Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily.

SRC homology 3 (SH3) domains are critical interaction modules that orchestrate the assembly of protein complexes involved in diverse biological processes. They facilitate transient protein-protein interactions by selectively interacting with proline-rich motifs (PRMs). A database search revealed 298 SH3 domains in 221 human proteins. Multiple sequence alignment of human SH3 domains is useful for phylogenetic analysis and determination of their selectivity towards PRM-containing peptides (PRPs). However, a more precise functional classification of SH3 domains is achieved by constructing a phylogenetic tree only from PRM-binding residues and using existing SH3 domain-PRP structures and biochemical data to determine the specificity within each of the 10 families for particular PRPs. In addition, the C-terminal proline-rich domain of the RAS activator SOS1 covers 13 of the 14 recognized proline-rich consensus sequence motifs, encompassing differential PRP pattern selectivity among all SH3 families. To evaluate the binding capabilities and affinities, we conducted fluorescence dot blot and polarization experiments using 25 representative SH3 domains and various PRPs derived from SOS1. Our analysis has identified 45 interacting pairs, with binding affinities ranging from 0.2 to 125 micromolar, out of 300 tested and potential new SH3 domain-SOS1 interactions. Furthermore, it establishes a framework to bridge the gap between SH3 and PRP interactions and provides predictive insights into the potential interactions of SH3 domains with PRMs based on sequence specifications. This novel framework has the potential to enhance the understanding of protein networks mediated by SH3 domain-PRM interactions and be utilized as a general approach for other domain-peptide interactions.

The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands.

Growth factor receptor-bound protein 2 (GRB2) is a trivalent adaptor protein and a key element in signal transduction. It interacts via its flanking nSH3 and cSH3 domains with the proline-rich domain (PRD) of the RAS activator SOS1 and via its central SH2 domain with phosphorylated tyrosine residues of receptor tyrosine kinases (RTKs; e.g. HER2). The elucidation of structural organization and mechanistic insights into GRB2 interactions, however, remain challenging due to their inherent flexibility. This study represents an important advance in our mechanistic understanding of how GRB2 links RTKs to SOS1. Accordingly, it can be proposed that (1) HER2 pYP-bound SH2 potentiates GRB2 SH3 domain interactions with SOS1 (an allosteric mechanism); (2) the SH2 domain blocks cSH3, enabling nSH3 to bind SOS1 first before cSH3 follows (an avidity-based mechanism); and (3) the allosteric behavior of cSH3 to other domains appears to be unidirectional, although there is an allosteric effect between the SH2 and SH3 domains.

Assembly of Dynamic Supramolecular Polymers on a DNA Origami Platform.

Biological processes rely on transient interactions that govern assembly of biomolecules into higher order, multi-component systems. A synthetic platform for the dynamic assembly of multicomponent complexes would provide novel entries to study and modulate the assembly of artificial systems into higher order topologies. Here, we establish a hybrid DNA origami-based approach as an assembly platform that enables dynamic templating of supramolecular architectures. It entails the site-selective recruitment of supramolecular polymers to the platform with preservation of the intrinsic dynamics and reversibility of the assembly process. The composition of the supramolecular assembly on the platform can be tuned dynamically, allowing for monomer rearrangement and inclusion of molecular cargo. This work should aid the study of supramolecular structures in their native environment in real-time and incites new strategies for controlled multicomponent self-assembly of synthetic building blocks.

Clinical course and prognostic factors of COVID-19 infection in an elderly hospitalized population.

