Multisystem inflammatory syndrome in children in western countries: decreasing incidence as the pandemic progresses? An observational multicenter international cross-sectional study

Multisystemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children (MIS-C) has been reported worldwide.1–7 The case definition of MIS-C has been estab- lished by different institutions and organizations such as the US Centers for Disease Control and Prevention (CDC) (May 14, 2020),8 the Royal College of Paediatrics and Child Health in the United Kingdom (RCPCH) (May 1, 2020)9,10 and the World Health Organi- zation (WHO) (May 15, 2020).1Postprint (published version

Falls Predict Acute Hospitalization in Parkinson's Disease

[Background] There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission.[Objective] To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort.[Methods] PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit.[Results] Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH.[Conclusion] Falls is an independent predictor of AH in PD patients.Peer reviewe

Ligand selectivity at GPCRs: from multitarget binding profiles to biased agonism

La caracterització de diversos fàrmacs capaços d’unir-se a receptors associats a proteïnes G (GPCR)s ha revelat que els seus mecanismes d’acció no eren tan simples com es creia. Primer, l’anàlisi de la seva afinitat d’unió per una sèrie de receptors va revelar que podien unir-se a múltiples dianes. Més tard, l’estudi de la seva eficàcia envers diferents vies de senyalització va revelar que alguns fàrmacs podien promoure selectivitat funcional. En aquesta tesi, s’han construït models a partir de noves dades estructurals i farmacològiques de diversos receptors per determinar les bases de l’afinitat de diferents compostos per múltiples GPCRs i estudiar la seva selectivitat funcional. La informació obtinguda pot permetre obtenir noves eines moleculars que ajudin a analitzar la rellevància de diversos modes d’activació en el tractament de malalties complexes com l’esquizofrènia. Aquesta informació també pot contribuir al disseny racional de nous fàrmacs capaços d’explotar diferents perfils de selectivitat i de discriminar entre efectes terapèutics i secundaris.Deeper characterization of drugs targeting G protein-coupled receptors (GPCR)s has shown that their mechanisms of action can be more complex than previously thought. On the one hand, binding affinity analyses towards a panel of related receptors have revealed that most drugs have affinity for multiple targets. On the other, characterization of drug efficacy for different receptor pathways has made evident that some ligands can selectively activate particular pathways, thus acting as biased agonists. In this work, we used models derived from new experimental data on receptor 3D structure and pharmacology to rationalize the structural determinants of multi-target affinity and biased agonism for different GPCR ligands. This insight can help obtain new molecular probes to assess the importance of specific affinity and efficacy profiles for the treatment of complex diseases such as schizophrenia. Furthermore, it can set the basis for the rational design of new ligands exploiting different forms of selectivity and capable of separating therapeutic effects from side effects

Codon optimization of the adenoviral fiber negatively impacts structural protein expression and viral fitness

Codon usage adaptation of lytic viruses to their hosts is determinant for viral fitness. In this work, we analyzed the codon usage of adenoviral proteins by principal component analysis and assessed their codon adaptation to the host. We observed a general clustering of adenoviral proteins according to their function. However, there was a significant variation in the codon preference between the host-interacting fiber protein and the rest of structural late phase proteins, with a non-optimal codon usage of the fiber. To understand the impact of codon bias in the fiber, we optimized the Adenovirus-5 fiber to the codon usage of the hexon structural protein. The optimized fiber displayed increased expression in a non-viral context. However, infection with adenoviruses containing the optimized fiber resulted in decreased expression of the fiber and of wild-type structural proteins. Consequently, this led to a drastic reduction in viral release. The insertion of an exogenous optimized protein as a late gene in the adenovirus with the optimized fiber further interfered with viral fitness. These results highlight the importance of balancing codon usage in viral proteins to adequately exploit cellular resources for efficient infection and open new opportunities to regulate viral fitness for virotherapy and vaccine development.This work was supported by grants from the Spanish Ministry of Economia y Competitividad BIO2014-57716-C2-2-R and receives partial support from the Generalitat de Catalunya SGR14/248. CIBER de Enfermedades Raras is an initiative of the ISCIII. CF group is partially financed by the Instituto de Salud Carlos III (IIS10/00014) and co-financed by Fondo Europeo de Desarrollo Regional (FEDER). We also acknowledge the support of COST Action BM1204 EUPancreas. E.V. was supported by a fellowship from the Gobierno Vasco, Spain

