307 research outputs found
The Total Fiscal Cost of Indirect Taxation: an Approximation Using Catalonia's Recent Input-output Table
Get PDFIn this note we quantify to what extent indirect taxation influences and distorts prices. To do so we use the networked accounting structure of the most recent input-output table of Catalonia, an autonomous region of Spain, to model price formation. The role of indirect taxation is considered both from a classical value perspective and a more neoclassical flavoured one. We show that they would yield equivalent results under some basic premises. The neoclassical perspective, however, offers a bit more flexibility to distinguish among different tax figures and hence provide a clearer disaggregate picture of how an indirect tax ends up affecting, and by how much, the cost structure.tax load, fiscal cost, indirect taxation decomposition
USP7 controls NGN3 stability and pancreatic endocrine lineage development
No full textUnderstanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited
Produção de recursos educacionais abertos com foco na disseminação do conhecimento: uma proposta de framework
Get PDFTese (doutorado) - Universidade Federal da Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia e Gestão do Conhecimento, Florianópolis, 2015.O movimento openness trata o conhecimento como um bem público, e os Recursos Educacionais Abertos (REAs), por sua vez, têm a intenção de promover a qualidade do ensino e levar a inovação para dentro do sistema educacional através de recursos disponibilizados abertamente, sob uma licença de uso. Uma análise da literatura sobre REA revelou não a falta, mas a dificuldade que os produtores de conteúdo têm para localizar os recursos desejados. Isto acontece pela carência de repositórios apropriados e/ou pela falta de padronização dos materiais por aqueles que os produzem. Neste sentido, esta tese tem o objetivo de elaborar e verificar um framework para a produção de REAs com foco na disseminação do conhecimento. Após uma busca sistemática da literatura, constitui-se um ciclo para a produção, composto pelas fases de análise e design, codificação, uso e avaliação, e publicação. Com base nos fatores de sucesso para a disseminação do conhecimento e confrontando-os com a literatura pesquisada sobre REA, chegou-se à proposição de um conjunto de requisitos para a produção de REAs com foco na disseminação do conhecimento, na forma de questões e objetivos. Esses requisitos foram verificados por um grupo de 16 especialistas, e as considerações foram analisadas e incorporadas ao framework. Posteriormente, houve o refinamento do texto das questões e dos objetivos com o auxílio de quatro não especialistas na temática REAs que analisaram a clareza e coerência destes, e novamente o framework sofreu ajustes. Por fim, o framework foi aplicado na prática com a produção de videoaulas por uma equipe interdisciplinar e foram realizadas as últimas adequações. Como principal resultado deste estudo tem-se um framework para a produção de REAs de modo a promover a disseminação do conhecimento. Além disso, três videoaulas que oferecem orientações para quem deseja fazer o caminho de Santiago de Compostela estão disponíveis na rede, demonstrando, assim, a ocorrência da disseminação do conhecimento. Produzir materiais respeitando as questões éticas e legais não é uma tarefa simples. Contar com um guia (meio) na produção de REAs possibilitará que novos materiais sejam reutilizados, revisados e recontextualizados, viabilizando a melhoria na qualidade dos materiais educacionais e provocando maior disseminação do conhecimento.Abstract : The openness movement treats knowledge as public good and open educational resources (OER), however, it has has the intention to promote quality and innovation into the educational system through resources made available openly, under a use license. An analysis of the literature on OER revealed no lack, but the difficulty that content producers have to locate the desired resources. It happens due to the lack of suitable repositories or/and by the lack of standardization for those who produce the materials. In this sense, this thesis aims to elaborate and verify a framework for the production of OER focusing on dissemination of knowledge. After a systematic search of the literature, it constitutes a cycle for producing OER that comprise the phases of analysis and design, coding, use and evaluation and publication. Based on success factors for the dissemination of knowledge and confronting them with the literature about OER, we propose a set of requirements for the production of OER focusing on dissemination of knowledge, in the form of questions and objectives. These requirements have been checked by a group of 16 experts and considerations examined and incorporated into the framework. Later, there was the refinement of the text of the questions and goals with the help of 4 non-specialists in this area that analyzed the clarity and consistency of these, and again the framework was adjusted. Finally, the framework was applied in practice with the production of video classes by an interdisciplinary team and the last adjustments occurred. The main result of this study has been a framework for producing OER in order to promote the dissemination of knowledge. In addition, three video classes giving tips for those who want to walk through the Camino de Santiago de Compostela, are available at the Internet and thus proving the occurrence of dissemination of knowledge. Producing materials respecting the ethical and legal issues is not a simple task. Counting on a guide for producing OER will enable new materials to be reused, reviewed and re-contextualized, making the improvement in quality possible and causing greater dissemination of knowledge
Rocio gemmata Schmitter-Soto, 2007, new species
No full textRocio gemmata Contreras-Balderas & Schmitter-Soto, new species Figures 22, 26 Archocentrus aff. octofasciatus, Schmitter-Soto 1998: 156 (preliminary detection). Holotype. ECOCH 4054, 64 mm SL (Fig. 26), the author, Jun. 11, 1999. Nameless cenote 12 km N of Leona Vicario, Quintana Roo, Mexico. Paratypes. ECOCH 1468, 3145, collected at the same karstic sinkhole by the author and H. C. Gamboa-Perez, and UANL 15046 (4), collected at Laguna Leona Vicario by S. Contreras-Balderas, co-discoverer of the species. Diagnosis. Unique autapomorphies (fig 14e in Schmitter-Soto, in press): spots on sides, larger than scales and not clearly aligned (vs. smaller than scales and rather well-aligned); stripe from snout to eye interrupted (vs. continuous); quadrate bone with a spine (vs. without a spine). In addition, maxilla reaching both a vertical and a horizontal line from orbit (vs. just to the ventral rim); cheek-scale rows modally 7 (vs. 6 or fewer); interradial scales on dorsal fin in one row (vs. distally in two rows); dorsal and anal fins not bearing filaments (vs. bearing filaments); anal and medial gut-loops not adjacent, well separated by the stomach and the liver (vs. always adjacent); rostral end of maxilla notched or at least concave (vs. convex, with no notch); caudal ocellus blue in life (vs. white). Description. D. XVIII,9-10; A. VIII -IX,7-8; pectoral 15-16. Gill rakers trapezoidal, bifid in larger specimens, their posterior ridge serrated. Scale rows on cheek 7; predorsal scales 14-15; pored lateral-line scales (not counting scales overlapping between the two segments of the lateral line) 28-30; scales from lateral line to origin of dorsal fin 4-4.5; scales from lateral line to base of first dorsal-fin ray 3.5 (further meristic data appear in Table 3). The smallest species of the genus Rocio; largest specimen examined, 70 mm SL. Body depth 41-46% of SL. Head length 35-41% of SL; orbital diameter 25-30% of head length (further morphometric data appear in Table 4). Head profile convex, straight above orbits. Lower lip at corner of mouth slightly curved downward, tapering. Pectoral fins often falling short of first anal-fin spine, pelvic fins always reaching at least first anal-fin spine. Dorsal and anal fins not bearing filaments. Just one row, up to 4 scales long, of interradial scales on both dorsal and anal fin rays. Gut simple, anal and anterior esophageal loops not adjacent; gut length may be greater than standard length; distance from last loop in gut to esophagus always less than 16% gut length. Genital papilla rounded, may be smaller than creased area of anus; pigmented only on base. Suborbital streak wide, blunt-ended (usually not visible in preserved specimens). Stripe from snout to eye diffuse, rather a darkening at rim of orbit. Large, iridescent, metallic green-blue speckles on cheek in life, turning blackish in ethanol. Eyes bronze-bluish. Bars on sides sometimes doubled medially; lateral blotch oval, sometimes ocellated. About six unordered rows of spots on sides, larger than scales; breast bronzeblackish with green-blue tinge in life. Dots on fins large, dark blue. Axil of pectoral fin with a dorsal spot; base of pectoral fin whitish. Distribution. Endemic to cenotes and small inland lakes in northern Quintana Roo, eastern Yucatan Peninsula, Mexico (Fig. 22). Etymology. Latin gemmata, meaning “bejeweled,” in reference to the large, bright green and blue cheek and opercle spots in life. An adjective. Remarks. The authorship of this species is joint with S. Contreras-Balderas, who independently collected and recognized it as distinct.Published as part of Juan J. Schmitter-Soto, 2007, A systematic revision of the genus Archocentrus (Perciformes: Cichlidae), with the description of two new genera and six new species., pp. 1-78 in Zootaxa 1603 on pages 61-6
The fifth commandment and other short stories by Rocio Qespi
No full textRocío Qespi is a Peruvian author who writes short stories that center around the themes of love, chess, and personal experiences. Her prose is a rich tapestry of allusions to the work of other Latin American authors and artists as well as a reference to events from her own life. As her translator, I had the opportunity to work closely with the author as I resolved problems encountered during the process of translating her prose. Following a brief introduction that describes these problems and their solutions, is a selection of the translated stories taken from the collection El cuarto mandamiento, which has been published by Mundo Ajeno in Peru.M.A.Includes bibliographical references (p. 91-94)
“El Rocio” de las mujeres. Una visión de algunas de las artistas de los carteles de la fiesta.
