Dye-conjugated complementary lipophilic nucleosides as useful probes to study association processes by fluorescence resonance energy transfer

Modern supramolecular chemistry relies on the combination of diverse analytical techniques that can provide complementary information on complex self-assembly landscapes. Among them, resonance energy transfer, monitored by fluorescence emission spectroscopy, arises as a sensitive and convenient phenomenon to report binding intermolecular interactions. The use of molecular probes labelled with suitable complementary energy-transfer pairs can provide valuable information about the thermodynamics, kinetics and self-sorting characteristics of a particular self-assembled system. The objective of this work is to generate a set of nucleoside FRET probes that can be reliably employed to prove and analyse quantitatively H-bonding interactions between complementary Watson-Crick pairs. We first describe the preparation of a set of lipophilic nucleosides that are linked to a π-conjugated functional fragment. The bases include guanosine and 2-aminoadenosine as purine heterocycles, and cytidine and uridine as complementary pyrimidine bases. The π-conjugated moiety comprises either a short phenylene-ethynylene oligomer, a bithiophene, or a BODIPY dye. We then demonstrate that the last two chromophores constitute an energy donor-acceptor couple and that donor emission quenching can be related to the ratio of molecules bound to the complementary acceptor pair. Hence, fluorescence spectroscopy in combination with resonance energy transfer, is shown here to be a useful tool to study and quantify the association and self-sorting events between complementary and non-complementary nucleosides in apolar aromatic solvents, where the binding strength is considerably high, and sensitive techniques that employ low concentrations are demandedFunding from the European Research Council (ERC-Starting Grant 279548 PROGRAM-NANO) and MINECO (CTQ2014-57729-P) is gratefully acknowledged. E. F. would like to thank the Sharif University of Technology of Iran for financial support. D. S.M. would like to acknowledge Comunidad de Madrid for financial support through contract PEJ16/IND/AI-084

G-arylated hydrogen-bonded cyclic tetramer assemblies with remarkable thermodynamic and kinetic stability

The preparation and self-assembly of novel G-C dinucleoside monomers that are equipped with electron-poor aryl groups at the G-N2 amino group have been studied. Such monomers associate via Watson-Crick H-bonding into discrete unstrained tetrameric macrocycles that arise as a thermodynamically and kinetically stabilized product in a wide variety of experimental conditions, including very polar solvent environments and low concentrations. G-arylation produces an increased stability of the cyclic assembly, as a result of a subtle interplay between enthalpic and entropic effects involving the solvent coordination sphereFunding from the European Research Council (ERC-StG 279548) and MINECO (CTQ2011-23659) is gratefully acknowledge

Foro de debate: seguridad de las alternativas a la transfusión alogénica en el paciente quirúrgico y/o crítico

Estos últimos años han aparecido alertas de seguridad, no siempre bien sustentadas, que cuestionan el uso de algunas alternativas farmacológicas a la transfusión de sangre alogénica y/o lo restringen en indicaciones establecidas. Asistimos también a la preconización de otras alternativas, incluyendo productos hemáticos y fármacos antifibrinolíticos, sin que haya una base científica sólida que lo justifique. Por iniciativa del Grupo de Estudios Multidisciplinares sobre Autotransfusión y del Anemia Working Group Espana¿ se reunió a un panel multidisciplinar de 23 expertos del área de cuidados de la salud en un foro de debate para: 1) analizar las diferentes alertas de seguridad en torno a ciertas alternativas a la transfusión; 2) estudiar los antecedentes que las han propiciado, la evidencia que las sustentan y las consecuencias que conllevan para la práctica clínica, y 3) emitir una valoración argumentada de la seguridad de cada alternativa a la transfusión cuestionada, según el uso clínico de la misma. Los integrantes del foro mantuvieron contactos por vía telemática y una reunión presencial en la que presentaron y discutieron las conclusiones sobre cada uno de los elementos examinados. Se elaboró un primer documento que fue sometido a 4 rondas de revisión y actualización hasta alcanzar un consenso, unánime en la mayoría de los casos. Presentamos la versión final del documento, aprobada por todos los miembros del panel, esperando sea de utilidad para nuestros colegas

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia (SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias (SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6 sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: «La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE)

Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients

OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. METHODS: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. RESULTS: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis. CONCLUSION: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients

International conference on the healthy effect of virgin olive oil

Ageing represents a great concern in developed countries because the number of people involved and the pathologies related with it, like atherosclerosis, morbus Parkinson, Alzheime's disease, vascular dementia, cognitive decline, diabetes and cancer. Epidemiological studies suggest that a Mediterranean diet (which is rich in virgin olive oil) decreases the risk of cardiovascular disease. The Mediterranean diet, rich in virgin olive oil, improves the major risk factors for cardiovascular disease, such as the lipoprotein profile, blood pressure, glucose metabolism and antithrombotic profile. Endothelial function, inflammation and oxidative stress are also positively modulated. Some of these effects are attributed to minor components of virgin olive oil. Therefore, the definition of the Mediterranean diet should include virgin olive oil. Different observational studies conducted in humans have shown that the intake of monounsaturated fat may be protective against age-related cognitive decline and Alzheimer's disease. Microconstituents from virgin olive oil are bioavailable in humans and have shown antioxidant properties and capacity to improve endothelial function. Furthermore they are also able to modify the haemostasis, showing antithrombotic properties. In countries where the populations fulfilled a typical Mediterranean diet, such as Spain, Greece and Italy, where virgin olive oil is the principal source of fat, cancer incidence rates are lower than in northern European countries. The protective effect of virgin olive oil can be most important in the first decades of life, which suggests that the dietetic benefit of virgin olive oil intake should be initiated before puberty, and maintained through life. The more recent studies consistently support that the Mediterranean diet, based in virgin olive oil, is compatible with a healthier ageing and increased longevity. However, despite the significant advances of the recent years, the final proof about the specific mechanisms and contributing role of the different components of virgin olive oil to its beneficial effects requires further investigations. © 2005 Blackwell Publishing Ltd

Ruxolitinib in refractory acute and chronic graft-versus-host disease : a multicenter survey study

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1-5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1-10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23-67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63-89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients

A survey for variable young stars with small telescopes: II - mapping a protoplanetary disc with stable structures at 0.15 au

The HOYS citizen science project conducts long term, multifilter, high cadence monitoring of large YSO samples with a wide variety of professional and amateur telescopes. We present the analysis of the light curve of V1490 Cyg in the Pelican Nebula. We show that colour terms in the diverse photometric data can be calibrated out to achieve a median photometric accuracy of 0.02 mag in broadband filters, allowing detailed investigations into a variety of variability amplitudes over timescales from hours to several years. Using Gaia DR2 we estimate the distance to the Pelican Nebula to be 870 +70 −55 pc. V1490 Cyg is a quasi-periodic dipper with a period of 31.447 ± 0.011 d. The obscuring dust has homogeneous properties, and grains larger than those typical in the ISM. Larger variability on short timescales is observed in U and Rc−Hα, with U-amplitudes reaching 3 mag on timescales of hours, indicating the source is accreting. The Hα equivalent width and NIR/MIR colours place V1490 Cyg between CTTS/WTTS and transition disk objects. The material responsible for the dipping is located in a warped inner disk, about 0.15 AU from the star. This mass reservoir can be filled and emptied on time scales shorter than the period at a rate of up to 10−10 M�/yr, consistent with low levels of accretion in other T Tauri stars. Most likely the warp at this separation from the star is induced by a protoplanet in the inner accretion disk. However, we cannot fully rule out the possibility of an AA Tau-like warp, or occultations by the Hill sphere around a forming planet

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses