Síntesis y caracterización de hidrogeles injectables inspirados en la matriz extracelular para la regeneración de tejidos blandos

[ES] El objetivo de este trabajo consiste en sintetizar y caracterizar hidrogeles inyectables mixtos de gelatina y ácido hialurónico homogéneos, de cara a su empleo como materiales soporte para la regeneración de tejidos blandos. Antes de la gelificación de los hidrogeles, se optimizará la miscibilidad de los componentes variando el peso molecular y la viscosidad de las disoluciones precursoras. Además, se estudiará el empleo de soportes poliméricos de ácido poliláctico (PLLA) que puedan emplearse en combinación con los hidrogeles sintetizados para aquellas aplicaciones en las que se requiera mayores propiedades mecánicas. La caracterización incluirá tanto ensayos físico-químicos para la determinación de sus propiedades como ensayos biológicos que demuestren la viabilidad de estos sistemas en el campo de la ingeniería tisular.[CA] L’objectiu d’aquest treball consisteix en sintetitzar i caracteritzar hidrogels injectables mixtos de gelatina i àcid hialurònic homogenis, de cara al seu ús com materials suport per a la regeneració de teixits tous. Abans de la gelificació dels hidrogels, s’optimitzarà la miscibil·litat dels components variant el pes molecular i la viscositat de les dissolucions precursores. A més, s’estudiarà l’ús de suports polimèrics d’àcid polilàctic (PLLA) que poden ser utilitzats en combinació amb els hidrogels sintetitzats per a aquelles aplicacions en les quals es necessiten majors propietats mecàniques. La caracterització inclourà tant assajos físic-químics per la determinació de les seues propietats com assajos biològics que demostren la viabilitat d’aquests sistemes en el camp de l’enginyeria tissular.[EN] The aim of this work is to synthetize and characterize injectable mixed homogeneous hydrogels of gelatin and hyaluronic acid. These hydrogels can be used as support materials in the regeneration of soft tissues. Before hydrogel gelation, we will optimize the miscibility of the components by changes in its molecular weight and viscosity of precursor solutions. Moreover, the use of polymeric supports of polylactic acid (PLLA) will be studied in combination with hydrogels for the applications where high mechanical properties are required. The characterization will include physical and chemical assays for the determination of its properties and biological assays that can demonstrate the viability of these systems in the field of tissue engineering.Sanmartín Masiá, EDR. (2016). Síntesis y caracterización de hidrogeles injectables inspirados en la matriz extracelular para la regeneración de tejidos blandos. http://hdl.handle.net/10251/72198.TFG

Oculomotor deficits in children adopted from Eastern Europe

Aim: We aim to assess oculomotor behaviour in children adopted from Eastern Europe, who are at high risk of maternal alcohol consumption. Methods: This cross‐sectional study included 29 adoptees and 29 age‐matched controls. All of them underwent a complete ophthalmological examination. Oculomotor control, including fixation and saccadic performance, was assessed using a DIVE device, with eye tracking technology. Anthropometric and facial measurements were obtained from all the adopted children, to identify features of foetal alcohol spectrum disorders (FASD). Fixational and saccadic outcomes were compared between groups, and the effect of adoption and FASD features quantified. Results: Oculomotor performance was poorer in adopted children. They presented shorter (0.53 vs 1.43 milliseconds in the long task and 0.43 vs 0.82 in the short task) and more unstable fixations (with a bivariate contour ellipse area of 27.9 vs 11.6 degree2 during the long task and 6.9 vs 1.3 degree2 during the short task) and slower saccadic reactions (278 vs 197 milliseconds). Children with sentinel finding for FASD showed the worst oculomotor outcomes. Conclusion: Children adopted from Eastern Europe present oculomotor deficits, affecting both fixation and saccadic skills. We highlight prenatal exposure to alcohol as the main cause for these deficits

A high-throughput chemical screen in DJ-1β mutant flies identifies zaprinast as a potential Parkinson's disease treatment

Dopamine replacement represents the standard therapy for Parkinson's disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood-brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials

Anticancer activity driven by drug linker modification in a polyglutamic acid-based combination-drug conjugate

Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer–drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer–drug conjugates at supramolecular level to allow the design of more effective polymer–drug conjugates

Transmitted drug resistance to antiretroviral drugs in Spain during the period 2019–2021