No full textThe pilgrimage of "El Rocio" in Almonte, Huelva, has acquired an important role in
the national scene, as it is an event that brings together thousands of people from different
social, economic, etc. positions. The advertising poster is a way to promote this party but
at the same time it promotes artists from all peoples, as it is a means of publicizing the
personal work of each of these artists. Women, as in other aspects of art in general, have
gone from being represented on these posters to being the author of many of them, but
sometimes they continue to appear on the public scene in the background, hence the
importance of this article and the opportunity to hear from their own voice their opinions.La romería de “ El Rocio” en Almonte, Huelva, ha adquirido un papel importante en
la escena nacional, en cuanto a que se trata de un evento que aglutina miles de personas
de distintas posiciones sociales, económicas, etc. El cartel publicitario es un modo de
promocionar dicha fiesta pero al mismo tiempo se promociona artistas de todos los
pueblos, ya que es un medio de publicitar el trabajo personal de cada uno de estos
artistas. La mujer, al igual que en otros aspectos del arte en general, ha pasado de ser
representada en dichos carteles a ser la autora de muchos de ellos, pero a veces siguen
apareciendo en la escena publica en un segundo plano, de ahí la importancia de este
artículo y la oportunidad de oír de la voz propia de dichas artistas sus opiniones
Hyperglycemia-induced thioredoxin reductase degradation accelerates ferroptotic cell death propagation in diabetic renal tubules
No full textDiabetes mellitus and its complications stands as arguably the most formidable pandemic of the 21st century. While rodent models of diabetes mellitus have been extensively explored, none have managed to faithfully replicate the full spectrum of pathological hallmarks and secondary complications witnessed in diabetic patients. Among the commonly affected organs is the kidney, manifesting in the form of diabetic kidney disease (DKD). Recently, our clinical understanding of incretins as critical regulators of disease progression in diabetic patients including DKD has undergone significant expansion.
In particular, the incretin hormone gastric inhibitory polypeptide (GIP) axis has taken central stage. A ground-breaking development in this realm was the creation of a GIP receptor dominant negative (GIPRdn) mouse, exhibiting all the characteristic features observed in DKD patients. This study sheds light on the heightened susceptibility of these mice to lethal acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI). Notably, isolated renal GIPRdn-tubules displayed accelerated cell death propagation and increased tubular necrosis. Expanding on previous cell culture experiments involving hyperglycemia, it became apparent that tubules of GIPRdn mice express elevated levels of the intracellular thioredoxin interacting protein (TXNIP), previously reported to be responsible for the degradation of glucose transporter 1 (GLUT1). This phenomenon is crucial in maintaining intracellular glucose homeostasis. The study further indicates an association between TXNIP and the downregulation of thioredoxin reductase 1 (TXNRD1), a selenoenzyme playing a pivotal role in protecting renal tubules from ferroptosis in a glutathione-independent manner. Intriguingly, the inhibition of TXNRD1 with the small molecule ferroptocide (FTC) in GIPRdn tubules resulted in severe tubular necrosis, a condition effectively reversed by the ferroptosis inhibitor ferrostatin 1 (Fer-1). This nuanced exploration establishes a connection between DKD and a heightened sensitivity to kidney tubular ferroptosis, thereby presenting a potential avenue for intervention with ferrostatins. Importantly, the administration of a single dose of Fer-1 significantly prolonged the survival of GIPRdn mice following IRI. In conclusion, this study illuminates the intricate dynamics of DKD, highlighting a pronounced sensitization to kidney tubular ferroptosis. The findings suggest that ferrostatins, particularly exemplified by Fer-1, hold promise as potential therapeutic agents in mitigating the severity of this condition, offering hope for improved outcomes in individuals struggling with diabetes-related kidney complications.:Acknowledgments
Abstract
Zusammenfassung
List of abbreviations
List of tables
List of Figures
1. Introduction
1.1. Diabetes mellitus
1.1.1. Definition and description
1.1.2. Epidemiology
1.1.3. Classification of diabetes mellitus
1.1.4. Diagnosis of diabetes mellitus
1.1.5. Type 2 Diabetes Mellitus
1.1.6. Long-term complications of T2DM
1.1.6.1. Diabetic Nephropathy
1.1.6.2. Therapies for diabetic nephropathy
1.1.7. Animal models for diabetic kidney disease
1.1.7.1. Diabetic eNOS knockout mouse
1.1.7.2. Bradykinin B2 Receptor (B2R) deficient Ins2Akita/+ mouse
1.1.7.3. Decorin-deficient streptozotocin diabetic mouse
1.1.7.4. NONcNZO mouse
1.1.7.5. OVE26 mouse
1.1.7.6. Black and tan, brachyuric (BTBR) ob/ob mouse
1.1.8. Incretin hormones and GIPRdn diabetic mouse model
1.1.8.1. Generation of GIPRdn diabetic mouse model
1.2. Regulated cell death
1.3. Ferroptosis
1.3.1 Mechanism of ferroptosis
