Reurbanització Avda. Eduard Corbella, rotonda i continuació carril bici

L’objecte d’aquest projecte és la definició, justificació, i valoració de les obres per a la Reurbanització de l’avinguda Eduard Corbella, continuació carril bici i construcció rotonda E. Corbella. Això implica la redefinició i millora de l’espai públic mitjançant la definició d’una nova ordenació. Aquests treballs comporten per una banda la urbanització, així com millores de les xarxes de serveis de la urbanització. El projecte contempla les següents actuacions: - Demolicions i moviments de terres - Pavimentació i ferms - Jardineria i reg - Enllumenat públic - Xarxa de clavegueram - Xarxa de baixa tensió - Xarxa de telecomunicacions - Mobiliari urbà - Senyalització - Carril bici - Construcció rotonda La superfície de l’àmbit de l’obra és de : - Tram avinguda Vilamajor 2409,53 m2 - Tram avinguda E. Corbella est 2723,84 m2 - Tram rotonda/ E. Corbella oest 1119,65 m2 Una superfície total de 6253 m2 El tractament del projecte té en compte els següents objectius: - Nova ordenació del voral per tal de solucionar el problema dels arbres. - Materials de llarga durabilitat i baix manteniment: pedra granítica en vorades i rigoles, paviments peatonals de peces de formigó. - Nou enllumenat millorant la capacitat lumínica d’acord amb els criteris d’estalvi energètic. Sistemes de projecció en el pla horitzontal evitant contaminació lumínica i làmpades de vapor de sodi amb sistema de reducció de flux. - Nova xarxa de clavegueram - Nova xarxa de reg automatitzat - Soterrament de les xarxes aèries de baixa tensió - Soterrament de la xarxa de telecomunicacions - Continuació carril bici - Millora de l’accessibilitat eliminant les barreres arquitectòniques existents a nivell de paviments, amb un pendent longitudinal entre el 0,50 i el 2,50% i uns pendents transversals inferiors al 2%. Normativa vigent: Codi d’ Accessibilitat de Cataluny

Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors

NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells

Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times

Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents

Targeted covalent inhibitors hold promise for drug discovery, particularly for kinases. Targeting the catalytic lysine of epidermal growth factor receptor (EGFR) has attracted attention as a new strategy to overcome resistance due to the emergence of C797S mutation. Sulfonyl fluoride derivatives able to inhibit EGFRL858R/T790M/C797S by sulfonylation of Lys745 have been reported. However, atomistic details of this process are still poorly understood. Here, we describe the mechanism of inhibition of an innovative class of compounds that covalently engage the catalytic lysine of EGFR, through a sulfur(VI) fluoride exchange (SuFEx) process, with the help of hybrid quantum mechanics/molecular mechanics (QM/MM) and path collective variables (PCVs) approaches. Our simulations identify the chemical determinants accounting for the irreversible activity of agents targeting Lys745 and provide hints for the further optimization of sulfonyl fluoride agents

Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT1 and MT2 membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the (S) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the (S)-beta-methyl group favors the conformation that better fits the receptor binding site

Active deformation evidence in the offshore of western Calabria (southern Tyrrhenian Sea) from ultra-resolution multichannel seismic reflection data: results from the Gulf of Sant'Eufemia

An ultra-resolution, multichannel seismic reflection data set was collected during an oceanographic cruise organised in the frame of the “Earthquake Potential of Active Faults using offshore Geological and Morphological Indicators” (EPAF) project, which was founded by the Scientific and Technological Cooperation (Scientific Track 2017) between the Italian Ministry of Foreign Affairs and International Cooperation and the Ministry of Science, Technology and Space of the State of Israel. The data acquisition approach was based on innovative technologies for the offshore imaging of stratigraphy and structures along continental margins with a horizontal and vertical resolution at decimetric scale. In this work, we present the methodology used for the 2D HR-seismic reflection data acquisition and the preliminary interpretation of the data set. The 2D seismic data were acquired onboard the R/V Atlante by using an innovative data acquisition equipment composed by a dual-sources Sparker system and one HR 48-channel, slant streamers, with group spacing variable from 1 to 2 meters, at 10 kHz sampling rate. An innovative navigation system was used to perform all necessary computations to determining real-time positions of sources and receivers. The resolution of the seismic profiles obtained from this experiment is remarkable high respect to previously acquired seismic data for both scientific and industrial purposes. In addition to the seismic imaging, gravity core data were also collected for sedimentological analysis and to give a chronological constraint using radiocarbon datings to the shallower reflectors. The investigated area is located in the western offshore sector of the Calabrian Arc (southern Tyrrhenian Sea) where previous research works, based on multichannel seismic profiles coupled with Chirp profiles, have documented the presence of an active fault system. One of the identified faults was tentatively considered as the source of the Mw 7, 8 September 1905 seismic event that hit with highest macroseismic intensities the western part of central Calabria, and was followed by a tsunami that inundated the coastline between Capo Vaticano and the Angitola plain. On this basis, the earthquake was considered to have a source at sea, but so far, the location, geometry and kinematics of the causative fault are still poorly understood. In this study we provide preliminary results of the most technologically advanced ultra-high-resolution geophysical method used to reveal the 3D faulting pattern, the late Quaternary slip rate and the earthquake potential of the marine fault system located close to the densely populated west coast of Calabria

Evaluation of Nutritional Practices in the Critical Care patient (The ENPIC study): Does nutrition really affect ICU mortality?