To evaluate the prevalence of transmitted drug resistance (TDR) to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTI, NNRTI), protease inhibitors (PI), and integrase strand transfer inhibitors (INSTI) in Spain during the period 2019-2021, as well as to evaluate transmitted clinically relevant resistance (TCRR) to antiretroviral drugs. Reverse transcriptase (RT), protease (Pro), and Integrase (IN) sequences from 1824 PLWH (people living with HIV) were studied. To evaluate TDR we investigated the prevalence of surveillance drug resistance mutations (SDRM). To evaluate TCRR (any resistance level >= 3), and for HIV subtyping we used the Stanford v.9.4.1 HIVDB Algorithm and an in-depth phylogenetic analysis. The prevalence of NRTI SDRMs was 3.8% (95% CI, 2.8%-4.6%), 6.1% (95% CI, 5.0%-7.3%) for NNRTI, 0.9% (95% CI, 0.5%-1.4%) for PI, and 0.2% (95% CI, 0.0%-0.9%) for INSTI. The prevalence of TCRR to NRTI was 2.1% (95% CI, 1.5%-2.9%), 11.8% for NNRTI, (95% CI, 10.3%-13.5%), 0.2% (95% CI, 0.1%-0.6%) for PI, and 2.5% (95% CI, 1.5%-4.1%) for INSTI. Most of the patients were infected by subtype B (79.8%), while the majority of non-Bs were CRF02_AG (n = 109, 6%). The prevalence of INSTI and PI resistance in Spain during the period 2019-2021 is low, while NRTI resistance is moderate, and NNRTI resistance is the highest. Our results support the use of integrase inhibitors as first-line treatment in Spain. Our findings highlight the importance of ongoing surveillance of TDR to antiretroviral drugs in PLWH particularly with regard to first-line antiretroviral therapy

TFG 2012/2013

Amb aquesta publicació, EINA, Centre universitari de Disseny i Art adscrit a la Universitat Autònoma de Barcelona, dóna a conèixer el recull dels Treballs de Fi de Grau presentats durant el curs 2012-2013. Voldríem que un recull com aquest donés una idea més precisa de la tasca que es realitza a EINA per tal de formar nous dissenyadors amb capacitat de respondre professionalment i intel·lectualment a les necessitats i exigències de la nostra societat. El treball formatiu s’orienta a oferir resultats que responguin tant a paràmetres de rigor acadèmic i capacitat d’anàlisi del context com a l’experimentació i la creació de nous llenguatges, tot fomentant el potencial innovador del disseny.Con esta publicación, EINA, Centro universitario de diseño y arte adscrito a la Universidad Autónoma de Barcelona, da a conocer la recopilación de los Trabajos de Fin de Grado presentados durante el curso 2012-2013. Querríamos que una recopilación como ésta diera una idea más precisa del trabajo que se realiza en EINA para formar nuevos diseñadores con capacidad de responder profesional e intelectualmente a las necesidades y exigencias de nuestra sociedad. El trabajo formativo se orienta a ofrecer resultados que respondan tanto a parámetros de rigor académico y capacidad de análisis, como a la experimentación y la creación de nuevos lenguajes, al tiempo que se fomenta el potencial innovador del diseño.With this publication, EINA, University School of Design and Art, ascribed to the Autonomous University of Barcelona, brings to the public eye the Final Degree Projects presented during the 2012-2013 academic year. Our hope is that this volume might offer a more precise idea of the task performed by EINA in training new designers, able to speak both professionally and intellectually to the needs and demands of our society. The educational task is oriented towards results that might respond to the parameters of academic rigour and the capacity for contextual analysis, as well as to considerations of experimentation and the creation of new languages, all the while reinforcing design’s innovative potential

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Extracellular matrix inspired gelatin/hyaluronic acid injectable hydrogels

[EN] Gelatin injectable hydrogels have attracted attention for soft tissues regeneration; however, their poor mechanical properties limit their applications. The authors present a versatile strategy to enhance mechanical properties by mixing gelatin (Gel) with different proportions of hyaluronic acid (HA). The protein-polysaccharide systems are inspired by extracellular matrix and benefit from adhesive properties of RGD sequences in Gel and enhanced hydration and stiffness of HA. The authors were able to raise the Young s modulus from 4kPa to 6kPa and gelation times can be tuned between 4 to 9 min, giving surgeons the option of adapting the material to specific requirements.The authors are grateful for the financial support received from the Spanish Ministry of Economy and Competitiveness through the MAT2013-46467-C4-1-R Project (including Feder funds) and the BES-2011-046144 grant. The CIBER-BBN initiative is funded by the VI National R&D&I Plan 2008-2011, "Iniciativa Ingenio 2010," Consolider Program. CIBER actions are financed by the "Instituto de Salud Carlos III" with assistance from the European Regional Development Fund.Sanmartín-Masiá, E.; Poveda-Reyes, S.; Gallego Ferrer, G. (2017). Extracellular matrix inspired gelatin/hyaluronic acid injectable hydrogels. International Journal of Polymeric Materials. 66(6):280-288. https://doi.org/10.1080/00914037.2016.1201828S280288666Hoffman, A. S. (2012). Hydrogels for biomedical applications. Advanced Drug Delivery Reviews, 64, 18-23. doi:10.1016/j.addr.2012.09.010Toh, W. S., & Loh, X. J. (2014). Advances in hydrogel delivery systems for tissue regeneration. Materials Science and Engineering: C, 45, 690-697. doi:10.1016/j.msec.2014.04.026Annabi, N., Tamayol, A., Uquillas, J. A., Akbari, M., Bertassoni, L. E., Cha, C., … Khademhosseini, A. (2013). 25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine. Advanced Materials, 26(1), 85-124. doi:10.1002/adma.201303233Levett, P. A., Melchels, F. P. W., Schrobback, K., Hutmacher, D. W., Malda, J., & Klein, T. J. (2013). Chondrocyte redifferentiation and construct mechanical property development in single-component photocrosslinkable hydrogels. Journal of Biomedical Materials Research Part A, 102(8), 2544-2553. doi:10.1002/jbm.a.34924Chopra, A., Lin, V., McCollough, A., Atzet, S., Prestwich, G. D., Wechsler, A. S., … Janmey, P. A. (2012). Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors. Journal of Biomechanics, 45(5), 824-831. doi:10.1016/j.jbiomech.2011.11.023Turner, W. S., Schmelzer, E., McClelland, R., Wauthier, E., Chen, W., & Reid, L. M. (2007). Human hepatoblast phenotype maintained by hyaluronan hydrogels. 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Injectable composites of loose microfibers and gelatin with improved interfacial interaction for soft tissue engineering. Polymer, 74, 224-234. doi:10.1016/j.polymer.2015.08.018Shin, H., Olsen, B. D., & Khademhosseini, A. (2012). The mechanical properties and cytotoxicity of cell-laden double-network hydrogels based on photocrosslinkable gelatin and gellan gum biomacromolecules. Biomaterials, 33(11), 3143-3152. doi:10.1016/j.biomaterials.2011.12.050Levett, P. A., Hutmacher, D. W., Malda, J., & Klein, T. J. (2014). Hyaluronic Acid Enhances the Mechanical Properties of Tissue-Engineered Cartilage Constructs. PLoS ONE, 9(12), e113216. doi:10.1371/journal.pone.0113216Levett, P. A., Melchels, F. P. W., Schrobback, K., Hutmacher, D. W., Malda, J., & Klein, T. J. (2014). A biomimetic extracellular matrix for cartilage tissue engineering centered on photocurable gelatin, hyaluronic acid and chondroitin sulfate. 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Extracellular matrix–inspired gelatin/hyaluronic acid injectable hydrogels

[EN] Gelatin injectable hydrogels have attracted attention for soft tissues regeneration; however, their poor mechanical properties limit their applications. The authors present a versatile strategy to enhance mechanical properties by mixing gelatin (Gel) with different proportions of hyaluronic acid (HA). The protein-polysaccharide systems are inspired by extracellular matrix and benefit from adhesive properties of RGD sequences in Gel and enhanced hydration and stiffness of HA. The authors were able to raise the Young s modulus from 4kPa to 6kPa and gelation times can be tuned between 4 to 9 min, giving surgeons the option of adapting the material to specific requirements.The authors are grateful for the financial support received from the Spanish Ministry of Economy and Competitiveness through the MAT2013-46467-C4-1-R Project (including Feder funds) and the BES-2011-046144 grant. The CIBER-BBN initiative is funded by the VI National R&D&I Plan 2008-2011, "Iniciativa Ingenio 2010," Consolider Program. CIBER actions are financed by the "Instituto de Salud Carlos III" with assistance from the European Regional Development Fund.Sanmartín-Masiá, E.; Poveda-Reyes, S.; Gallego Ferrer, G. (2017). Extracellular matrix inspired gelatin/hyaluronic acid injectable hydrogels. International Journal of Polymeric Materials. 66(6):280-288. https://doi.org/10.1080/00914037.2016.1201828280288666Hoffman, A. S. (2012). Hydrogels for biomedical applications. Advanced Drug Delivery Reviews, 64, 18-23. doi:10.1016/j.addr.2012.09.010Toh, W. S., & Loh, X. J. (2014). Advances in hydrogel delivery systems for tissue regeneration. Materials Science and Engineering: C, 45, 690-697. doi:10.1016/j.msec.2014.04.026Annabi, N., Tamayol, A., Uquillas, J. A., Akbari, M., Bertassoni, L. E., Cha, C., … Khademhosseini, A. 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Aliskiren prevents the toxic effects of peritoneal dialysis fluids during chronic dialysis in rats.

The benefits of long-term peritoneal dialysis (PD) in patients with end-stage renal failure are short-lived due to structural and functional changes in the peritoneal membrane. In this report, we provide evidence for the in vitro and in vivo participation of the renin-angiotensin-aldosterone system (RAAS) in the signaling pathway leading to peritoneal fibrosis during PD. Exposure to high-glucose PD fluids (PDFs) increases damage and fibrosis markers in both isolated rat peritoneal mesothelial cells and in the peritoneum of rats after chronic dialysis. In both cases, the addition of the RAAS inhibitor aliskiren markedly improved damage and fibrosis markers, and prevented functional modifications in the peritoneal transport, as measured by the peritoneal equilibrium test. These data suggest that inhibition of the RAAS may be a novel way to improve the efficacy of PD by preventing inflammation and fibrosis following peritoneal exposure to high-glucose PDFs