1.3.1.1 Sensitization to ferroptosis by ether phospholipids
1.3.1.2 Hydropersulfides and ferroptosis
1.3.2 Ferroptosis inducers (FINs) and inhibitors
1.3.3 Ferroptosis in the kidney
1.4 Aims
2. Materials and Methods
2.1. Reagents
2.2. Experimental models: cell lines and mouse strains
2.2.1. Cell culture conditions
2.2.2. Mice
2.2.2.1. Genotyping
2.2.2.1.1. DNA isolation
2.2.2.1.2. Polymerase Chain Reaction (PCR)
2.2.2.1.3. Gel electrophoresis
2.2.2.2. Body weight
2.2.2.3. Blood glucose
2.2.2.4. Blood collection and serum parameters
2.2.3. Isolation of primary murine renal tubules
2.2.4. Generation of a 3D-printed double chamber
2.3. Experimental procedures
2.3.1. Plating and treatment of cells
2.3.2. Fluorescence activated cell sorting (FACS)
2.3.3. Western Blotting (WB)
2.3.4. Induction of cell death on isolated murine tubules
2.3.5. LDH release assay
2.3.6. Evaluation of speed of cell death propagation (exponential plateau – growth equation)
2.3.7. Time lapse imaging and processing of the time lapse data
2.3.8. Fluorescence Lifetime Imaging Microscopy (FLIM)
2.3.8.1. Time domain data analysis
2.3.8.2. FLIM time lapse video generation
2.3.9. Thioredoxin Reductase Activity assay
2.3.10. Bilateral kidney Ischemia and Reperfusion injury (IRI)
2.3.11. Immunohistology and semi-quantitative scoring
2.3.12. Measurements of sulfur-containing metabolites by ultra-performance liquid
chromatography-mass spectroscopy (LC-MS)
2.4. Statistical analysis
3. Results
3.1. Characterization of diabetic kidney disease in GIPRdn mice
3.1.1. Blood glucose
viii
3.1.2. Body weight
3.1.3. Serum parameters
3.1.4. Histological analysis of the kidneys
3.2. The spontaneous death of GIPRdn tubules is characterized by a non-random
pattern of necrotic cell death
3.3. GIPRdn tubules are more prone to undergo spontaneous death compared to
WT tubules
3.4. Spontaneous necrosis of GIPRdn and WT tubules is partially mediated by
ferroptosis
3.5. GIPRdn tubules show downregulation of the PRX pathway compared to the
non-diabetic tubules
3.6. GIPRdn tubules show altered hydropersulfides pathway
3.7. GIPRdn tubules show altered etherglycerophospholipids (etherPLs) pathway.
3.8. Ferrostatin-1 but not Empagliflozin reverses ferroptosis induction in
different cell lines as well as in isolated kidney tubules
3.9. GIPRdn mice are more sensitive to IRI-induced acute kidney injury compared
to their WT littermates
3.10. Ferrostatin-1 ameliorates the sensitivity of GIPRdn to ischemia reperfusion
injury-induced acute kidney injury
4. Discussion
4.1. The GIPRdn mouse model
4.2 Ferroptosis in diabetic nephropathy
4.2.1. Ferroptotic cell death is involved in the spontaneous death of diabetic tubules
4.2.2. Possible mechanisms behind the enhanced sensitivity of the GIPRdn kidney tubules to
ferroptosis
4.3. Therapeutic consequences of the study
4.3.1. SGLT2 inhibitor empagliflozin does not have a protective effect on diabetic tubules
undergoing spontaneous death
4.4. Outlook and limitations of the study
Reference
Hyperglycemia-induced thioredoxin reductase degradation accelerates ferroptotic cell death propagation in diabetic renal tubules
Get PDFDiabetes mellitus and its complications stands as arguably the most formidable pandemic of the 21st century. While rodent models of diabetes mellitus have been extensively explored, none have managed to faithfully replicate the full spectrum of pathological hallmarks and secondary complications witnessed in diabetic patients. Among the commonly affected organs is the kidney, manifesting in the form of diabetic kidney disease (DKD). Recently, our clinical understanding of incretins as critical regulators of disease progression in diabetic patients including DKD has undergone significant expansion.
In particular, the incretin hormone gastric inhibitory polypeptide (GIP) axis has taken central stage. A ground-breaking development in this realm was the creation of a GIP receptor dominant negative (GIPRdn) mouse, exhibiting all the characteristic features observed in DKD patients. This study sheds light on the heightened susceptibility of these mice to lethal acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI). Notably, isolated renal GIPRdn-tubules displayed accelerated cell death propagation and increased tubular necrosis. Expanding on previous cell culture experiments involving hyperglycemia, it became apparent that tubules of GIPRdn mice express elevated levels of the intracellular thioredoxin interacting protein (TXNIP), previously reported to be responsible for the degradation of glucose transporter 1 (GLUT1). This phenomenon is crucial in maintaining intracellular glucose homeostasis. The study further indicates an association between TXNIP and the downregulation of thioredoxin reductase 1 (TXNRD1), a selenoenzyme playing a pivotal role in protecting renal tubules from ferroptosis in a glutathione-independent manner. Intriguingly, the inhibition of TXNRD1 with the small molecule ferroptocide (FTC) in GIPRdn tubules resulted in severe tubular necrosis, a condition effectively reversed by the ferroptosis inhibitor ferrostatin 1 (Fer-1). This nuanced exploration establishes a connection between DKD and a heightened sensitivity to kidney tubular ferroptosis, thereby presenting a potential avenue for intervention with ferrostatins. Importantly, the administration of a single dose of Fer-1 significantly prolonged the survival of GIPRdn mice following IRI. In conclusion, this study illuminates the intricate dynamics of DKD, highlighting a pronounced sensitization to kidney tubular ferroptosis. The findings suggest that ferrostatins, particularly exemplified by Fer-1, hold promise as potential therapeutic agents in mitigating the severity of this condition, offering hope for improved outcomes in individuals struggling with diabetes-related kidney complications.:Acknowledgments
