Textile and Film-Based Modular Facades

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Noninvasive near-infrared live imaging of human adult mesenchymal stem cells transplanted in a rodent model of Parkinson’s disease

Background: We have previously shown that human mesenchymal stem cells (hMSCs) can reduce toxin-induced neurodegeneration in a well characterized rodent model of Parkinson's disease. However, the precise mechanisms, optimal cell concentration required for neuroprotection, and detailed cell tracking need to be defined. We exploited a near-infrared imaging platform to perform noninvasive tracing following transplantation of tagged hMSCs in live parkinsonian rats.Methods: hMSCs were labeled both with a membrane intercalating dye, emitting in the near-infrared 815 nm spectrum, and the nuclear counterstain, Hoechst 33258. Effects of near-infrared dye on cell metabolism and proliferation were extensively evaluated in vitro. Tagged hMSCs were then administered to parkinsonian rats bearing a 6-hydroxydopamine-induced lesion of the nigrostriatal pathway, via two alternative routes, ie, intrastriatal or intranasal, and the cells were tracked in vivo and ex vivo using near-infrared technology.Results: In vitro, NIR815 staining was stable in long-term hMSC cultures and did not interfere with cell metabolism or proliferation. A significant near-infrared signal was detectable in vivo, confined around the injection site for up to 14 days after intrastriatal transplantation. Conversely, following intranasal delivery, a strong near-infrared signal was immediately visible, but rapidly faded and was completely lost within 1 hour. After sacrifice, imaging data were confirmed by presence/absence of the Hoechst signal ex vivo in coronal brain sections. Semiquantitative analysis and precise localization of transplanted hMSCs were further performed ex vivo using near-infrared imaging.Conclusion: Near-infrared technology allowed longitudinal detection of fluorescent-tagged cells in living animals giving immediate information on how different delivery routes affect cell distribution in the brain. Near-infrared imaging represents a valuable tool to evaluate multiple outcomes of transplanted cells, including their survival, localization, and migration over time within the host brain. This procedure considerably reduces the number of animal experiments needed, as well as interindividual variability, and may favor the development of efficient therapeutic strategies promptly applicable to patients

