Highly solvatochromic and tunable fluorophores based on a 4,5-quinolimide scaffold: Novel CDK5 probes

Novel 4,5-quinolimide-based fluorophores are more solvatochromic and red-shifted than known naphthalimide analogues. Conjugation of one of these fluorophores to a peptide derived from CDK5 kinase demonstrated its sensitivity for monitoring the interaction with its regulatory partner p25. Introduction of the quinolimide-labelled peptide into living glioblastoma cells probed the interaction with endogenous p25.The work was supported by the Spanish Ministerio de Economía y Competividad grant SAF2012-32209 and the CSIC grant 2012280E096. J. A. G.-V. held a JAEdoc research contract from the CSIC and now is supported by a Marie-Curie fellowship EC-FP7 Framework (PIEF-GA-2013-623151). The work was also supported by the CNRS and a grant from Canceropole GSO 2015-E03 to MCM and has benefited from the facilities and expertise of the Montpellier RIO imaging facility (www.mri.cnrs.fr) at the Centre de Recherches en Biochimie Macromoléculaire, MontpellierPeer Reviewe

Smart lanthanide antennas for sensing water

Two new families of lanthanide antennas are described. 8-Methoxy- 4,5-dihydrocyclopenta[de]quinolin-2(1H)-one phosphonates or carboxylates behave as selective antennas exhibiting Eu3+ luminescence in organic solvents, while quinolin-2(1H)-one analogues selectively sensitize the Tb3+ emission. These emissions are quenched by H2O addition. Based on this behaviour, the new lanthanide antennas can be used as highly sensitive water sensors.Spanish Ministerio de Economia y Competividad SAF2012-32209 FU2015-67284-RMinisterio de Ciencia e Innovacion/Agencia Estatal de Investigacion/European Regional Development Fund CTQ2017-85658-R CTQ2015-63997-C2Consejo Superior de Investigaciones Cientificas (CSIC) 201580E07

Lanthanide-based peptide biosensor to monitor CDK4/cyclin D kinase activity

We describe a lanthanide biosensor that responds to CDK4 kinase activity in melanoma cell extracts through a significant and dose dependent increase in luminescence, thanks to sensitization of a DOTA[Tb3+] complex incorporated into a CDK4 substrate peptide by a unique tryptophan residue in an adjacent phosphoaminoacid binding moietyThis work was funded by the CNRS (Centre National de la Recherche Scientifique) and a Marie-Curie fellowship EC-FP7 Framework (PIEF-GA-2013-623151) supporting JAGV. CB was funded by the INCA (PRTK-2014). Financial support from the Spanish MINECO (CTQ2015-70698-R), the Xunta de Galicia (Centro singular de investigacio´n de Galicia accreditation 2016–2019), and the European Union (European Regional Development Fund – ERDF), are gratefully acknowledgedS

Septic arthritis of the knee due to Prevotella loescheii following tooth extraction

This is a case report of septic arthritis of the knee due to Prevotella loescheii, in a patient with advanced arthrosis. Two weeks beforehand he had undergone a dental root extraction without antibiotic prophylaxis. His knee had become inflamed 48 hours after extraction and he was started on ibuprofen and steroid treatment (prescribed by his primary health care doctor). With a provisional diagnosis of septic arthritis, synovial fluid was taken for study. Antimicrobial therapy was commenced with amoxicillin/clavulanic acid and the patient progressed satisfactorily. Prevotella loescheii was identified by anaerobic culture. A site of origin for the infection was never found. Joint infection is generally secondary to haematogenous dissemination of bacteria from habitual sites such as odontogenic locations. We suggest that patients with inflammatory arthropathies should be considered as candidates for antibiotic prophylaxis in oral surgery and invasive dental procedures. We suggest, in these cases, the use of antibiotic with spectrum against aerobic and anaerobic bacteria

Seeding and Growth of β-Amyloid Aggregates upon Interaction with Neuronal Cell Membranes

In recent years, the prevalence of amyloid neurodegenerative diseases such as Alzheimer’s disease (AD) has significantly increased in developed countries due to increased life expectancy. This amyloid disease is characterized by the presence of accumulations and deposits of β-amyloid peptide (Aβ) in neuronal tissue, leading to the formation of oligomers, fibers, and plaques. First, oligomeric intermediates that arise during the aggregation process are currently thought to be primarily responsible for cytotoxicity in cells. This work aims to provide further insights into the mechanisms of cytotoxicity by studying the interaction of Aβ aggregates with Neuro-2a (N2a) neuronal cells and the effects caused by this interaction. For this purpose, we have exploited the advantages of advanced, multidimensional fluorescence microscopy techniques to determine whether different types of Aβ are involved in higher rates of cellular toxicity, and we measured the cellular stress caused by such aggregates by using a fluorogenic intracellular biothiol sensor. Stress provoked by the peptide is evident by N2a cells generating high levels of biothiols as a defense mechanism. In our study, we demonstrate that Aβ aggregates act as seeds for aggregate growth upon interacting with the cellular membrane, which results in cell permeability and damage and induces lysis. In parallel, these damaged cells undergo a significant increase in intracellular biothiol levels.Spanish Ministerio de Ciencia, Innovacion y Universidades CTQ2014-56370-R CTQ2017-86568-R CTQ2017-86125-PSpanish Agencia Estatal de InvestigacionEuropean Union (EU