Abstract
Zusammenfassung
List of abbreviations
List of tables
List of Figures
1. Introduction
1.1. Diabetes mellitus
1.1.1. Definition and description
1.1.2. Epidemiology
1.1.3. Classification of diabetes mellitus
1.1.4. Diagnosis of diabetes mellitus
1.1.5. Type 2 Diabetes Mellitus
1.1.6. Long-term complications of T2DM
1.1.6.1. Diabetic Nephropathy
1.1.6.2. Therapies for diabetic nephropathy
1.1.7. Animal models for diabetic kidney disease
1.1.7.1. Diabetic eNOS knockout mouse
1.1.7.2. Bradykinin B2 Receptor (B2R) deficient Ins2Akita/+ mouse
1.1.7.3. Decorin-deficient streptozotocin diabetic mouse
1.1.7.4. NONcNZO mouse
1.1.7.5. OVE26 mouse
1.1.7.6. Black and tan, brachyuric (BTBR) ob/ob mouse
1.1.8. Incretin hormones and GIPRdn diabetic mouse model
1.1.8.1. Generation of GIPRdn diabetic mouse model
1.2. Regulated cell death
1.3. Ferroptosis
1.3.1 Mechanism of ferroptosis
1.3.1.1 Sensitization to ferroptosis by ether phospholipids
1.3.1.2 Hydropersulfides and ferroptosis
1.3.2 Ferroptosis inducers (FINs) and inhibitors
1.3.3 Ferroptosis in the kidney
1.4 Aims
2. Materials and Methods
2.1. Reagents
2.2. Experimental models: cell lines and mouse strains
2.2.1. Cell culture conditions
2.2.2. Mice
2.2.2.1. Genotyping
2.2.2.1.1. DNA isolation
2.2.2.1.2. Polymerase Chain Reaction (PCR)
2.2.2.1.3. Gel electrophoresis
2.2.2.2. Body weight
2.2.2.3. Blood glucose
2.2.2.4. Blood collection and serum parameters
2.2.3. Isolation of primary murine renal tubules
2.2.4. Generation of a 3D-printed double chamber
2.3. Experimental procedures
2.3.1. Plating and treatment of cells
2.3.2. Fluorescence activated cell sorting (FACS)
2.3.3. Western Blotting (WB)
2.3.4. Induction of cell death on isolated murine tubules
2.3.5. LDH release assay
2.3.6. Evaluation of speed of cell death propagation (exponential plateau – growth equation)
2.3.7. Time lapse imaging and processing of the time lapse data
2.3.8. Fluorescence Lifetime Imaging Microscopy (FLIM)
2.3.8.1. Time domain data analysis
2.3.8.2. FLIM time lapse video generation
2.3.9. Thioredoxin Reductase Activity assay
2.3.10. Bilateral kidney Ischemia and Reperfusion injury (IRI)
2.3.11. Immunohistology and semi-quantitative scoring
2.3.12. Measurements of sulfur-containing metabolites by ultra-performance liquid
chromatography-mass spectroscopy (LC-MS)
2.4. Statistical analysis
3. Results
3.1. Characterization of diabetic kidney disease in GIPRdn mice
3.1.1. Blood glucose
viii
3.1.2. Body weight
3.1.3. Serum parameters
3.1.4. Histological analysis of the kidneys
3.2. The spontaneous death of GIPRdn tubules is characterized by a non-random
pattern of necrotic cell death
3.3. GIPRdn tubules are more prone to undergo spontaneous death compared to
WT tubules
3.4. Spontaneous necrosis of GIPRdn and WT tubules is partially mediated by
ferroptosis
3.5. GIPRdn tubules show downregulation of the PRX pathway compared to the
non-diabetic tubules
3.6. GIPRdn tubules show altered hydropersulfides pathway
3.7. GIPRdn tubules show altered etherglycerophospholipids (etherPLs) pathway.
3.8. Ferrostatin-1 but not Empagliflozin reverses ferroptosis induction in
different cell lines as well as in isolated kidney tubules
3.9. GIPRdn mice are more sensitive to IRI-induced acute kidney injury compared
to their WT littermates
3.10. Ferrostatin-1 ameliorates the sensitivity of GIPRdn to ischemia reperfusion
injury-induced acute kidney injury
4. Discussion
4.1. The GIPRdn mouse model
4.2 Ferroptosis in diabetic nephropathy
4.2.1. Ferroptotic cell death is involved in the spontaneous death of diabetic tubules
4.2.2. Possible mechanisms behind the enhanced sensitivity of the GIPRdn kidney tubules to
ferroptosis
4.3. Therapeutic consequences of the study
4.3.1. SGLT2 inhibitor empagliflozin does not have a protective effect on diabetic tubules
undergoing spontaneous death
4.4. Outlook and limitations of the study
Reference
Hyperglycemia-induced thioredoxin reductase degradation accelerates ferroptotic cell death propagation in diabetic renal tubules
No full textDiabetes mellitus and its complications stands as arguably the most formidable pandemic of the 21st century. While rodent models of diabetes mellitus have been extensively explored, none have managed to faithfully replicate the full spectrum of pathological hallmarks and secondary complications witnessed in diabetic patients. Among the commonly affected organs is the kidney, manifesting in the form of diabetic kidney disease (DKD). Recently, our clinical understanding of incretins as critical regulators of disease progression in diabetic patients including DKD has undergone significant expansion.