Essays in macroeconomics

Esta tesis consta de tres capítulos, cada uno de los cuales analiza temas relevantes en el campo de la Macroeconomía. La investigación realizada en los tres capítulos se basa en la metodología de los modelos dinámicos de equilibrio general. Los fundamentos microeconómicos se encuentran en el núcleo de este tipo de modelos, en los que los agentes forman sus expectativas sobre el futuro de manera racional. Esta metodología ha demostrado ser una herramienta poderosa para abordar un gran conjunto de problemas económicos. El primer capítulo, ``Risk Aversion, Entrepreneurship and Wealth Distribution'', explora el efecto de la heterogeneidad en la aversión al riesgo sobre el emprendimiento, el comportamiento del ahorro y la distribución de la riqueza. La distribución de la riqueza es uno de los temas más debatidos no solo en la política contemporánea, sino también en los medios de comunicación y en ámbitos académicos. En particular, la gran concentración de riqueza en la parte superior de la distribución, que se observa en muchas economías avanzadas, se ha situado en el centro del debate. La relevancia de este problema no se ha visto socavada a pesar de la dificultad que supone estimar los niveles de riqueza acumulada en manos de los hogares más ricos. Apoyado por razones empíricas, el marco teórico para analizar la distribución de la riqueza debe incluir tanto el emprendimiento como la heterogeneidad de las preferencias. Con este objetivo, en el primer capítulo se desarrolla un modelo de elección ocupacional con agentes heterogéneos en el que los hogares varían en su aversión al riesgo, se enfrentan a perturbaciones idiosincrásicas no asegurables, tienen restricciones financieras y deben decidir si convertirse en trabajadores o en emprendedores. Esta decisión se basa en una combinación de la aversión al riesgo individual, las habilidades específicas en cada ocupación y los niveles de riqueza acumulados. Como resultado se obtiene que la aversión al riesgo tiene un efecto directo e indirecto en la decisión de ahorro y en la ocupación de los agentes. Por un lado, una mayor aversión al riesgo disuade a los agentes de convertirse en emprendedores y, por lo tanto, los ahorros destinados a superar las restricciones financieras son menores. Por otro lado, una mayor aversión al riesgo también conduce a un mayor ahorro por motivo de precaución que, indirectamente, atenúa las restricciones financieras y hace que la opción de convertirse en emprendedor sea más atractiva. En el modelo desarrollado, el último efecto domina, y los agentes con mayor aversión al riesgo acumulan mayores niveles de riqueza y también se convierten en emprendedores. La contribución más importante de este modelo es que permite desentrañar los efectos que la aversión al riesgo y las fricciones financieras tienen sobre el emprendimiento, que es un factor clave para explicar la desigualdad en la acumulación de la riqueza. El segundo capítulo se titula ``Long-term business relationships, bargaining and monetary policy'' y es un trabajo conjunto con Mirko Abbritti y Tommaso Trani. Su motivación se deriva de la creciente literatura empírica que documenta la importancia de las relaciones comerciales a largo plazo y los procesos de negociación sobre la rigidez de los precios y las dinámicas empresariales. Este artículo introduce relaciones comerciales entre empresas (B2B) a largo plazo y procesos de negociación de precios en un modelo monetario de equilibrio general dinámico estocástico (DSGE) estándar. El modelo se basa en dos suposiciones. Primero, tanto los productores mayoristas como los minoristas necesitan gastar recursos para formar nuevas relaciones comerciales. Segundo, una vez que se forma una relación comercial, el precio se establece en una negociación bilateral entre las empresas. El modelo proporciona un marco riguroso para estudiar el efecto de las relaciones comerciales a largo plazo y los procesos de negociación sobre la política monetaria y la dinámica del ciclo económico. Además, se demuestra que estas relaciones comerciales reducen tanto el papel de asignación de los precios intermedios como los efectos reales de las perturbaciones de la política monetaria. También encontramos que el modelo hace un gran trabajo al replicar los segundos momentos y las correlaciones cruzadas de los datos, y que mejora con respecto al modelo de referencia Neo Keynesiano en explicar dichos estadísticos. El tercer y último capítulo de esta tesis, ``On Staggered Prices and Optimal Inflation'', es coautoreado con uno de mis directores, Miguel Casares. En este artículo se calcula la tasa de inflación óptima en estado estacionario bajo dos especificaciones de rigidez de precios diferentes, Calvo (1983) y Taylor (1980), en un modelo con competencia monopolística. Encontramos que la tasa óptima de inflación en estado estacionario es siempre positiva. Este resultado es robusto a los cambios en el grado de rigidez de los precios. En ambos casos con rigidez de precios, la tasa de inflación óptima es aproximadamente igual al cociente entre la tasa de descuento y la elasticidad de Dixit-Stiglitz. Para calibraciones estándar, el coste de bienestar de la inflación es cuantitativamente pequeño, pero significativamente más alto si los precios son rígidos a la Calvo que si son rígidos a la Taylor.Fundación Banco Sabadell, Fundación Bancaria Caja Navarra y Universidad Pública de NavarraPrograma de Doctorado en Economía, Empresa y Derecho (RD 99/2011)Ekonomiako, Enpresako eta Zuzenbideko Doktoretza Programa (ED 99/2011

Plasma exosome profile in st-elevation myocardial infarction patients with and without out-of-hospital cardiac arrest

The identification of new biomarkers allowing an early and more accurate characterization of patients with ST-segment elevation myocardial infarction (STEMI) is still needed, and exosomes represent an attractive diagnostic tool in this context. However, the characterization of their protein cargo in relation to cardiovascular clinical manifestation is still lacking. To this end, 35 STEMI patients (17 experiencing resuscitated out-of-hospital cardiac arrest (OHCA-STEMI) and 18 uncomplicated) and 32 patients with chronic coronary syndrome (CCS) were enrolled. Plasma exosomes were characterized by the nanoparticle tracking analysis and Western blotting. Exosomes from STEMI patients displayed a higher concentration and size and a greater expression of platelet (GPIIb) and vascular endothelial (VE-cadherin) markers, but a similar amount of cardiac troponin compared to CCS. In addition, a difference in exosome expression of acute-phase proteins (ceruloplasmin, transthyretin and fibronectin) between STEMI and CCS patients was found. GPIIb and brain-associated marker PLP1 accurately discriminated between OHCA and uncomplicated STEMI. In conclusion, the exosome profile of STEMI patients has peculiar features that differentiate it from that of CCS patients, reflecting the pathophysiological mechanisms involved in STEMI. Additionally, the exosome expression of brain-and platelet-specific markers might allow the identification of patients experiencing ischemic brain injury in STEMI