From Forms to Flows: an Approach to the [Eco]systemic Urban Project

The awareness of the effects of climate change set significant challenges to urbanism, requiring transdisciplinary approaches capable of giving efficient responses for the contemporary city and territory. A teaching programme set up in the framework of academic cooperation with other European schools through competitive Erasmus+ projects has explored the potential of urban metabolism at the scale of the urban project. Throughout several courses, the analytical and design reflection on the principles of sustainable development has been addressed at the scale of the urban fragment, testing tools, interpreting strategies and coming up with new design projects, merging rigorous and speculative approaches. Through a continuous exploration among students and teachers, some examples of what could be called [eco]systemic urbanism projects have been discussed and illustrated, going beyond the basic application of environmental standards and technical codes.La toma de conciencia de los efectos del cambio climático plantea importantes retos al urbanismo y exige aproximaciones transdisciplinares capaces de responder eficientemente en la ciudad y el territorio contemporáneos. Un programa nacido de la cooperación académica con otras escuelas europeas en el marco de los proyectos competitivos Erasmus+ ha explorado el potencial del metabolismo urbano a la escala del proyecto urbano. A lo largo de varios cursos, se ha aproximado una reflexión analítica y propositiva sobre las principios del desarrollo sostenible a la escala del fragmento urbano, ensayando herramientas, interpretando estrategias e inventando proyectos, buscando el equilibrio entre el rigor y la especulación. A través de una continua exploración entre estudiantes y profesores, se han discutido e ilustrado algunos ejemplos de lo que podría denominarse proyecto urbano [eco]sistémico, para ir más allá de la simple aplicación de estándares ambientales y códigos técnicos.Esta experiencia académica se ha beneficiado de los proyectos financiados Erasmus+ ID/2013- ERA-IP-236 y SP/2015-1-BE01-KA203-013200 que impulsaron incialmente su desarrollo.Peer Reviewe

De las formas a los flujos. Aproximación al proyecto urbano [eco]sistémico From Forms to Flows = An Approach to the [Eco]systemic Urban Project

Presentación a cargo de Joan Martí Elías, (Departament d'Urbanisme i Ordenació del Territori ETSAB | UPC)

A dynamic view of molecular switch behavior at serotonin receptors: implications for functional selectivity

Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5-HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and β-arrestin signaling at the 5-HT1B receptor but clearly favoring β-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro-switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity.This work was funded by the Ministerio de Educación y Ciencia, grant number SAF2009-13609-C04-04, and La MARATÓ de TV3 Foundation, grant number 091010. MM-S is supported by a doctoral fellowship from the University and Research Secretariat of the Catalan Government and the European Social Fund (2013FI_B 00143). JS acknowledges support from the Instituto de Salud Carlos III FEDER (CP12/03139) and the GLISTEN European Research Networ

Two-dimensional free energy profile of the connector region of the 5-HT_2BR.

<p>To create this map two collective variables were used: the first coordinate (d₁) is the distance between C-4 of the F^6.44 and the Cα of residues 5.50, while the second one (d₂) is the distance between the C-4 of F^6.41 and the Cα of residue 5.54. As we can see, an active state of F^6.44 only exists when residue F^6.41 has adopted an active conformation and broken their hydrophobic contact. The point 4IB4 represents distances as they are found in the crystal structure of the 5-HT_2BR.</p

Details of the molecular dynamics simulations performed.

<p>*This number of replicates was performed for each receptor.</p><p>Details of the molecular dynamics simulations performed.</p

Ergotamine structure and schematic representation of the position of micro-switches in the ergotamine-serotonin receptor complexes.

<p>X-crystal structures are shown in thick sticks representation whereas simulation shows frames every 200 ns of the 2.5 µs concatenated trajectories. A) Representative ergotamine poses (depicted in orange) in its binding pocket (top ten receptor interacting residues in yellow). The extracellular part of helix 5 (grey) forms and additional turn stabilized by water (red) in the 5-HT_2B receptor. Extended interactions of ergotamine with helix 5 can anchor together helix 5 and 6 (grey dashed line connecting yellow interacting residues), an effect which is not seen in the 5-HT_1B receptor (red cross) B) Relative positions of F^6.44 of the P-I-F motif in both receptors and amount of helix 6 rotation (from residue 6.44 to 6.50) measured with the SIMULAID framework for the analysis of MD simulations (inset). C) Different conformations of the residues forming the D/RY motif in the 5-HT_1B and 5-HT_2B receptors.</p