INTRODUCTION: Older subjects have a higher risk of COVID-19 infection and a greater mortality. However, there is a lack of studies evaluating the characteristics of this infection at advanced age. PATIENTS AND METHODS: We studied 404 patients ≥ 75 years (mean age 85.2 ±â€¯5.3 years, 55 % males), with PCR-confirmed COVID-19 infection, attended in two hospitals in Madrid (Spain). Patients were followed-up until they were discharged from the hospital or until death. RESULTS: Symptoms started 2-7 days before admission, and consisted of fever (64 %), cough (59 %), and dyspnea (57 %). A total of 145 patients (35.9 %) died a median of 9 days after hospitalization. In logistic regression analysis, predictive factors of death were age (OR 1.086; 1.015-1.161 per year, p = 0.016), heart rate (1.040; 1.018-1.061 per beat, p < 0.0001), a decline in renal function during hospitalization (OR 7.270; 2.586-20.441, p < 0.0001) and worsening dyspnea during hospitalization (OR 73.616; 30.642-176.857, p < 0.0001). Factors predicting survival were a female sex (OR 0.271; 0.128-0.575, p = 0.001), previous treatment with RAAS inhibitors (OR 0.459; 0.222-0.949, p = 0.036), a higher oxygen saturation at admission (OR 0.901; 0.842-0.963 per percentage point increase, p = 0.002), and a greater platelet count (OR 0.995; 0.991-0.999 per 106/L, p = 0.025). CONCLUSION: Elderly patients with COVID-19 infection have a similar clinical course to younger individuals. Previous treatment with RAAS inhibitors, and demographic, clinical and laboratory data influence prognosis.

Supramolecular Nanoscaffolds within Cytomimetic Protocells as Signal Localization Hubs.

The programmed construction of functional synthetic cells requires spatial control over arrays of biomolecules within the cytomimetic environment. The mimicry of the natural hierarchical assembly of biomolecules remains challenging due to the lack of an appropriate molecular toolbox. Herein, we report the implementation of DNA-decorated supramolecular assemblies as dynamic and responsive nanoscaffolds for the localization of arrays of DNA signal cargo within hierarchically assembled complex coacervate protocells. Protocells stabilized with a semipermeable membrane allow trafficking of single-stranded DNA between neighboring protocells. DNA duplex operations demonstrate the responsiveness of the nanoscaffolds to different input DNA strands via the reversible release of DNA cargo. Moreover, a second population of coacervate protocells with nanoscaffolds featuring a higher affinity for the DNA cargo enabled chemically programmed communication between both protocell populations. This combination of supramolecular structure and function paves the way for the next generation of protocells imbued with programmable, lifelike behaviors.

Dynamic modulation of proximity-induced enzyme activity using supramolecular polymers.

Synthetic supramolecular polymers are used as dynamic nanoscaffolds for the activation of the apoptotic signalling enzyme caspase-9. Recruitment of caspase-9 to the nanoscaffold results in an increase in enzymatic activity due to enhanced proximity, with a bell-shaped response as a function of nanoscaffold concentration. The modularity of the system allows for dynamic regulation of enzyme activity through variation of the recruitment-motif density along the supramolecular polymer.

Fenotipo de la haptoglobina y presencia de enfermedad vascular subclínica: estudio poblacional / Phenotype of haptoglobin and presence of subclinical vascular disease: Population study

Introducción y objetivos: La haptoglobina es una proteína implicada en la protección frente al daño oxidativo producido por el hierro de la hemoglobina. Esta proteína es polimórfica, con 3 isomorfas prevalentes en la población. Los portadores de la isoforma Hp2-2 tienen una menor capacidad antioxidante, y en la población con diabetes, un mayor riesgo de enfermedad vascular subclínica y de complicaciones cardiovasculares. Nuestro objetivo fue evaluar si dicha isomorfa se asocia con un mayor riesgo de arteriosclerosis carotídea en sujetos con y sin diabetes, libres de enfermedad cardiovascular. Pacientes y métodos: Estudio realizado en una población de entre 45 y 74años de edad seleccionada aleatoriamente del área noroeste de Madrid. Los participantes fueron caracterizados en cuanto a su estatus glucémico mediante una sobrecarga oral de glucosa y la determinación de la concentración de Hb1Ac. A todos ellos se les determinó el fenotipo de la haptoglobina mediante un ensayo inmunoenzimático y la presencia de arteriosclerosis carotídea mediante ecografía. Resultados: De los 1.256 participantes incluidos en el presente análisis (edad media 61,6 ± 6 años, 41,8% varones), la distribución de las isoformas de la haptoglobina fue la siguiente: Hp1-1: 13,3%, Hp1-2: 48,5% y Hp2-2: 38,2%. En comparación con los sujetos Hp1-1 y Hp1-2, aquellos con el fenotipo Hp2-2 tuvieron una mayor prevalencia de dislipemia (53,3% vs 43%, p < 0,0001) e hipertensión arterial (39,2% vs 32,2%, p = 0,012), y recibieron con más frecuencia tratamiento con estatinas (31,5% vs 21,6%, p < 0,0001) y con antihipertensivos (38,4% vs 30,8%, p = 0,006). Los portadores de la isoforma Hp2-2 tuvieron una mayor prevalencia de placas carotídeas (OR: 1,35; IC 95%: 1,07-1,69; p = 0,011), sin diferencias en dicha prevalencia en función del estatus glucémico. No existieron diferencias en el grosor íntima-media entre los diferentes fenotipos. La relación del fenotipo Hp2-2 con la presencia de placas en carótida fue independiente de la edad, del sexo, de la presencia de factores de riesgo (dislipemia, hipertensión y diabetes), de la concentración de colesterol LDL, proteína C reactiva y ácido úrico, de la presión arterial y del tratamiento con estatinas y antihipertensivos (OR: 1,31; IC 95%: 1,01-1,70; p = 0,044). Conclusión: Los sujetos con el fenotipo Hp2-2 de la haptoglobina tienen una mayor prevalencia de arteriosclerosis carotídea, que es independiente de la presencia de otros factores de riesgo cardiovascular y de su estatus glucémico

