Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.post-print5895 K

Influence of obstructive sleep apnea on systemic inflammation in pregnancy

Background: Obstructive sleep apnea (OSA) is prevalent in pregnancy and it is associated with adverse pregnancy-related outcomes such as gestational diabetes, pre-eclampsia, and low birth weight. Maternal systemic inflammation is proposed to be one of the main intermediate mechanisms. However, the effects of OSA on systemic inflammation are unknown in normal pregnancy. Methods: Women in the 3rd trimester underwent hospital polysomnography to evaluate whether OSA increases systemic inflammation in normal pregnancy and its potential association with adverse fetal outcomes. OSA was defined as an apnea–hypopnea index (AHI) of = 5 h-1. Plasma cytokines levels (TNF-a, IL-1ß, IL-6, IL-8, and IL-10) were determined by multiple immunoassays. Results: We included 11 patients with OSA and 22 women with AHI < 5 h-1, who were homogeneous in age, and body mass index (BMI). Women with OSA had significant higher levels of TNF-a, IL-1ß, IL-8, and IL-10. We found significant correlations between AHI during REM and TNF-a (r = 0.40), IL-1ß (r = 0.36), IL-6 (r = 0.52), IL-8 (r = 0.43), between obstructive apnea index and TNF-a (r = 0.46) and between AHI and IL-1ß (r = 0.43). We also found that CT90% was related to IL-8 (r = 0.37). There were no significant differences in neonatal characteristics; however, we found inverse correlations between TNF-a and IL-8 with birth weight (both r = -0.48), while IL-8 showed a significant inverse relationship with neonatal gestational age (r = -0.48). Conclusions: OSA in our normal pregnancy population was associated with higher systemic inflammation, which was related to obstructive events, especially during REM sleep. Moreover, systemic inflammation was inversely correlated with neonatal birth weight and age

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Estrategias terapéuticas basadas en microglia para la enfermedad de Alzheimer y taupatías relacionadas

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de Lectura: 01-07-2022Esta tesis tiene embargado el acceso al texto completo hasta el 01-01-2024This work has been developed at Instituto Fundación Teófilo Hernando (Madrid) – Autonomous University of Madrid and at Karolinska Institutet (Stockholm). The completion of this doctoral thesis has been possible thanks to the financial support provided by the Ministry of Education, Culture and Sport (FPU 16/03239), the Ministry of Science, Innovation and Universities (SAF2015-63935R and RTI2018-095793-B100) and the Community of Madrid (B2017/BDM- 3827

Business Plan for the Implementation of a Fintech in Perú

El presente plan de negocio realiza el planteamiento y análisis [proyectado] de la implementación de una fintech en la realidad nacional, con la finalidad de hacer frente a la necesidad latente de gran cantidad de peruanos de un acceso eficiente, innovador y directo a entidades financieras que le permitan ahorrar, pues, si bien hacen uso de uno o más bancos en su día a día, no suelen utilizar los canales digitales existentes para llevar a cabo sus operaciones, ya sean para pagos, consumos u otros. En el primer capítulo se describe el modelo de negocio, así como su escalabilidad. Se da énfasis en la propuesta de valor, pues esta debe mantenerse en el tiempo e impactar de manera positiva en los clientes. El segundo capítulo describe el problema, el mercado meta y el lanzamiento de un aplicativo como propuesta de solución. Todo esto es validado gracias a la realización de experimentos y el análisis de los resultados de estos, reforzándolos con la ejecución de un concierge que permitirá analizar la intención de compra de los clientes potenciales. En el tercer capítulo se plantea ingresos y costos y gastos de inversión, operación y financiamiento del lanzamiento del aplicativo, expresando funciones, objetivos e indicadores de las diversas áreas de trabajo necesarias para la implementación de Coiny. Finalmente, en el cuarto capítulo, se exponen las conclusiones y recomendaciones obtenidas con la elaboración del presente plan de negocio, con la intención de optimizar los esfuerzos del lanzamiento de la solución propuesta al mercado.The present business plan carries out the approach and [projected] analysis of the implementation of a fintech in the national reality, with the intention of addressing the latent need of many Peruvians for efficient, innovative and direct access to financial institutions. that allow them to save money, given that, even if they make use of one or more banks in their day to, they do not usually use the digital channels to carry out their operations, whether these are payments, consumptions or else. The first chapter describes the business model, as well as its scalability. Emphasis is placed on the value proposition, as this must be maintained over time and have a positive impact on the clients. The second chapter describes the problem, the target market and the launch of an application as a solution proposal. All this is validated by the fulfilment of experiments and the analysis of the results of these, reinforcing them with the execution of a concierge that will allow to detect the purchase intention of potential customers. In the third chapter, income and costs and expenses of investment, operation and financing of the launch of the application are presented, expressing functions, objectives and indicators of the various work areas necessary for the implementation of Coiny. Finally, in the fourth chapter, the conclusions and recommendations obtained with the preparation of this business plan are presented, with the intention of optimizing the efforts of the launch of the proposed solution into the market.Trabajo de investigació

Implication of type 4 NADPH oxidase (NOX4) in tauopathy

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data