Reverse-selective polymer-ionic liquid membranes for light paraffin gas separations

Natural gas plays a major role as both a relatively clean-burning fossil fuel and a precursor to hydrogen, ethylene, and numerous chemical commodities. With advancements in horizontal drilling and hydraulic fracturing, abundant shale resources are a growing piece of the global energy transition puzzle. Shale gas is richer in C₂₊ hydrocarbons than conventional natural gas which presents challenges and opportunities to centralized gas processing infrastructure. Membranes offer an energy efficient alternative separation technology for fractionating the light C₂₊ hydrocarbons at modular scales. Reverse-selective membranes may offer an economic advantage given their typically high productivities. Reverse-selective polymers, much like ionic liquids and other solvents, discriminate between gas molecules based primarily on solubility differences. Unlike traditional solvents, however, ionic liquids are negligibly volatile and can be combined with polymers into stable membrane platforms, albeit with lesser understood transport properties. In this thesis, a comprehensive study of the light paraffin gas transport properties of 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, or [hmim][Tf₂N], ionic liquid supported in poly(1-trimethylsilyl-1-propyne), or PTMSP, membranes is presented, along with preliminary work on some alternative polymer-ionic liquid combinations. The thermal, mechanical, and swelling properties of these supported ionic liquid membranes (SILMs) were initially characterized for various ionic liquid loadings. The pure-gas permeation, sorption, and diffusion properties of SILMs were then determined and compared with those of the neat parent materials. While prior work on SILMs for gas separations is widespread, few studies focus on light paraffin separations, and fewer still evaluate mixed-gas transport properties or pronounced plasticizing effects of the polymer support on the gas transport properties. A mixed-gas permeation system was built and validated to probe the more industrially relevant mixture properties. Unlike in the neat PTMSP, pronounced permeability increases with rising C₂₊ activities were noted in SILMs. A plasticization model was fit to the diffusion data of the three lightest paraffin gases to better understand the impact of ionic liquid content on plasticization. With increasing ionic liquid content, a clear transition in the C₂₊ sorption behavior was observed from a rigid, open glass (dual-mode) to a dense, softer material (Flory-Huggins). A new hybrid model was proposed to fit sorption isotherms in all regimes of this transition. Lastly, an atypical volume expansion behavior was observed in preliminary SILM dilation studies and an optical transition matching the inflection in the C₂₊ sorption isotherms and permeability curves was identifiedChemical Engineerin

Gestión y administración de los espacios públicos por parte de las municipalidades a través del plan de desarrollo urbano : caso riberas de los ríos en el departamento de Lambayeque

Esta investigación aborda el estudio del análisis del sistema urbano y su vulnerabilidad ante riesgos de desastres: caso riberas de los ríos en el departamento de Lambayeque, así como los espacios públicos, plan de desarrollo urbano, plan de incentivos municipales, a través del cual se busca mejorar la gestión municipal y en el cual se pretende como propuesta la inserción del plan de desarrollo urbano para incentivar su elaboración en las autoridades ediles del departamento de Lambayeque. El desorden urbano con que crecen las capitales de las tres provincias de la región Lambayeque, es a consecuencia de la falta de interés de las autoridades y funcionarios ediles, para ejecutar su gestión conforme a los planes de desarrollo urbano, el cual es un documento técnico donde se plasma la planificación urbana ordenada y sostenida de una ciudad. Allí se proponen estrategias que se discuten entre las autoridades locales y la sociedad civil. El problema central es la posesión de la población en lugares como las riberas de los ríos en busca de un lugar donde vivir, sin embargo ello hace que dicha población se encuentre vulnerable ante los desastres naturales como sucedió con el caso del fenómeno de las lluvias del niño costero. Por lo que al ser espacio público dichas riberas, se deberían de enmarcar en el plan de desarrollo urbano como fin preventivo. En conclusión, si se comprende el plan de desarrollo urbano a la ley N° 29332 Ley que crea el plan de incentivos a la mejora de la gestión municipal, como mecanismo de gestión y administración de los espacios públicos con el fin de incentivar la ejecución de los planes de desarrollo urbano por parte de las municipalidades, entonces se podrá mitigar la vulnerabilidad de las poblaciones ubicadas en las riberas de los ríos ante riesgos de desastres en el departamento de Lambayeque

Epothilone-d rescues cognition and attenuates alzheimer’s disease-like pathology in APP/PS1 mice