In particular, the incretin hormone gastric inhibitory polypeptide (GIP) axis has taken central stage. A ground-breaking development in this realm was the creation of a GIP receptor dominant negative (GIPRdn) mouse, exhibiting all the characteristic features observed in DKD patients. This study sheds light on the heightened susceptibility of these mice to lethal acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI). Notably, isolated renal GIPRdn-tubules displayed accelerated cell death propagation and increased tubular necrosis. Expanding on previous cell culture experiments involving hyperglycemia, it became apparent that tubules of GIPRdn mice express elevated levels of the intracellular thioredoxin interacting protein (TXNIP), previously reported to be responsible for the degradation of glucose transporter 1 (GLUT1). This phenomenon is crucial in maintaining intracellular glucose homeostasis. The study further indicates an association between TXNIP and the downregulation of thioredoxin reductase 1 (TXNRD1), a selenoenzyme playing a pivotal role in protecting renal tubules from ferroptosis in a glutathione-independent manner. Intriguingly, the inhibition of TXNRD1 with the small molecule ferroptocide (FTC) in GIPRdn tubules resulted in severe tubular necrosis, a condition effectively reversed by the ferroptosis inhibitor ferrostatin 1 (Fer-1). This nuanced exploration establishes a connection between DKD and a heightened sensitivity to kidney tubular ferroptosis, thereby presenting a potential avenue for intervention with ferrostatins. Importantly, the administration of a single dose of Fer-1 significantly prolonged the survival of GIPRdn mice following IRI. In conclusion, this study illuminates the intricate dynamics of DKD, highlighting a pronounced sensitization to kidney tubular ferroptosis. The findings suggest that ferrostatins, particularly exemplified by Fer-1, hold promise as potential therapeutic agents in mitigating the severity of this condition, offering hope for improved outcomes in individuals struggling with diabetes-related kidney complications.:Acknowledgments
Abstract
Zusammenfassung
List of abbreviations
List of tables
List of Figures
1. Introduction
1.1. Diabetes mellitus
1.1.1. Definition and description
1.1.2. Epidemiology
1.1.3. Classification of diabetes mellitus
1.1.4. Diagnosis of diabetes mellitus
1.1.5. Type 2 Diabetes Mellitus
1.1.6. Long-term complications of T2DM
1.1.6.1. Diabetic Nephropathy
1.1.6.2. Therapies for diabetic nephropathy
1.1.7. Animal models for diabetic kidney disease
1.1.7.1. Diabetic eNOS knockout mouse
1.1.7.2. Bradykinin B2 Receptor (B2R) deficient Ins2Akita/+ mouse
1.1.7.3. Decorin-deficient streptozotocin diabetic mouse
1.1.7.4. NONcNZO mouse
1.1.7.5. OVE26 mouse
1.1.7.6. Black and tan, brachyuric (BTBR) ob/ob mouse
1.1.8. Incretin hormones and GIPRdn diabetic mouse model
1.1.8.1. Generation of GIPRdn diabetic mouse model
1.2. Regulated cell death
1.3. Ferroptosis
1.3.1 Mechanism of ferroptosis
1.3.1.1 Sensitization to ferroptosis by ether phospholipids
1.3.1.2 Hydropersulfides and ferroptosis
1.3.2 Ferroptosis inducers (FINs) and inhibitors
1.3.3 Ferroptosis in the kidney
1.4 Aims
2. Materials and Methods
2.1. Reagents
2.2. Experimental models: cell lines and mouse strains
2.2.1. Cell culture conditions
2.2.2. Mice
2.2.2.1. Genotyping
2.2.2.1.1. DNA isolation
2.2.2.1.2. Polymerase Chain Reaction (PCR)
2.2.2.1.3. Gel electrophoresis
2.2.2.2. Body weight
2.2.2.3. Blood glucose
2.2.2.4. Blood collection and serum parameters
2.2.3. Isolation of primary murine renal tubules
2.2.4. Generation of a 3D-printed double chamber
2.3. Experimental procedures
2.3.1. Plating and treatment of cells
2.3.2. Fluorescence activated cell sorting (FACS)
2.3.3. Western Blotting (WB)
2.3.4. Induction of cell death on isolated murine tubules
2.3.5. LDH release assay
2.3.6. Evaluation of speed of cell death propagation (exponential plateau – growth equation)
2.3.7. Time lapse imaging and processing of the time lapse data
2.3.8. Fluorescence Lifetime Imaging Microscopy (FLIM)
2.3.8.1. Time domain data analysis
2.3.8.2. FLIM time lapse video generation
2.3.9. Thioredoxin Reductase Activity assay
2.3.10. Bilateral kidney Ischemia and Reperfusion injury (IRI)
2.3.11. Immunohistology and semi-quantitative scoring
2.3.12. Measurements of sulfur-containing metabolites by ultra-performance liquid
chromatography-mass spectroscopy (LC-MS)