Fludarabine inhibits KV1.3 currents in human B lymphocytes

Fludarabine (F-ara-A) is a purine analog commonly used in the treatment of indolent B cell malignancies that interferes with different aspects of DNA and RNA synthesis. KV1.3 K+ channels are membrane proteins involved in the maintenance of K+ homeostasis and the resting potential of the cell, thus controlling signaling events, proliferation and apoptosis in lymphocytes. Here we show that F-ara-A inhibits KV currents in human B lymphocytes. Our data indicate that KV1.3 is expressed in both BL2 and Dana B cell lines, although total KV1.3 levels were higher in BL2 than in Dana cells. However, KV currents in the plasma membrane were similar in both cell lines and were abrogated by the specific KV1.3 channel inhibitor PAP-1, indicating that KV1.3 accounts for most of the KV currents in these cell lines. F-ara-A, at a concentration (3.5 μM) similar to that achieved in the plasma of fludarabine phosphate-treated patients (3 μM), inhibited KV1.3 currents by 61 ± 6.3% and 52.3 ± 6.3% in BL2 and Dana B cells, respectively. The inhibitory effect of F-ara-A was concentration-dependent and showed an IC50 value of 0.36 ± 0.04 μM and a nH value of 1.07 ± 0.15 in BL2 cells and 0.34 ± 0.13 μM (IC50) and 0.77 ± 0.11 (nH) in Dana cells. F-ara-A inhibition of plasma membrane KV1.3 was observed irrespective of its cytotoxic effect on the cells, BL2 cells being sensitive and Dana cells resistant to F-ara-A cytotoxicity. Interestingly, PAP-1, at concentrations as high as 10 μM, did not affect the viability of BL2 and Dana cells, indicating that blockage of KV1.3 in these cells is not toxic. Finally, F-ara-A had no effect on ectopically expressed KV1.3 channels, suggesting an indirect mechanism of current inhibition. In summary, our results describe the inhibitory effect of F-ara-A on the activity of KV1.3 channel. Although KV1.3 inhibition is not sufficient to induce cell death, further research is needed to determine whether it might still contribute to F-ara-A cytotoxicity in sensitive cells or be accountable for some of the clinical side effects of the drug.This study was supported by MINECO (SAF2013-45800-R, SAF2016-75021-R, RD12/0042/0019, CB/11/00222) and ISCIII (PI12/01135 and PI16/00895). The cost of this publication was paid in part by funds from the European Fund for Economic and Regional Development (FEDER). TG is supported by the Ramón y Cajal Program.Peer reviewedPeer Reviewe

The angiopoietin-like protein 4, apolipoprotein C3, and lipoprotein lipase axis is disrupted in patients with rheumatoid arthritis

Background: Modulators of triglyceride metabolism include lipoprotein lipase (LPL), angiopoietin-like protein 4 (ANGPTL4), and apolipoprotein C-3 (ApoC3). There is evidence on the influence of this triangle of molecules on an increased risk of atherosclerotic cardiovascular disease (CV) in the general population. Patients with rheumatoid arthritis (RA) present changes in lipid profiles and accelerated CV disease. In the present study, we set out to study whether the ANGPTL4, ApoC3, and LPL axis differs in subjects with RA compared to controls. In a further step, we investigated the relationship of this axis with subclinical atherosclerosis in patients with RA. Methods: Cross-sectional study that included 569 individuals, 323 patients with RA and 246 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in patients and controls. Carotid intima-media thickness (cIMT) and carotid plaques were assessed in RA patients. A multivariable analysis was performed to assess whether the ANGPTL4, ApoC3, and LPL axis was altered in RA and to study its relationship with RA dyslipidemia and subclinical carotid atherosclerosis. Results: Most lipid profile molecules did not differ between patients and controls. Despite this, and after fully multivariable analysis including CV risk factors, use of statins, and changes in the lipid profile caused by the disease itself, patients with RA showed higher serum levels of ANGPTL4 (beta coef. 295 [95% CI 213-376] ng/ml, p<0.001) and ApoC3 (beta coef. 2.9 [95% CI 1.7-4.0] mg/dl, p<0.001), but lower circulating LPL (beta coef. -174 [95% CI -213 to - 135] ng/ml, p<0.001). ANGPTL4 serum levels were positively and independently associated with a higher cIMT in patients with RA after fully multivariable adjustment. Conclusion: The axis consisting in ANGPTL4, ApoC3, and LPL is disrupted in patients with RA. ANGPTL4 serum levels are positively and independently associated with a higher cIMT in RA patients.Funding: This work was supported by a grant to IFA from the Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 and by Fondo Europeo de Desarrollo Regional - FEDER - (Fondo de Investigaciones Sanitarias, PI17/00083)

