Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

Parkinson’s disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD

Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagic as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the SNCA gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a CTSD-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance, but also restored endo-lysosome and autophagy function in human and murine neurons as well as tissue. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden.authorsversionepub_ahead_of_prin

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi). Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed. Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging–evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group). Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapineassociated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n=698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6%), weight gain (69.3%), and increased sleep necessity (65.9%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10%). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Defects in ER–endosome contacts impact lysosome function in hereditary spastic paraplegia

Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER–endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell–derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER–endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.This work was supported by grants to E. Reid: UK Medical Research Council Project Grant (MR/M00046X/1), Wellcome Trust Senior Research Fellowship in Clinical Science (082381), Project Grant from United States Spastic Paraplegia Foundation, Project Grant from Tom Wahlig Stiftung, and Project Grant form UK HSP Family Group. J.R. Edgar is supported by the Wellcome Trust (grant 086598). T. Newton and G. Pearson are supported by the Medical Research Council PhD studentships (G0800117 and MR/K50127X/1). F. Berner was supported by the National Institute for Health Research Biomedical Research Centre at Addenbrooke's Hospital. B. Winner is supported by the Tom Wahlig Advanced Fellowship, the German Federal Ministry of Education and Research (01GQ113), the Bavarian Ministry of Education and Culture, Sciences and Arts in the framework of the Bavarian Molecular Biosystems Research Network and ForIPS, and the Interdisciplinary Centre for Clinical Research (University Hospital of Erlangen, N3 and F3). Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award (100140) and Equipment Grant (093026)

Producción de maiz (Zea mays L.) bajo dos sistemas de labranza y tres métodos de control de malezas, efecto sobre la dinámica de las malezas y el crecimiento y rendimiento del cultivo

Durante la época de primera (junio a septiembre de 1995) se llevó a cabo el presente experimento en la finca experimental La Compañía, localizada en el municipio de San Mareos, Carazo. Los objetivos perseguidos fueron evaluar la influencia de dos sistemas de labranza y tres métodos de control de malezas sobre el comportamiento de la malezas y el crecimiento y rendimiento del cultivo de maíz. (Zea mays L.), así como analizar desde el punto de vista económico la factibilidad de los tratamientos evaluados. Los factores incluidos en el experimento fueron establecidos en diseño de parcelas divididas con distribución en bloques completos al azar, con cuatro repeticiones, constituyéndose en la parcela principal , la labranza del suelo (cero y mínima) y los controles de malezas en las sub-parcelas, estos fueron: paraquat más chapia(pre-emergente y control mecánico a los 28 dias después de la siembra), paraquat (pro-emergente) y paraquat más paraquat (pre-emergente y post-emergente). Los resultados obtenidos muestran que el sistema de labranza cero presentó la mayor abundancia, cobertura y biomasa de malezas. El método de control de malezas que reflejó el mejor efecto sobre las malezas fue el control a base de pre más post-emergente, el cual obtuvo los menores valores en abundancia, diversidad, cobertura y biomasa de malezas. Los mejores resultados en cuanto a rendimiento se obtuvieron con labranza cero y control a base de pre-emergente más chapia. En lo que respecta a variables de crecimiento del cultivo, los sistemas de labranzas y controles de malezas no manifestaron diferencias significativas sobre las variables en estudio. El sistema de labranza que ofrece mayores beneficios netos y mejores rendimientos fue labranza cero. En cuanto a los controles de malezas, el mejor rendimiento y mejor rentabilidad se obtuvo con el control a base de pre-emergente más chapia

Evaluación de la situación laboral de los egresados de ngeniería Civil de la Facultad de Ciencias Matemáticas y Físicas desde el año 2005