2.4. Statistical analysis
3. Results
3.1. Characterization of diabetic kidney disease in GIPRdn mice
3.1.1. Blood glucose
viii
3.1.2. Body weight
3.1.3. Serum parameters
3.1.4. Histological analysis of the kidneys
3.2. The spontaneous death of GIPRdn tubules is characterized by a non-random
pattern of necrotic cell death
3.3. GIPRdn tubules are more prone to undergo spontaneous death compared to
WT tubules
3.4. Spontaneous necrosis of GIPRdn and WT tubules is partially mediated by
ferroptosis
3.5. GIPRdn tubules show downregulation of the PRX pathway compared to the
non-diabetic tubules
3.6. GIPRdn tubules show altered hydropersulfides pathway
3.7. GIPRdn tubules show altered etherglycerophospholipids (etherPLs) pathway.
3.8. Ferrostatin-1 but not Empagliflozin reverses ferroptosis induction in
different cell lines as well as in isolated kidney tubules
3.9. GIPRdn mice are more sensitive to IRI-induced acute kidney injury compared
to their WT littermates
3.10. Ferrostatin-1 ameliorates the sensitivity of GIPRdn to ischemia reperfusion
injury-induced acute kidney injury
4. Discussion
4.1. The GIPRdn mouse model
4.2 Ferroptosis in diabetic nephropathy
4.2.1. Ferroptotic cell death is involved in the spontaneous death of diabetic tubules
4.2.2. Possible mechanisms behind the enhanced sensitivity of the GIPRdn kidney tubules to
ferroptosis
4.3. Therapeutic consequences of the study
4.3.1. SGLT2 inhibitor empagliflozin does not have a protective effect on diabetic tubules
undergoing spontaneous death
4.4. Outlook and limitations of the study
Reference
Uso Aumentaty Author (RA) Como Estrategia Didáctica Para Mejorar los Aprendizajes Relacionados con el Componente Biológico en los Estudiantes del Grado Noveno
No full textDigitalLa presente investigación tuvo como objetivo primordial “Implementar Aumentaty Author como estrategia didáctica, para el mejoramiento los procesos de enseñanza en Ciencias Naturales en los estudiantes del grado 9° en la Institución Educativa Pijiguayal”. Para lo cual se diseñaron y aplicaron varios instrumentos de tipo mixto como Prueba diagnóstica, encuesta y entrevista, lo que permitió evidenciar una problemática relacionada con los procesos de enseñanza-aprendizaje que tenían los estudiantes en el área de ciencias naturales y que ameritaba la implementación de una estrategia didáctica que ayudara a mejorar dicha realidad. El estudio cuenta con un enfoque mixto realizada con 20 estudiantes del grado en mención y un muestreo de tipo no probabilístico que permitió cualificar y obtener información sobre la problemática abordada.
Dentro del procedimiento diseñado se plantearon tres (3) fases en las que se integraron los objetivos necesarios para lograr el impacto esperado. Por ello, se utilizó como medio didáctico y tecnológico la herramienta Aumentaty Author y Zoom; con las cuales se diseñaron y aplicaron 7 actividades de aprendizajes. Dentro de los resultados, se evidencia un cambio muy significativo si se analizan los resultados desde le nivel bajo; los cuales muestran cero por ciento de los estudiantes dicha categoría y mostrando que del 20% en nivel alto ahora han avanzado en un 55% y 35% en superior.