Introduction and objectives: Haptoglobin is a protein involved in the protection against oxidative damage caused by iron in haemoglobin. This protein is polymorphic, with 3 isomorphs prevalent in the population. The carriers of the Hp2-2 isoform have a lower antioxidant capacity and, in the population with diabetes, an increased risk of subclinical vascular disease and cardiovascular complications. The objective of this study was to evaluate whether this isomorphy is associated with an increased risk of carotid arteriosclerosis in subjects with and without diabetes, and free of cardiovascular disease. Patients and methods: A study was conducted in a population between 45 and 74years of age, randomly selected from the northwest area of Madrid. The participants were characterised in terms of their glycaemic status by oral glucose overload and the determination of the concentration of Hb1Ac. The haptoglobin phenotypes in all of them were determined by means of an immunoenzymatic assay, and the presence of carotid arteriosclerosis by ultrasound. Results: Of the 1,256 participants included in the present analysis (mean age 61.6 ± 6 years, 41.8% males), the distribution of the isoforms of haptoglobin was as follows: Hp1-1: 13.3%, Hp1-2: 48.5%, and Hp2-2: 38.2%. In comparison with subjects Hp1-1 and Hp1-2, those with the Hp2-2 phenotype had a higher prevalence of dyslipidaemia (53.3% vs 43%; P < .0001) and arterial hypertension (39.2% vs. 32.2%, P = .012), and they more frequently received treatment with statins (31.5% vs 21.6%, P < .0001), and with antihypertensive agents (38.4% vs 30.8%, P = .006). The carriers of the Hp2-2 isoform had a higher prevalence of carotid plaques (OR: 1.35, 95%CI: 1.07-1.69, P = .011), with no differences in that prevalence as regards the glycaemic status. There were no differences in the intima-media thickness between the different phenotypes. The relationship of the Hp2-2 phenotype with the presence of plaques in the carotid was independent of age, gender, presence of risk factors (dyslipidaemia, hypertension and diabetes), the concentration of LDL-cholesterol, C-reactive protein and uric acid, blood pressure, and treatment with statins, and hypertensive drugs (OR: 1.31, 95% CI 1.01-1.70, P = .044). Conclusion: Subjects with the Hp2-2 phenotype of haptoglobin have a higher prevalence of carotid arteriosclerosis, which is independent of the presence of other cardiovascular risk factors and their glycaemic status

Phenotype of haptoglobin and presence of subclinical vascular disease: Population study. / Fenotipo de la haptoglobina y presencia de enfermedad vascular subclínica: estudio poblacional.