This research work addresses the problem of the relevance of the curriculum of Civil Engineering Career Construction of roads in accordance with the evaluation of students, upon completing their studies, given that on completion of their studies job gain a place in the labor market according to their professional profile, therefore track to graduate, and continuous updating of the same, to see their work situation regarding the execution of road works, and the labor sector in which the subject plays, trying to ensure the quality to meet it raises the needs of graduates and companies according to the graduate­business features, achieving an academic building with timely and relevant research educational offerings, where the student learning environment based on cases involving the development of their skills and professional skills. Furthermore, this study according to the organic law on higher education requires, as this can measure the success of the educational institution based on the collection and analysis of information from the practice of its graduates and studies, improving processes institutional effectiveness, providing graduate satisfaction with the institution, as these studies identify the needs of the labor market and reach a successful employment according to the graduate professional profile.El presente trabajo investigativo aborda el problema de la pertinencia de los planes de estudios de Ingeniería Civil de la Carrera de Construcción de Vías de Comunicación de acuerdo con la evaluación de los estudiantes, al momento de concluir sus estudios, dado que al culminar sus estudios no obtienen una plaza de trabajo en el mercado laboral acorde a su perfil profesional, por ello se plantea un seguimiento a egresados, y una actualización permanente del mismo, para conocer su situación laboral en cuanto a la ejecución de obras viales, y el sector laboral en el que se desempeñan el sujeto, intentando asegurar la calidad para satisfacer las necesidades de los egresados y las empresas acorde a las características egresado ­empresa, logrando un fortalecimiento académico con una oferta educativa investigativa pertinente y oportuna, en donde el ambiente de aprendizaje del estudiante se base en casos que conlleven al desarrollo de sus destrezas y habilidades profesionales. Además, este estudio según la ley orgánica de educación superior lo exige, ya que en este se podrá medir el éxito de la institución educativa basándose en la recopilación y análisis de la información del ejercicio profesional de sus egresados y de los estudios realizados, mejorando procesos de efectividad institucional, brindando satisfacción al egresado con la institución, ya que estos estudios identifican las necesidades del mercado laboral y se llegara a una inserción laboral exitosa acorde al perfil profesional el egresado

La lógica hermenéutica y didáctica: un fundamento teórico para promover el aprendizaje de la apreciación icono-plástica en la enseñanza preuniversitaria

El articulo promueve la hermenéutica como presupuesto investigativo, a partir de su esencia básica, es decir, configurar la comprensión, explicación e investigación y la concepción intertextual icónica como modelación para estudiar el icono plástico (la obra plástica), ya que es uno de los referentes de la apreciación artística, y a su vez constituye una de las aristas para desarrollar la cultura artística estética; de hecho los educandos y los docentes se adentraría en el mundo de la alfabetización visual, o sea, gestionar desde diferentes ángulos los presupuestos de una cultura visual, ya que este mundo postmoderno lo impone, y estamos convocado a convivir con la información visual, que se encuentra por doquier. Además recoge los presupuestos de la didáctica de las humanidades como base para sistematizar las teorías y concepciones didácticas en el proceso de enseñanza-aprendizaje con un carácter desarrollador e interdisciplinario, a partir de la relación teórica y la práctica, que constituye la sistematización de los generadores hermenéuticos visuales, que se dividen en dos grupos: configuradores y diferenciadores.hermenéutica, intertextualidad, didáctica, icono plástico, generadores, configuradores, diferenciadores, sistematización.

Una mirada semiótica de la significación del icono plástico como vía para desarrollar el aprendizaje visual (apreciación icono- plástica)

La investigación esboza los fundamentos de la semiótica como ciencia de la interpretación y de la comunicación en diferentes momentos, además ubica a los fundamentales teóricos de la disciplina, tanto en el contexto universal, como en las investigaciones educativas. Por otro lado, se connota el código y los signos como referentes esenciales para la comprensión de la apreciación artística, en especial los criterios de la apreciación icono- plástica. También se enfatiza en los códigos de estructuración visual como aporte fundamental del artículo.Códigos, signos, conectores visuales, semiótica visual, icono plástico, signo icónico.