Enteral nutrition; Intensive care unit; MortalityNutrició enteral; Unitat de Cures Intensives; MortalitatNutrición enteral; Unidad de Cuidados Intensivos; MortalidadBackground & aims: The importance of artificial nutritional therapy is underrecognized, typically being considered an adjunctive rather than a primary therapy. We aimed to evaluate the influence of nutritional therapy on mortality in critically ill patients. Methods: This multicenter prospective observational study included adult patients needing artificial nutritional therapy for >48 h if they stayed in one of 38 participating intensive care units for ≥72 h between April and July 2018. Demographic data, comorbidities, diagnoses, nutritional status and therapy (type and details for ≤14 days), and outcomes were registered in a database. Confounders such as disease severity, patient type (e.g., medical, surgical or trauma), and type and duration of nutritional therapy were also included in a multivariate analysis, and hazard ratios (HRs) and 95% confidence intervals (95%CIs) were reported. Results: We included 639 patients among whom 448 (70.1%) and 191 (29.9%) received enteral and parenteral nutrition, respectively. Mortality was 25.6%, with non-survivors having the following characteristics: older age; more comorbidities; higher Sequential Organ Failure Assessment (SOFA) scores (6.6 ± 3.3 vs 8.4 ± 3.7; P < 0.001); greater nutritional risk (Nutrition Risk in the Critically Ill [NUTRIC] score: 3.8 ± 2.1 vs 5.2 ± 1.7; P < 0.001); more vasopressor requirements (70.4% vs 83.5%; P=0.001); and more renal replacement therapy (12.2% vs 23.2%; P=0.001). Multivariate analysis showed that older age (HR: 1.023; 95% CI: 1.008-1.038; P=0.003), higher SOFA score (HR: 1.096; 95% CI: 1.036-1.160; P=0.001), higher NUTRIC score (HR: 1.136; 95% CI: 1.025-1.259; P=0.015), requiring parenteral nutrition after starting enteral nutrition (HR: 2.368; 95% CI: 1.168-4.798; P=0.017), and a higher mean Kcal/Kg/day intake (HR: 1.057; 95% CI: 1.015-1.101; P=0.008) were associated with mortality. By contrast, a higher mean protein intake protected against mortality (HR: 0.507; 95% CI: 0.263-0.977; P=0.042). Conclusions: Old age, higher organ failure scores, and greater nutritional risk appear to be associated with higher mortality. Patients who need parenteral nutrition after starting enteral nutrition may represent a high-risk subgroup for mortality due to illness severity and problems receiving appropriate nutritional therapy. Mean calorie and protein delivery also appeared to influence outcomes

Parenteral Nutrition: Current Use, Complications, and Nutrition Delivery in Critically Ill Patients

Complementary parenteral nutrition; Critically ill patients; Enteral nutritionNutrición parenteral complementaria; Pacientes críticamente enfermos; Nutrición enteralNutrició parenteral complementària; Pacients crítics; Nutrició enteralBackground: Parenteral nutrition (PN) is needed to avoid the development of malnutrition when enteral nutrition (EN) is not possible. Our main aim was to assess the current use, complications, and nutrition delivery associated with PN administration in adult critically ill patients, especially when used early and as the initial route. We also assessed the differences between patients who received only PN and those in whom EN was initiated after PN (PN-EN). Methods: A multicenter (n = 37) prospective observational study was performed. Patient clinical characteristics, outcomes, and nutrition-related variables were recorded. Statistical differences between subgroups were analyzed accordingly. Results: From the entire population (n = 629), 186 (29.6%) patients received PN as initial nutrition therapy. Of these, 74 patients (11.7%) also received EN during their ICU stay (i.e., PN-EN subgroup). PN was administered early (<48 h) in the majority of patients (75.3%; n = 140) and the mean caloric (19.94 ± 6.72 Kcal/kg/day) and protein (1.01 ± 0.41 g/kg/day) delivery was similar to other contemporary studies. PN showed similar nutritional delivery when compared with the enteral route. No significant complications were associated with the use of PN. Thirty-two patients (43.3%) presented with EN-related complications in the PN-EN subgroup but received a higher mean protein delivery (0.95 ± 0.43 vs 1.17 ± 0.36 g/kg/day; p = 0.03) compared with PN alone. Once adjusted for confounding factors, patients who received PN alone had a lower mean protein intake (hazard ratio (HR): 0.29; 95% confidence interval (CI): 0.18-0.47; p = 0.001), shorter ICU stay (HR: 0.96; 95% CI: 0.91-0.99; p = 0.008), and fewer days on mechanical ventilation (HR: 0.85; 95% CI: 0.81-0.89; p = 0.001) compared with the PN-EN subgroup. Conclusion: The parenteral route may be safe, even when administered early, and may provide adequate nutrition delivery. Additional EN, when possible, may optimize protein requirements, especially in more severe patients who received initial PN and are expected to have longer ICU stays. NCT Registry: 03634943.The present study was funded by the Spanish Society of Metabolism and Nutrition (SENPE: Sociedad Española de Nutrición y Metabolismo): Best Working Group Project Award at the SENPE National Congress in 2022