INTRODUCTION AND OBJECTIVES: Haptoglobin is a protein involved in the protection against oxidative damage caused by iron in haemoglobin. This protein is polymorphic, with 3 isomorphs prevalent in the population. The carriers of the Hp2-2 isoform have a lower antioxidant capacity and, in the population with diabetes, an increased risk of subclinical vascular disease and cardiovascular complications. The objective of this study was to evaluate whether this isomorphy is associated with an increased risk of carotid arteriosclerosis in subjects with and without diabetes, and free of cardiovascular disease. PATIENTS AND METHODS: A study was conducted in a population between 45 and 74years of age, randomly selected from the northwest area of Madrid. The participants were characterised in terms of their glycaemic status by oral glucose overload and the determination of the concentration of Hb1Ac. The haptoglobin phenotypes in all of them were determined by means of an immunoenzymatic assay, and the presence of carotid arteriosclerosis by ultrasound. RESULTS: Of the 1,256 participants included in the present analysis (mean age 61.6±6years, 41.8% males), the distribution of the isoforms of haptoglobin was as follows: Hp1-1: 13.3%, Hp1-2: 48.5%, and Hp2-2: 38.2%. In comparison with subjects Hp1-1 and Hp1-2, those with the Hp2-2 phenotype had a higher prevalence of dyslipidaemia (53.3% vs 43%; P<.0001) and arterial hypertension (39.2% vs. 32.2%, P=.012), and they more frequently received treatment with statins (31.5% vs 21.6%, P<.0001), and with antihypertensive agents (38.4% vs 30.8%, P=.006). The carriers of the Hp2-2 isoform had a higher prevalence of carotid plaques (OR: 1.35, 95%CI: 1.07-1.69, P=.011), with no differences in that prevalence as regards the glycaemic status. There were no differences in the intima-media thickness between the different phenotypes. The relationship of the Hp2-2 phenotype with the presence of plaques in the carotid was independent of age, gender, presence of risk factors (dyslipidaemia, hypertension and diabetes), the concentration of LDL-cholesterol, C-reactive protein and uric acid, blood pressure, and treatment with statins, and hypertensive drugs (OR: 1.31, 95%CI 1.01-1.70, P=.044). CONCLUSION: Subjects with the Hp2-2 phenotype of haptoglobin have a higher prevalence of carotid arteriosclerosis, which is independent of the presence of other cardiovascular risk factors and their glycaemic status.

Multivalent Ultrasensitive Interfacing of Supramolecular 1D Nanoplatforms.

Multivalent display on linear platforms is used by many biomolecular systems to effectively interact with their corresponding binding partners in a dose-responsive and ultrasensitive manner appropriate to the biological system at hand. Synthetic supramolecular multivalent displays offer a matching approach for the modular and bottom-up construction and systematic study of dynamic 1D materials. Fundamental studies into multivalent interactions between such linear, 1D materials have been lacking because of the absence of appropriate modular nanoplatforms. In this work we interfaced two synthetic multivalent linear nanoplatforms based on a dynamic supramolecular polymer, formed by hybrid discotic-oligonucleotide monomers, and a series of complementary DNA-duplex-based multivalent ligands, also with appended short oligonucleotides. The combination of these two multivalent nanoplatforms provides for the first time entry to study multivalent effects in dynamic 1D systems, of relevance for the conceptual understanding of multivalency in biology and for the generation of novel multivalent biomaterials. Together the two nanoscaffolds provide easy access to libraries of multivalent ligands with tunable affinities. The DNA scaffold allows for exact control over valency and spatial ligand distribution, and the discotic supramolecular polymer allows for dynamic adaptation and control over receptor density. The interaction between the two nanoplatforms was studied as a function of ligand interaction strength, valency, and density. Usage of the enhancement parameter ß allowed quantification of the effects of ligand valency and affinity. The results reveal a generalized principle of additive binding increments. Receptor density is shown to be crucially and nonlinearly correlated to complex formation, leading to ultrasensitive responses. The results reveal that, not unlike biomolecular signaling, high density multivalent display of receptors is crucial for functionally increased affinities.

Understanding complex supramolecular landscapes: non-covalent macrocyclization equilibria examined by fluorescence resonance energy transfer.

As molecular self-assembled systems increase in complexity, due to a large number of participating entities and/or the establishment of multiple competing equilibria, their full understanding becomes likewise more complicated, and the use of diverse analytical techniques that can afford complementary information is required. We demonstrate in this work that resonance excitation energy transfer phenomena, measured by fluorescence spectroscopy in combination with other optical spectroscopies, can be a valuable tool to obtain supplementary thermodynamic data about complex supramolecular landscapes that other methods fail to provide. In particular, noncovalent macrocyclization processes of lipophilic dinucleosides are studied here by setting up a competition between intra- and intermolecular association processes of Watson-Crick H-bonding pairs. Multiwavelength analysis of the monomer emission changes allowed us to determine cyclotetramerization constants and to quantify chelate cooperativity, which was confirmed to be substantially larger for the G-C than for the A-U pair. Furthermore, when bithiophene-BODIPY donor-acceptor energy transfer probes are employed in these competition experiments, fluorescence and circular dichroism spectroscopy measurements in different regions of the visible spectrum additionally reveal intermolecular interactions occurring simultaneously at both sides of the macrocyclization reaction: the cyclic product, acting as a host for the competitor, and the monomer reactant, ultimately leading to macrocycle denaturation.

