Surface induced selective delamination of amphiphilic ABA block copolymer thin films

This is the result of an ongoing collaboration with Dr. N. Sommerdijk’s Biomaterials group at the University of Eindhoven (the Netherlands) and illustrates the close collaboration that exists in pursuing the design and application of novel polymeric materials between the two groups. This details work on a physical phenomenon (selective delamination) and key materials (amphiphilic block copolymers) that have subsequently been applied in the design of novel biomaterials. These results have appeared in a larger body of work including Advanced Materials, Angewandtie Chemie International Edition and the Journal of Materials Chemistry

High performance mass spectrometry for advanced interactomics studies

Fibroblast growth factor-2 (FGF-2) is a glycosaminoglycan (GAG) binding protein, involved in different biological processes, such as angiogenesis, bone signaling, embryonic development, morphogenesis or cartilage metabolism. GAGs, one of its binding partners, are long-unbranched polysaccharides exhibiting a repeating disaccharide unit. Moreover, preceding studies have shown that GAGs play an important role in tissue development, cellular behavior or extracellular matrix (ECM) organization. The FGF-GAG noncovalent interactions are of high importance in the biological and biomedical fields of research, as a result of their influence in the tissue regeneration and cell proliferation processes. Here, we have employed one of the most advanced mass spectrometric (MS) techniques consisting of fully automated chip-nanoelectrospray (nanoESI), coupled to a quadrupole time-of-flight (QTOF) MS for studying the FGF-GAG noncovalent complexes. The experiments were conducted in 10 mM ammonium acetate/formic acid, pH 6.8, by incubating FGF-2 and CS disaccharides dissolved in buffer; aliquots were collected after 5, 10, 30, 60 and 90 minutes and further submitted to chip-based MS analysis. For the first time, a CS disaccharide was involved in a binding assay with FGF-2. The detected complexes in the screening experiments were further characterized by top-down fragmentation in tandem MS (MS/MS) using collision induced-dissociation (CID) at low ion acceleration energies. CID MS/MS provided data showing for the first time that the binding process occurs via SO3 located at C4 in the GalNAc moiety

Demonstrating the antinociceptive action of renin-angiotensin system modulators in mice

Research done in the present study belongs to a wider area of experimental determinations on nociception models, when using laboratory animals. Their aim is to determine the ED50 value (Efficient dose 50) in conditions of inflammatory (chemical stimulus) and non-inflammatory (thermic stimulus) antinociception of some renin-angiotensin system modulators: captopril, ramipril, candesartan. The experimental determinations were realized accordingly to bioethical regulations concerning laboratory animals. The study has used Swiss mice, weighing between 20-30g, being held in constant temperature (21°C ± 2°C) and a dark / light cycle of 12 hours (7.00 AM / 7.00 PM). The researched substances are administered as CMC-Na 0.1% suspensions in geometrical progression doses. The following nociception models have been used: abdominal constrictive response test, hot plate test, formalin test. The abdominal constrictive response test has been evaluated as quantal, the hot plate test and the formalin test have been interpreted as gradual. The regression line, the correlation coefficient and the interval of trust for each substance and studied model have been analyzed. The obtained ED50 values are compared to each other to evaluate the potency of the substances for each nociception model. The obtained data is used for realizing fixed-ratio antinociceptive combinations

The Stellar Content of Nearby Star-Forming Galaxies. III. Unravelling the Nature of the Diffuse Ultraviolet Light

We investigate the nature of the diffuse intra-cluster ultraviolet light seen in twelve local starburst galaxies, using long-slit ultraviolet spectroscopy obtained with the Space Telescope Imaging Spectrograph (STIS) aboard the Hubble Space Telescope (HST). We take this faint intra-cluster light to be the field in each galaxy, and compare its spectroscopic signature with STARBURST99 evolutionary synthesis models and with neighboring star clusters. Our main result is that the diffuse ultraviolet light in eleven of the twelve starbursts lacks the strong O-star wind features that are clearly visible in spectra of luminous clusters in the same galaxies. The difference in stellar features dominating cluster and field spectra indicate that the field light originates primarily from a different stellar population, and not from scattering of UV photons leaking out of the massive clusters. We consider several scenarios to understand the lack of observed O stars in the field, and their implications for the origin of the field stellar population. If the field stellar populations formed in situ, the field must either have an IMF which is steeper than Salpeter (3.0-3.5) or a Salpeter slope with an upper mass cutoff of 30-50 solar masses. If star formation occurs primarily in star clusters, the field could be composed of older, faded clusters, and/or a population which is coeval with the luminous clusters but lower in mass. If the field is composed of older, dissolving clusters, we estimate that star clusters (regardless of mass) need to dissolve on timescales 7-10 Myr to create the field (abridged).Comment: 25 pages, 6 figures, 7 tables; accepted, to appear ApJ 2005, vol. 62

C-Terminus Glycans with Critical Functional Role in the Maturation of Secretory Glycoproteins

The N-glycans of membrane glycoproteins are mainly exposed to the extracellular space. Human tyrosinase is a transmembrane glycoprotein with six or seven bulky N-glycans exposed towards the lumen of subcellular organelles. The central active site region of human tyrosinase is modeled here within less than 2.5 Å accuracy starting from Streptomyces castaneoglobisporus tyrosinase. The model accounts for the last five C-terminus glycosylation sites of which four are occupied and indicates that these cluster in two pairs - one in close vicinity to the active site and the other on the opposite side. We have analyzed and compared the roles of all tyrosinase N-glycans during tyrosinase processing with a special focus on the proximal to the active site N-glycans, s6:N337 and s7:N371, versus s3:N161 and s4:N230 which decorate the opposite side of the domain. To this end, we have constructed mutants of human tyrosinase in which its seven N-glycosylation sites were deleted. Ablation of the s6:N337 and s7:N371 sites arrests the post-translational productive folding process resulting in terminally misfolded mutants subjected to degradation through the mannosidase driven ERAD pathway. In contrast, single mutants of the other five N-glycans located either opposite to the active site or into the N-terminus Cys1 extension of tyrosinase are temperature-sensitive mutants and recover enzymatic activity at the permissive temperature of 31°C. Sites s3 and s4 display selective calreticulin binding properties. The C-terminus sites s7 and s6 are critical for the endoplasmic reticulum retention and intracellular disposal. Results herein suggest that individual N-glycan location is critical for the stability, regional folding control and secretion of human tyrosinase and explains some tyrosinase gene missense mutations associated with oculocutaneous albinism type I

The Dust Opacity of Star-Forming Galaxies

Presence of dust in galaxies removes half or more of the stellar energy from the UV-optical budget of the Universe and has profound impact on our understanding of how galaxies evolve. Measures of opacity in local galaxies are reviewed together with widely used theoretical and empirical methods for quantifying its effects. Existing evidence shows that the dust content of nearby galaxies depends not only on their morphology, but also on their luminosity and activity level. A digression is devoted to starbursts in view of their potential relevance for measures of opacity in distant galaxies. Scarcity of coherent multiwavelength datasets hampers our ability to derive reliable obscuration estimates in intermediate and high redshift galaxies. This, in turn, limits the reliability of inferred physical quantities, such as star formation rates, stellar population ages, galaxy luminosity functions, and others.Comment: Invited Review for PASP, to appear in December 2001. 84 pages, including 6 tables and 11 embedded figures; uses AAS Latex macr

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes