen-induced superoxide production in vivo. It is suggested that these substances act through a direct effect on flavin oxidases. However, it was not possible to correlate free polyamine content of L. glaber with their hypothetical inhibitory role during oxidative stress, probably owing to the plant's natural tolerance to the herbicide tested. Therefore, tobacco, a more sensitive species, was tested for methyl viologen toxicity. High concentrations of methyl viologen induced free polyamine levels in crude extracts and intercellular fluids. However, only free polyamine content in the intercellular fluids was increased in plants treated with low methyl viologen concentrations. These results support the notion that polyamine metabolism in the apoplast is involved in the physiological response to oxidative stress.
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A number of new 2',3'-fused oxirane derivatives were synthesized for structure-activity relationship study. Many of these derivatives exhibit high potency against Candida spp. In addition, sordarin manno epoxide derivative 6 presents in vivo therapeutic effect in mice and is considered a promising antifungal lead within this series.
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Antifúngicos/química , Antifúngicos/síntesis química , Candida/efectos de los fármacos , Óxido de Etileno/análogos & derivados , Óxido de Etileno/síntesis química , Antifúngicos/farmacología , Diseño de Fármacos , Compuestos Epoxi/síntesis química , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Óxido de Etileno/química , Óxido de Etileno/farmacología , Indenos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A number of novel 3'-O-acyl and alkyl sordarins were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida albicans, Candida pseudotropicalis, Candida tropicalis and Cryptococcus neoformans.
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Antifúngicos/síntesis química , Antifúngicos/farmacología , Antifúngicos/química , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Indenos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A number of novel 3',4'-fused dioxolane and dioxane sordarin derivatives were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida spp. and Cryptococcus neoformans.