Integrated Short-term Palliative Rehabilitation to improve quality of life and equitable care access in incurable cancer (INSPIRE): a multinational European research project

Background: Disability related to incurable cancer affects over a million Europeans each year and people with cancer rank loss of function among the most common unmet supportive care needs. Objectives: To test the clinical and cost-effectiveness of an integrated short-term palliative rehabilitation intervention, to optimise function and quality of life in people affected by incurable cancer. Design: This is a multinational, parallel group, randomised, controlled, assessor blind, superiority trial. Methods: The INSPIRE consortium brings together leaders in palliative care, oncology and rehabilitation from partner organisations across Europe, with complementary expertise in health service research, trials of complex interventions, mixed-method evaluations, statistics and economics. Partnership with leading European civil society organisations ensures citizen engagement and dissemination at the highest level. We will conduct a multinational randomised controlled trial across five European countries, recruiting participants to assess the effectiveness of palliative rehabilitation for people with incurable cancer on the primary outcome – quality of life – and secondary outcomes including disability, symptom burden and goal attainment. To support trial conduct and enhance analysis of trial data, we will also conduct: comparative analysis of current integration of rehabilitation across oncology and palliative care services; mixed-method evaluations of equity and inclusivity, processes and implementation for the intervention, at patient, health service and health system levels. Finally, we will conduct an evidence synthesis, incorporating INSPIRE findings, and a Delphi consensus to develop an international framework for palliative rehabilitation practice and policy, incorporating indicators, core interventions, outcomes and integration methods. Scientific contribution: If positive, the trial could produce a scalable and equitable intervention to improve function and quality of life in people with incurable cancer and reduce the burden of care for their families. It could also upskill the practitioners involved and motivate future research questions. The intervention could be adapted and integrated into different health systems using existing staff and services, with little or no additional cost

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Background and Objective: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far. Methods: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic. Results: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive. Conclusions: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Glutamate Induces Mitochondrial Dynamic Imbalance and Autophagy Activation: Preventive Effects of Selenium

Glutamate-induced cytotoxicity is partially mediated by enhanced oxidative stress. The objectives of the present study are to determine the effects of glutamate on mitochondrial membrane potential, oxygen consumption, mitochondrial dynamics and autophagy regulating factors and to explore the protective effects of selenium against glutamate cytotoxicity in murine neuronal HT22 cells. Our results demonstrated that glutamate resulted in cell death in a dose-dependent manner and supplementation of 100 nM sodium selenite prevented the detrimental effects of glutamate on cell survival. The glutamate induced cytotoxicity was associated with mitochondrial hyperpolarization, increased ROS production and enhanced oxygen consumption. Selenium reversed these alterations. Furthermore, glutamate increased the levels of mitochondrial fission protein markers pDrp1 and Fis1 and caused increase in mitochondrial fragmentation. Selenium corrected the glutamate-caused mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria. Finally, glutamate activated autophagy markers Beclin 1 and LC3-II, while selenium prevented the activation. These results suggest that glutamate targets the mitochondria and selenium supplementation within physiological concentration is capable of preventing the detrimental effects of glutamate on the mitochondria. Therefore, adequate selenium supplementation may be an efficient strategy to prevent the detrimental glutamate toxicity and further studies are warranted to define the therapeutic potentials of selenium in animal disease models and in human

The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of Familial Hemiplegic Migraine type 1 (FHM-1)

A knock-in (KI) mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the \u3b11 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT) neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining) migraine attacks, such as TNF\u3b1, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNF\u3b1 potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNF\u3b1 receptor TNFR2. However, sustained TNF\u3b1 neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNF\u3b1 does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNF\u3b1 enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP. \ua9 2013 Hullugundi et al