R46L polymorphism in the PCSK9 gene: Relationship to lipid levels, subclinical vascular disease, and erectile dysfunction.

BACKGROUND: The R46L variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has been related to lipid levels and cardiovascular disease. OBJECTIVE: To evaluate the influence of this polymorphism on subclinical vascular disease and erectile dysfunction (ED). METHODS: We analyzed the association of the PCSK9 rs11591147 single-nucleotide polymorphism with lipid levels, intima-media thickness (IMT), and the ankle-brachial index, in 1188 adults free of cardiovascular disease, randomly selected from the population. In 473 male participants, we also investigated its relationship with ED. The association of the R46L polymorphism with lipid levels was also assessed in 2 cohorts of 1103 prepuberal children and 830 adolescents. RESULTS: The prevalence of the T allele was 2.9% in adults. Low-density lipoprotein cholesterol (LDL-cholesterol) levels did not vary according to this polymorphism (134 ± 32 vs 134 ± 31 mg/dL, for the TT + GT vs GG carriers, respectively, P = .931). Despite equal LDL-cholesterol levels, adults carrying the T allele had a lower mean common carotid IMT (0.685 ± 0.09 vs 0.723 ± 0.127 mm; P = .035), a lower maximum common carotid IMT (0.819 ± 0.11 vs 0.865 ± 0.159 mm; P = .040), and, in males, a lower prevalence of ED (36.8% vs 61%: P = .036), than GG carriers. Prevalence of the T allele was 3.2% in both cohorts of children. They had lower levels of LDL-cholesterol than GG subjects (100 vs 109 mg/dL; P = .060, for prepuberal children, and 85 vs 99 mg/dL; P = .010 for adolescents). CONCLUSION: In our population, an association between the PCSK9 R46L variant and LDL-cholesterol levels is observed in children. In adults, although its association with lipid levels is not evident, there is a significant relationship between the PCSK9 R46L variant and markers of subclinical atherosclerosis, including IMT and ED.

Factores de riesgo asociados con el grosor íntima-media y la presencia de placas en arteria carótida: Estudio ESPREDIA / Risk factors associated with the carotid intima-media thickness and plaques: ESPREDIA Study

Objetivo: Evaluar si existen diferencias en el perfil de factores de riesgo asociados con el grosor íntima-media (GIM) y la presencia de placas carotídeas. Métodos: Estudio transversal de base poblacional, en 1.475 sujetos de entre 45 y 75años de edad, seleccionados de forma aleatoria de los registros de Atención Primaria del área noroeste de Madrid. Se les realizó una exploración física, una analítica y se les determinó el GIM en carótida común y la presencia de placas mediante ecografía. Resultados: El GIM medio de la población fue de 0,725±0,132mm. El 47% presentaban placas carotídeas. En el análisis multivariante, los factores relacionados con el GIM fueron: edad (β0,227, p<0,0001), sexo (β0,104, p<0,0001), presencia de hipertensión (β0,082, p=0,002), diabetes (β0,130, p<0,0001) y tabaquismo activo (β0,107, p<0,0001), presión arterial sistólica (PAS) (β0,219, p<0,0001) y concentración de colesterol LDL (β0,074, p=0,003), y de forma inversa, presión arterial diastólica (PAD) (β−0,124, p=0,001) y concentraciones de colesterol HDL (β−0,111, p<0,0001) y triglicéridos (β−0,060, p=0,028). La presencia de placas se asoció de forma directa con edad (OR1,08; IC95%: 1,05-1,10), sexo (OR1,95; IC95%: 1,52-2,51), tabaquismo activo (OR2,75; IC95%: 1,92-3,95), antecedente de hipertensión (OR1,58; IC95%: 1,22-2,04) y de diabetes (OR1,84; IC95%: 1,31-2,58), consumo de estatinas (OR1,56; IC95%: 1,19-2,04) y PAS (OR1,03; IC95%: 1,02-1,05), y de forma inversa con PAD (OR0,98; IC95%: 0,96-0,99). Conclusión: Los factores de riesgo asociados con el GIM y la presencia de placas son similares, un dato que apoya el continuo entre la hipertrofia de la capa muscular y el desarrollo de arteriosclerosis (AU)