AIMS: Cognitive decline in Alzheimer's disease (AD) patients has been linked to synaptic damage and neuronal loss. Hyperphosphorylation of tau protein destabilizes microtubules leading to the accumulation of autophagy/vesicular material and the generation of dystrophic neurites, thus contributing to axonal/synaptic dysfunction. In this study, we analyzed the effect of a microtubule-stabilizing compound in the progression of the disease in the hippocampus of APP751SL/PS1M146L transgenic model. METHODS: APP/PS1 mice (3 month-old) were treated with a weekly intraperitoneal injection of 2 mg/kg epothilone-D (Epo-D) for 3 months. Vehicle-injected animals were used as controls. Mice were tested on the Morris water maze, Y-maze and object-recognition tasks for memory performance. Abeta, AT8, ubiquitin and synaptic markers levels were analyzed by Western-blots. Hippocampal plaque, synaptic and dystrophic loadings were quantified by image analysis after immunohistochemical stainings. RESULTS: Epo-D treated mice exhibited a significant improvement in the memory tests compared to controls. The rescue of cognitive deficits was associated to a significant reduction in the AD-like hippocampal pathology. Levels of Abeta, APP and ubiquitin were significantly reduced in treated animals. This was paralleled by a decrease in the amyloid burden, and more importantly, in the plaque-associated axonal dystrophy pathology. Finally, synaptic levels were significantly restored in treated animals compared to controls. CONCLUSION: Epo-D treatment promotes synaptic and spatial memory recovery, reduces the accumulation of extracellular Abeta and the associated neuritic pathology in the hippocampus of APP/PS1 model. Therefore, microtubule stabilizing drugs could be considered therapeutical candidates to slow down AD progression. Supported by FIS-PI12/01431 and PI15/00796 (AG),FIS-PI12/01439 and PI15/00957(JV)Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

In vitro modeling of dysfunctional glial cells in neurodegenerative diseases using human pluripotent stem cells

Most neurodegenerative diseases are characterized by a complex and mostly still unresolved pathology. This fact, together with the lack of reliable models, have precluded the development of effective therapies counteracting the disease progression. In the past few years, several studies have evidenced that lack of proper functionality of glial cells (astrocytes, microglia and oligodendrocytes) has a key role in the pathology of several neurodegenerative conditions including Alzheimer´s disease, amyotrophic lateral sclerosis and multiple sclerosis among others. However, this glial dysfunction is poorly modelled by available animal models, and we hypothesize that patientderived cells can serve as a better platform where to study this glial dysfunction. In this sense, human pluripotent stem cells (hPSCs) has revolutionized the field allowing the generation of disease-relevant neural cell types that can be used for disease modelling, drug screening and, possibly, cell transplantation purposes. In the case of the generation of oligodendrocytes (OLs) from hPSCs, we have developed a fast and robust protocol to generate surface antigen O4-positive (O4+) and myelin basic protein-positive OLs from hPSCs in only 22 days, including from patients with multiple sclerosis or amyotrophic lateral sclerosis. The generated cells resemble primary human OLs at the transcriptome level and can myelinate neurons in vivo. Using in vitro OLneuron co-cultures, effective myelination of neurons can also be demonstrated. This platform is being translated as well to the generation of the other glial cell types, allowing the derivation of patient-specific glial cells where to model disease-specific dysfunction. This methodology can be used for elucidating pathogenic pathways associated with neurodegeneration and to identify therapeutic targets susceptible of drug modulation, contributing to the development of novel and effective drugs for these devastating disorders.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by PI18/01557 (to AG) and P18/1556 (to JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and PI-0276-2018 grant (to JAGL) from Consejeria de Salud of Junta de Andalucia. JAGL held a postdoctoral contract from the I Research Plan Propio of the University of Malaga. CV and KE were supported by IWT-SBO-150031-iPSCAF and the Thierry Lathran Foundation grant – ALS-OL, and KN by FWO1166518

SYSTEMIC ADMINISTRATION OF EPOTHYLONE-D RECUES MEMORY AND AMELIORATES ALZHEIMER’S DISEASE-LIKE PATHOLOGY IN APP/PS1 MICE

Aims Cognitive and memory decline in Alzheimer's disease (AD) patients is highly related to synaptic dysfunction and neuronal loss. Tau hyperphosphorylation destabilizes microtubules leading to axonal transport failure, accumulation of autophagy/vesicular material and the generation of dystrophic neurites, thus contributing to axonal/synaptic dysfunction. In this study, we analyzed the effect of a microtubule-stabilizing drug in the progression of the disease in an APP751SL/PS1M146L transgenic model. Method APP/PS1 mice (3 month-old) were weekly treated with 2 mg/kg intraperitoneal injections of Epothilone-D (Epo-D) for 3 months. Vehicle-injected animals were used as controls. For memory performance, animals were tested on the object-recognition tasks, Y-maze and Morris water maze. Levels of Abeta, ubiquitin, AT8 and synaptic markers were analyzed by Western-blot. Hippocampal plaque burden, dystrophic and synaptic loadings were quantified after immunostaining by image analysis. Results Epo-D treated mice showed a significant improvement in the performance of hippocampus-associated cognitive tests compared to controls. This memory recovery correlated with a significant reduction in the AD-like hippocampal pathology. Abeta, APP and ubiquitin levels were significantly reduced in treated animals, and a decrease in both the plaque loading and the axonal pathology was also found. Finally, synaptic levels were significantly preserved in treated animals in comparison with controls. Conclusion Epo-D treatment promotes synaptic and cognitive improvement, reduces the accumulation of extracellular Abeta and the associated neuritic pathology in the hippocampus of APP/PS1 model. Therefore, microtubule stabilizing drugs could be considered therapeutical candidates to slow down AD progression.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by FIS-PI15/00796 (AG), FIS-PI15/00957(JV) and co-financed by FEDER funds from European Union

Coexistance of different damage-associated myeloid populations in the hippocampus of Alzheimer's patients

Parenchymal microglia are the brain-resident immune cells capable of responding to damage. Though the role of microglial cells in the development/progression of AD is still unknown, a dysfunctional response has recently gained support since the identification of genetic risk factors related to microglial. In this sense, we reported an attenuated microglial activation in the hippocampus of AD patients, including a degenerative process of the microglial population in the dentate gyrus. On the other hand, it is also known that others myeloid components could also be involved in the neurodegenerative process. However, the implication of the diverse immune cells in the human pathology have not been determined yet. In this work, we analyzed the phenotypic profile displayed by damage-associated myeloid cells in the hippocampus of AD brains. For this purpose, immunohistochemistry and image analysis approaches have been carried out in non-demented controls and AD cases. Damage-associated myeloid cells from Braak II and Braak VI individuals were clustered around amyloid plaques and expressed Iba1, TMEM119, CD68, Trem2 and CD45high. A subset of these cells also expressed ferritin. However, and even though some Braak II individuals accumulated CD45-positive plaques, only AD patients exhibited parenchymal infiltration of CD163-positive cells, along with a decrease of the resident microglial marker TMEM119. Moreover, a negative correlation was observed between CD163 and TMEM119 intensities in Braak VI patients, showing a functional cooperation among these different myeloid populations. Taken together, these findings suggest the existence of different populations of amyloid-associated myeloid cells in the hippocampus during disease progression. The differential contribution of these myeloid populations to the pathogenesis remains to be elucidated. The dynamic of the myeloid molecular phenotypes associated to AD pathology needs to be considered for guarantee clinical success.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglial response differences between amyloidogenic transgenic models and Alzheimer’s disease patients

Aims: The continuing failure to develop an effective treatment for Alzheimer’s disease (AD) reveals the complexity for AD pathology. Increasing evidence indicates that neuroinflammation involving particularly microglial cells contributes to disease pathogenesis. Here we analyze the differences in the microglial response between APP/PS1 model and human brains. Methods: RT-PCR, western blots, and immunostaining were performed in the hippocampus of human post mortem samples (from Braak II to Braak V-VI) and APP751SL/PS1M146L mice. In vitro studies to check the effect of S1 fractions on microglial cells were assayed. Results: In APP based models the high Abeta accumulation triggers a prominent microglial response. On the contrary, the microglial response detected in human samples is, at least, partial or really mild. This patent difference could simple reflect the lower and probably slower Abeta production observed in human hippocampal samples, in comparison with models or could reflect the consequence of a chronic long-standing microglial activation. However, beside this differential response, we also observed a prominent microglial degenerative process in Braak V-VI samples that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus of the hippocampal formation, might be mediated by the accumulation of toxic soluble phospho-tau species. Conclusions: These differences need to be considered when delineating animal models that better integrate the complexity of AD pathology and, therefore, guarantee clinical translation. Correcting dysregulated brain inflammatory responses might be a promising avenue to restore cognitive function. Supported by grants FIS PI15/00796 and FIS PI15/00957 co-financed by FEDER funds from European Union, and by Junta de Andalucia Proyecto de Excelencia CTS385 2035.Financiado por FIS PI15/00796 y FIS PI15/0095, cofinanciado por los fondos FEDER de la Unión Europea, y por Junta de Andalucia Proyecto de Excelencia CTS385 2035. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglial responses in the human Alzheimer’s disease frontal cortex

The continuing failure to develop an effective treatment for Alzheimer’s disease (AD) reveals the complexity for this pathology. Increasing evidence indicates that neuroinflammation involving particularly microglial cells contributes to AD pathogenesis. The actual view, based on the findings in APP based models, gives a cytotoxic/proinflammatory role to activated microglia. However, we have previously reported a limited activation and microglial degeneration in the hippocampus of AD patients in contrast with that observed in amyloidogenic models. Here, we evaluated the microglial response in a different region of AD brains, the frontal cortex. Post mortem tissue from controls (Braak 0-II) and AD patients (Braak V-VI) including familial cases, were obtained from Spain Neurological Tissue Banks. Cellular (immunohistochemistry and image analysis) and molecular (qPCR and western blots) approaches were performed. Frontal cortex of AD patients (Braak V-VI) showed strong microglial activation similar to that observed in amyloidogenic mice. These strongly activated microglial cells, predominantly located surrounding amyloid plaques, could drive the AD pathology and, in consequence, could be implicated in the pathology progression. Furthermore, different microglial responses were observed between sporadic and familial AD cases. These findings in the frontal cortex were highly in contrast to the attenuated activation and degenerative morphology displayed by microglial cells in the hippocampus of AD patients. Regional differences in the microglial response suggest different functional states of microglial cells in a region-specific manner. All together, these data provide a better understanding of the immunological mechanisms underlying AD progression and uncover new potential therapeutic targets to fight this devastating neurodegenerative disease.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Unio

Resistance Curves in the Tensile and Compressive Longitudinal Failure of Composites

This paper presents a new methodology to measure the crack resistance curves associated with fiber-dominated failure modes in polymer-matrix composites. These crack resistance curves not only characterize the fracture toughness of the material, but are also the basis for the identification of the parameters of the softening laws used in the analytical and numerical simulation of fracture in composite materials. The method proposed is based on the identification of the crack tip location by the use of Digital Image Correlation and the calculation of the J-integral directly from the test data using a simple expression derived for cross-ply composite laminates. It is shown that the results obtained using the proposed methodology yield crack resistance curves similar to those obtained using FEM-based methods in compact tension carbon-epoxy specimens. However, it is also shown that the Digital Image Correlation based technique can be used to extract crack resistance curves in compact compression tests for which FEM-based techniques are inadequate

Decoding damage-associated microglia in post mortem hippocampus of Alzheimer’s disease patients

The relationship between Alzheimer’s disease (AD) and neuroinflammation has become stronger since the identification of several genetic risk factors related to microglial function. Though the role of microglial cells in the development/progression of AD is still unknown, a dysfunctional response has recently gained support. In this sense, we have reported an attenuated microglial activation associated to amyloid plaques in the hippocampus of AD patients, including a prominent degenerative process of the microglial population in the dentate gyrus, which was in contrast to the exacerbated microglial response in amyloidogenic models. This microglial degeneration could compromise their normal role of surveying the brain environment and respond to the damage. Here, we have further analyzed the phenotypic profile displayed by the damage-associated microglial cells by immunostaining and qPCR in the hippocampus of postmortem samples of AD patients (Braak V-VI) and control cases (Braak 0-II). Damage-associated microglial cells of Braak V-VI individuals were clustered around amyloid plaques and expressed Iba1, CD68, Trem2, TMEM119 and CD45high. A subset of these cells also expressed ferritin. On the contrary, these microglia down-regulated homeostatic markers, such as Cx3cr1 and P2ry12. The homeostatic and ramified microglial cells of non-demented Braak II cases were characterized by Iba1, CX3CR1, P2ry12, TMEM119 and CD45low expression. The dynamic of the microglial molecular phenotypes associated to AD pathology needs to be considered for better understand the disease complexity and, therefore, guarantee clinical success. Correcting dysregulated brain inflammatory responses might be a promising avenue to prevent/slow cognitive decline.Universidad de Málaga. Campus de excelencia Internacional-Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union