A multicomponent reaction platform towards multimodal near-infrared BODIPY dyes for STED and fluorescence lifetime imaging

We report a platform combining multicomponent reaction synthesis and automated cell-based screening to develop biocompatible NIR-BODIPY fluorophores. From a library of over 60 fluorophores, we optimised compound NIRBD-62c as a multimodal probe with suitable properties for STED super-resolution and fluorescence lifetime imaging. Furthermore, we employed NIRBD-62c for imaging trafficking inside cells and to examine how pharmacological inhibitors can alter the vesicular traffic between intracellular compartments and the plasma membrane

APORTACIONES COROLÓGICAS PARA LA FLORA VASCULAR DEL SURESTE IBÉRICO

This paper compiles chorological novelties from SE Spain, new records for Albacete province (Blupeurum gibraltaricum, Crataegus granatensis and Castellia tuberculosa), Almería province (Lathyrus annus and Teline monspessulana) and Murcia province (Cleome violacea, Gagea pratensis, Iberis pectinata, Lepidium villarsii subsp. villarsii, Teline monspessulana, Oxalis articulata y Sparganium erectum subsp. Neglectum). Several taxa located in aloctone siliceous sands are cited, probably introduced in an accidental way, actually like adventitious (Coronilla repanda subsp. dura, Hymenocarpos hamosus, Ononis baetica, Ornithopus compressus). Moreover, it has been amplified the distribution of two rare orchid in Murcia (Ophrys incubacea, Serapias lingua).Se recopilan novedades corológicas para la flora del sureste ibérico, que se corresponden con nuevas citas provinciales para Albacete (bupléurum gibraltaricum, Crataegus granatensis y Castellia tuberculosa), Almería (Lathyrus annnus y Teline monspessulana) y Murcia (Cleome violacea, Gagea pratensis, Iberis pectinata, Lepidium villarsii subsp. villarsii, Teline monspessulana, Oxalis articulata y Sparganium erectum subsp. Neglectum). Asimismo, se citan taxones localizados en arenas silíceas alóctonas, posiblemente introducidos de forma accidental y que en la actualidad presentan un carácter adventicio (Coronilla repanda subsp. dura, Hymenocarpos hamosus, Ononis baetica, Ornithopus compressus). Además, se amplía el conocimiento sobre el área de distribución de dos orquídeas poco conocidas en Murcia (Ophrys incubacea, Serapias lengua)

APORTACIONES COROLÓGICAS, NOMENCLATURALES Y TAXONÓMICAS PARA LA FLORA DEL SURESTE IBÉRICO

This paper shows a relationship of chorological notes of Albacete and Murcia. Some of them are new plants for these provinces. Linaria oligantha, Misopates orontium subsp. pusillus and Narcissus yepesii are new species for Albacete. Cenchrus ciliaris, Ornithogalum arabicum and Ranunculus parviflorus are new species for Murcia. Also some chorological notes about barely cited taxa are shown (Astragalus glaux, Narcissus alcaracensis, Narcissus hedraeanthus and Potentilla neumanniana). Two new taxa are combined (Anthemis chrysantha subsp. jimenezii and Centaurea jimenezii) and a new variety is described (Teucrium buxifolium var. Terciae).En el presente trabajo se ofrece una serie de referencias corológicas para el sureste ibérico, de las cuales, unas son nuevas citas provinciales para Albacete (Linaria oligantha, Misopates orontium subsp. pusillus y Narcissus yepesii) y para Murcia (Cenchrus ciliaris, Ornithogalum arabicum y Ranunculus parviflorus) y otras amplían el conocimiento del área de distribución de especies escasamente citadas (Astragalus glaux, Narcissus alcaracensis, Narcissus hedraeanthus y Potentilla neumanniana). Además se combinan 2 nuevos táxones (Anthemis chrysantha subsp. jimenezii y Centaurea jimenezii) y se describe una nueva variedad (Teucrium buxifolium var. Terciae)