Objective: To evaluate whether there were any differences in the risk factor profile associated with either the intima-media thickness (IMT) or the presence of carotid plaques. Methods: Cross-sectional study in 1475 subjects between 45 and 75years, randomly selected from the population of the Northwest area of Madrid (Spain). They had a physical exam, blood analysis, and ultrasound measurement of the IMT and of the presence of plaques. Results: Mean IMT was 0.725±0.132mm. Forty seven percent of the participants had carotid plaques. In multivariate analysis, factors directly associated with the IMT were, age (β0.227, P<.0001), sex (β0.104, P<.0001), presence of hypertension (β0.082, P=.002), diabetes (β0.130, P<.0001) and current smoking (β0.107, P<.0001), systolic blood pressure (SBP) (β0.219, P<.0001) and LDL-cholesterol levels (β0.074, P=.003), and inversely, diastolic blood pressure (DBP) (β−0.124, P=.001), HDL-cholesterol (β−0.111, P<.0001) and triglyceride levels (β−0.060, P=.028). The presence of plaques was directly associated with age (OR1.08; 95%CI: 1.05-1.10), sex (OR1.95; 95%CI: 1.52-2.51), current smoking (OR2.75; 95%CI: 1.92-3.95), history of hypertension (OR1.58; 95%CI: 1.22-2.04) or diabetes (OR1.84; 95%CI: 1.31-2.58), statin treatment (OR1.56; 95%CI: 1.19-2.04) and SBP (OR1.03; 95%CI: 1.02-1.05), and inversely with DBP (OR0.98; 95%CI: 0.96-0.99). Conclusion: Factors associated with the IMT and the presence of plaques are similar, a finding that support a continuum between muscular layer hypertrophy and arteriosclerosis development (AU)

Relationship of the Adherence to a Mediterranean Diet and Its Main Components with CRP Levels in the Spanish Population.

Background: Adherence to a Mediterranean diet seems to be inversely associated with C-reactive protein (CRP) concentration. A 14-point Mediterranean Diet Adherence Screener (MEDAS) has been developed to assess dietary compliance. Objective: The aim of this study was to assess whether each of the MEDAS questions as well as their final score were associated with the levels of CRP in general Spanish population. METHODS: Cross-sectional analysis of 1411 subjects (mean age 61 years, 43.0% males) randomly selected from the general population. CRP levels were determined by a commercial ELISA kit. Adherence to the Mediterranean diet was measured by the 14-point MEDAS. Results: There was an inverse correlation between adherence to the Mediterranean diet and the CRP concentration, even after adjusting by age, gender, hypertension, metabolic syndrome, body mass index, statin treatment and hypertension treatment (p = 0.041). Subjects who consume ≥2 servings of vegetables per day (p = 0.003), ≥3 pieces of fruit per day (p = 0.003), ≥1 serving of butter, margarine, or cream per day (p = 0.041) or ≥3 servings of fish/seafood per week (p = 0.058) had significantly lower levels of CRP. Conclusions: Adherence to a Mediterranean-type diet measured by a simple questionnaire is associated with lower CRP concentration. However, this association seems to be particularly related to a higher consumption of vegetables, fruits, dairy products, and fish.

Dual-Input Regulation and Positional Control in Hybrid Oligonucleotide/Discotic Supramolecular Wires.

The combination of oligonucleotides and synthetic supramolecular systems allows for novel and long-needed modes of regulation of the self-assembly of both molecular elements. Discotic molecules were conjugated with short oligonucleotides and their assembly into responsive supramolecular wires studied. The self-assembly of the discotic molecules provides additional stability for DNA-duplex formation owing to a cooperative effect. The appended oligonucleotides allow for positional control of the discotic elements within the supramolecular wire. The programmed assembly of these hybrid architectures can be modulated through the DNA, for example, by changing the number of base pairs or salt concentration, and through the discotic platform by the addition of discotic elements without oligonucleotide handles. These hybrid supramolecular-DNA structures allow for advanced levels of control over 1D dynamic platforms with responsive regulatory elements at the interface with biological systems.