Por lo que se logra concluir que el uso de las nuevas tecnologías y de la RA como estrategia principal, no solo generar cambios a nivel curricular, académico y didáctico, sino que influyen en aspectos de interés y motivación en los educandos, tal como se evidencia en los resultados obtenidos en la prueba final y en la encuesta de satisfacción.The main objective of the present research was to "Implement Augmenting Author as a didactic strategy, to improve the teaching processes in Natural Sciences in 9th grade students at the Pijiguayal Educational Institution." For which, several instruments of a mixed type were designed and applied such as diagnostic test, survey and interview, which allowed to show a problem related to the teaching-learning processes that students had in the area of Natural Sciences and that merited the implementation of a didactic strategy that will help to improve this reality. The study has a mixed approach carried out with 20 students of the grade in question and a non-probabilistic sampling that allowed qualifying and obtaining information on the problem addressed. Within the designed procedure, three (3) phases were proposed in which the necessary objectives were integrated to achieve the expected impact. For this reason, the tool Augmentaty Author and Zoom was used as a didactic and technological means; with which 7 learning activities were designed and applied. Within the results, a very significant change is evidenced if the results are analyzed from a low level; which show zero percent of the students said category and showing that of the 20% in high level now they have advanced in 55% and 35% in superior. Therefore, it is possible to conclude that the use of new technologies and AR as the main strategy, not only generate changes at the curricular, academic and didactic level, but also influence aspects of interest and motivation in students, as evidenced in the results obtained in the final test and in the satisfaction surveyINTRODUCCIÓN ................................................................................................... 18
1. DESCRIPCIÓN DEL PROYECTO .................................................................. 19
1.1 PLANTEAMIENTO DEL PROBLEMA ....................................................... 19
1.1.1 Descripción de la situación problema ................................................. 19
1.1.2 Identificación del problema ................................................................. 21
1.1.3 Árbol de problemas sobre el bajo desempeño en los aprendizajes en las Ciencias Naturales ..................................................................................... 22
1.1.4 Formulación del problema .................................................................. 22
1.2 ALCANCE ................................................................................................. 23
1.3 JUSTIFICACIÓN ....................................................................................... 23
1.4 OBJETIVOS .............................................................................................. 25
1.4.1 Objetivo general ................................................................................. 25
1.4.2 Objetivos específicos ......................................................................... 25
2 BASES TEÓRICAS ......................................................................................... 26
2.1 MARCO DE ANTECEDENTES ................................................................ 26
2.1.1 Antecedentes históricos ..................................................................... 26
2.1.2 Antecedentes legales. ........................................................................ 28
2.1.3 Antecedentes investigativos ............................................................... 31
2.2 MARCO TEÓRICO ................................................................................... 36
2.2.1 Aprendizaje Significativo de David Ausubel ....................................... 36
2.2.2 Aprendizaje Colaborativo de Vygotsky ............................................... 37
2.2.3 Conectivismo ...................................................................................... 38
2.3 MARCO CONCEPTUAL (opcional) .......................................................... 39
2.3.1 Relación entre la ciencia y la tecnología ............................................ 39
2.3.2 La enseñanza de las ciencias y la educación ambiental .................... 39
2.3.3 El papel del laboratorio ....................................................................... 39
2.3.4 Conocimiento científico básico ........................................................... 40
2.3.5 Realidad aumentada .......................................................................... 40
2.4 MARCO TECNOLÓGICO ......................................................................... 41
2.4.1 Aspectos Generales de Aumentaty Author ........................................ 41
2.4.2 Requisitos del Sistema de Aumentaty Author .................................... 41
2.4.3 Importancia de Aumentaty Author ...................................................... 42
2.4.4 Características que ofrece Aumentaty Author .................................... 42
3 DISEÑO METODOLÓGICO ............................................................................ 45
3.1 TIPO DE INVESTIGACIÓN ...................................................................... 45
3.2 HIPÓTESIS ............................................................................................... 46
3.3 VARIABLES .............................................................................................. 46
3.4 POBLACIÓN Y MUESTRA ....................................................................... 47
3.4.1 MUESTRA .......................................................................................... 47
3.4.2 Técnica de Muestreo .......................................................................... 47
3.5 PROCEDIMIENTO ................................................................................... 48
3.5.1 Impacto Esperado .............................................................................. 49
3.6 INSTRUMENTOS DE RECOLECCIÓN DE INFORMACIÓN .................... 49
3.7 TÉCNICAS DE ANÁLISIS DE DATOS ..................................................... 50
4 Consideraciones Éticas ................................................................................... 51
5 DIAGNÓSTICO INICIAL .................................................................................. 52
5.1 Análisis de la prueba diagnóstica ............................................................. 52
5.2 Análisis de la encuesta aplicada a los docentes ....................................... 60
5.3 Análisis de la encuesta realizada a los estudiantes .................................. 64
6 ESTRUCTURA DE LA PROPUESTA DE INTERVENCIÓN ............................ 68
6.1 PROPUESTA PEDAGÓGICA ................................................................... 68
6.2 PROPUESTA PEDAGÓGICA (Ingeniería del proyecto) ........................... 70
6.3 COMPONENTE TECNOLÓGICO ............................................................. 76
6.3.1 Proceso de Instalación Aumentaty Author ......................................... 78
6.4 Implementación ........................................................................................ 82
7 ANÁLISIS E INTERPRETACIÓN DE DATOS ................................................. 89
7.1.1 Resultados de la encuesta de satisfacción ........................................ 92
7.1.2 Análisis Global.................................................................................... 94
8 CONCLUSIONES ............................................................................................ 96
9 LIMITACIONES ............................................................................................... 98
10 IMPACTO / recomendaciones / TRABAJOS FUTUROS ............................. 99
11 REFERENCIAS BIBLIOGRÁFICAS ........................................................... 101
12 ANEXOS .................................................................................................... 107MaestríaMagíster en Tecnologías Digitales Aplicadas a la Educación1°e
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