Risk factors associated with the carotid intima-media thickness and plaques: ESPREDIA Study. / Factores de riesgo asociados con el grosor íntima-media y la presencia de placas en arteria carótida: Estudio ESPREDIA.

OBJECTIVE: To evaluate whether there were any differences in the risk factor profile associated with either the intima-media thickness (IMT) or the presence of carotid plaques. METHODS: Cross-sectional study in 1475 subjects between 45 and 75years, randomly selected from the population of the Northwest area of Madrid (Spain). They had a physical exam, blood analysis, and ultrasound measurement of the IMT and of the presence of plaques. RESULTS: Mean IMT was 0.725±0.132mm. Forty seven percent of the participants had carotid plaques. In multivariate analysis, factors directly associated with the IMT were, age (ß0.227, P<.0001), sex (ß0.104, P<.0001), presence of hypertension (ß0.082, P=.002), diabetes (ß0.130, P<.0001) and current smoking (ß0.107, P<.0001), systolic blood pressure (SBP) (ß0.219, P<.0001) and LDL-cholesterol levels (ß0.074, P=.003), and inversely, diastolic blood pressure (DBP) (ß-0.124, P=.001), HDL-cholesterol (ß-0.111, P<.0001) and triglyceride levels (ß-0.060, P=.028). The presence of plaques was directly associated with age (OR1.08; 95%CI: 1.05-1.10), sex (OR1.95; 95%CI: 1.52-2.51), current smoking (OR2.75; 95%CI: 1.92-3.95), history of hypertension (OR1.58; 95%CI: 1.22-2.04) or diabetes (OR1.84; 95%CI: 1.31-2.58), statin treatment (OR1.56; 95%CI: 1.19-2.04) and SBP (OR1.03; 95%CI: 1.02-1.05), and inversely with DBP (OR0.98; 95%CI: 0.96-0.99). CONCLUSION: Factors associated with the IMT and the presence of plaques are similar, a finding that support a continuum between muscular layer hypertrophy and arteriosclerosis development.

Semisynthetic Bioluminescent Sensor Proteins for Direct Detection of Antibodies and Small Molecules in Solution.

Single-step immunoassays that can be performed directly in solution are ideally suited for point-of-care diagnostics. Our group recently developed a new platform of bioluminescent sensor proteins (LUMABS; LUMinescent AntiBody Sensor) that allow antibody detection in blood plasma. Thus far, LUMABS has been limited to the detection of antibodies recognizing natural peptide epitopes. Here, we report the development of semisynthetic LUMABS sensors that recognize nonpeptide epitopes. The non-natural amino acid para-azidophenylalanine was introduced at the position of the original antibody-recognition sites as a chemical handle to enable site-specific conjugation of synthetic epitope molecules coupled to a dibenzocylcooctyne moiety via strain-promoted click chemistry. The approach was successfully demonstrated by developing semisynthetic LUMABS sensors for antibodies targeting the small molecules dinitrophenol and creatinine (DNP-LUMABS and CR-LUMABS) with affinities of 5.8 pM and 1.3 nM, respectively. An important application of these semisynthetic LUMABS is the detection of small molecules using a competitive assay format, which is demonstrated here for the detection of creatinine. Using a preassembled complex of CR-LUMABS and an anti-creatinine antibody, the detection of high micromolar concentrations of creatinine was possible both in buffer and in 1:1 diluted blood plasma. The use of semisynthetic LUMABS sensors significantly expands the range of antibody targets and enables the application of LUMABS sensors for the ratiometric bioluminescent detection of small molecules using a competitive immunoassay format.

Correction: First Case of Legionnaire's Disease Caused by Legionella anisa in Spain and the Limitations on the Diagnosis of Legionella non-pneumophila Infections.

[This corrects the article DOI: 10.1371/journal.pone.0159726.].

First Case of Legionnaire's Disease Caused by Legionella anisa in Spain and the Limitations on the Diagnosis of Legionella non-pneumophila Infections.

Legionnaires' disease is a severe form of pneumonia, with worldwide relevance, caused by Legionella spp. Approximately 90% of all cases of legionellosis are caused by Legionella pneumophila, but other species can also be responsible for this infection. These bacteria are transmitted by inhalation of aerosols or aspiration of contaminated water. In Spain, environmental studies have demonstrated the presence of Legionella non-pneumophila species in drinking water treatment plants and water distribution networks. Aware that this evidence indicates a risk factor and the lack of routine assays designed to detect simultaneously diverse Legionella species, we analyzed 210 urine samples from patients presenting clinical manifestations of pneumonia using a semi-nested PCR for partial amplification of the 16S rDNA gene of Legionella and a diagnostic method used in hospitals for Legionella antigen detection. In this study, we detected a total of 15 cases of legionellosis (7.1%) and the first case of Legionnaires' disease caused by L. anisa in Spain. While the conventional method used in hospitals could only detect four cases (1.9%) produced by L. pneumophila serogroup 1, using PCR, the following species were identified: Legionella spp. (10/15), L. pneumophila (4/15) and L. anisa (1/15). These results suggest the need to change hospital diagnostic strategies regarding the identification of Legionella species associated with this disease. Therefore, the detection of Legionella DNA by PCR in urine samples seems to be a suitable alternative method for a sensitive, accurate and rapid diagnosis of Legionella pneumonia, caused by L. pneumophila and also for L. non-pneumophila species.

Peripheral Atherosclerosis in Patients With Erectile Dysfunction: A Population-Based Study.

INTRODUCTION: The presence of erectile dysfunction (ED) could be a warning of vascular disease in different arterial territories. AIM: The aim of this study was to investigate the association between ED and the presence of atherosclerosis in 2 different vascular beds: carotid and lower limbs. METHODS: A total of 614 volunteers between 45 and 74 years of age (mean age 61.0 years) were randomly selected from the general population. ED was assessed using the International Index of Erectile Function (IIEF-5). Ankle-brachial index (ABI) measurement and carotid atherosclerosis were evaluated by echo-Doppler. MAIN OUTCOME MEASURES: Mean carotid intima-media thickness (IMT), prevalence of carotid plaques, mean ABI, and prevalence of ABI < 0.9 were the main outcome measures. RESULTS: ED was present in 373 subjects (59.7%). Mean carotid IMT was significantly higher in men with ED (0.762 ± 0.151 mm vs 0.718 ± 0.114 mm, P < .001). Also the global prevalence of carotid plaques was more frequent in men with ED (63.8% vs 44.8%, P < .001), even after adjusting by age, cardiovascular risk factors, and ongoing treatment (P = .039). Both the IMT and the prevalence of carotid plaques increased significantly with ED severity (P trend .004 and <.001, respectively). There were no significant differences between groups neither in mean ABI nor in the prevalence of subjects with ABI < 0.9. However, there was a trend to a lower ABI and a higher prevalence of ABI < 0.9 with increasing ED severity. CONCLUSION: In the general population, the presence of ED identifies subjects with higher atherosclerosis burden in carotid arteries but not in the lower extremities.

Cáncer y enfermedad cardiovascular / Cancer and cardiovascular disease

Los pacientes que sobreviven a un cáncer tienen una menor supervivencia a largo plazo en parte debida al incremento de las enfermedades cardiovasculares (ECV). Algunos fármacos quimioterápicos, la radioterapia craneal y torácica y, sobre todo, el trasplante de células hematopoyéticas se asocian a un incremento de la incidencia de eventos cardiovasculares comparados con la población general. Algunos de estos tratamientos favorecen el desarrollo de un síndrome metabólico que podría ser el intermediario entre dichos tratamientos y el desarrollo de las ECV. Se recomienda en los supervivientes de un cáncer fomentar estilos de vida saludables y el control estricto de los factores de riesgo cardiovascular

Survivors of cancer have a shorter survival in the long term partly due to the increase in cardiovascular diseases (CVD). Some chemotherapy drugs, thoracic and cranial radiotherapy and above all the transplantation of hematopoietic cells are associated with an increase in the incidence of cardiovascular events compared with general population. Some of these treatments favor the development of a metabolic syndrome that could be the intermediary between these treatments and the development of CVD. It is recommended for cancer survivors to promote healthy lifestyles and the strict control of cardiovascular risk factors