Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer's disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.This research was funded by the Institute of Research Valdecilla (IDIVAL), grant number: NVAL 19/23, approval date: 1 january 202

Cellular Senescence in Neurodegenerative Diseases

Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.This study was supported by Fundación Tatiana Pérez de Guzmán el Bueno, IDIVAL, the grant reference (NVAL 19/23) and the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; PSI-2016-76194-R, AEI/FEDER, EU)

Mouse Models of Down Syndrome as a Tool to Unravel the Causes of Mental Disabilities

Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition due to alterations in GABAA-mediated transmission and disturbances in the glutamatergic, noradrenergic and cholinergic systems, among others, has also been demonstrated. DS cognitive dysfunction caused by neurodevelopmental alterations is worsened in later life stages by neurodegenerative processes. A number of pharmacological therapies have been shown to partially restore morphological anomalies concomitantly with cognition in these mice. In conclusion, the use of mouse models is enormously effective in the study of the neurobiological substrates of mental disabilities in DS and in the testing of therapies that rescue these alterations. These studies provide the basis for developing clinical trials in DS individuals and sustain the hope that some of these drugs will be useful in rescuing mental disabilities in DS individuals

Los locutorios como espacios de integración : las tecnologías de la información y la comunicación en la construcción de redes e identidades

Resum.La acelerada y masiva implementación de las TIC en las sociedades contemporáneas pone de manifiesto el papel cada vez más relevante que éstas están tomando, no sólo como medio de acceso a la información, sino especialmente como forma de integración y participación ciudadana en un mundo de carácter glocal. De ahí que los espacios de acceso público a las TIC (cibercafés, bibliotecas, telecentros o locutorios) aparezcan como enclaves esenciales en los que indagar el impacto social que producen las nuevas tecnologías en sujetos y colectivos, así como para analizar las apropiaciones que sus usuarios/as hacen de las TIC, especialmente aquellas dirigidas a generar y consolidar redes sociales. En este artículo, tras revisar la literatura científico-social de los principales lugares de acceso público a TIC, nos acercaremos concretamente a los espacios denominados locutorios, tratando sus características y las formas específicas de vinculación y relación que sus usuarios/as más frecuentes, la población migrante, establece en ellos. De esta forma, el locutorio es tratado como un lugar-metáfora de los procesos migratorios en un mundo globalizado. En la discusión defenderemos el concepto de estación de asociaciones como útil antropológico para caracterizarlosIt's clear that the accelerated and massive implementation in contemporary societies of ICTs makes their role ever more relevant, not just as means of information access but especially insofar as the role they play in forming citizen integration and participation modes that have a glocal character. Hence, public ICT access spaces (cybercafés, libraries, telecenters, or public call centers (locutorios)) appear to be essential enclaves where one can investigate the social impact produced by these new technologies on subjects and collectives, as well as to analyze how users put them to use, particularly those ICTs aimed at the promotion and consolidation of social networks. This article first offers a review of the scientific-social literature focused on the principal public ICT access spaces. It treats the specific characteristics and means of the links and relationships frequent users, the immigrant population, establish in the public call center. As such, it is treated as a place-metaphor for migratory processes in a globalized world. The discussion defends the concept of association stations as an anthropological tool to help elucidate the characteristics of this space

La psicología social en España : estructuras de comunidades

Este trabajo se enmarca en el espacio de la 'Psicología social de la ciencia' (Domènech, Íñiguez, Pallí y Tirado 2000; Iñiguez y Pallí, 2002; Moscovici, 1993; Shadish & Fuller, 1994; Shadish & Neimeyer, 1989). La Psicología social contribuye a los estudios sociales de la ciencia y la tecnología con el estudio de las interacciones y factores sociales que se dan en el marco de la producción científica y específicamente, promoviendo la idea de que el conocimiento es el resultado de un trabajo conjunto. El presente trabajo considera a la propia Psicología social como objeto de análisis. Específicamente pretende fijar una historiografía de la Psicología social en España, analizar sus características, identificar su dinámica y describir sus prácticas. Para ello, manteniendo las características propias presentes en la corta tradición de la Psicología social de la ciencia, utiliza tanto el Análisis de Redes Sociales (ARS) por su reconocida eficacia en el estudio de comunidades científicas, como la Bibliometría, por su capacidad para analizar la estructura de la producción y la comunicación. En la investigación se analizan las comunicaciones presentadas en los 8 Congresos españoles de Psicología social, celebrados entre 1982 y 2000.This study forms part of a 'social psychology of science" (Domènech, Íñiguez, Pallí y Tirado 2000; Iñiguez y Pallí, 2002; Moscovici, 1993; Shadish & Fuller, 1994; Shadish & Neimeyer, 1989). Social psychology's contribution to the social understanding of science and technology is in its study of the interactional and social factors involved in the production of scientific knowledge, exploring the idea that knowledge is the product of joint endeavour. In the work reported here we take Social Psychology itself as the object of study. Specifically, we subject Social Psychology in Spain to a historical analysis, analysing its characteristics, identifying its development and describing its practices. To do so, we follow practices established in the short legacy social psychology of science. We use both social network analysis (SNA), for its acknowledged utility in the study of scientific communities, and bibliometrics, for what it tells us about the structure of scientific publication. We present an analysis of the papers presented at the eight Social Psychology conferences held in Spain between 1982 and 2000

El acceso público a las tecnologías de la información y la comunicación : el lugar de los locutorios en los procesos migratorios

En los últimos años han surgido en nuestras ciudades diferentes espacios que ofrecen servicios de acceso a las nuevas Tecnologías de la Información y la Comunicación. En este artículo nos centramos específicamente en los locutorios, lugares de acceso a las TIC y también a la telefonía convencional, que tienen mayoritariamente como usuarios/as a la población migrante y en movimiento. Hemos realizado un estudio cualitativo de tipo etnográfico, en el que se han aplicado técnicas de observación participante, entrevistas y grupos de discusión. Los resultados muestran que los locutorios, lejos de ser únicamente espacios que posibilitan el establecimiento y mantenimiento de vínculos a distancia, también articulan las relaciones in situ, conformándose como lugares de encuentro, esto es, como estación de asociaciones. Así, presentamos al locutorio como metáfora de la inmigración, ya que nos permite dar cuenta de su carácter nacional y transnacional, así como de las redes familiares y prácticas sociales que se generan en estos espacios sociotécnicoVarious places that offer access to new Information and Communication Technologies (ICT) have emerged in our cities in recent years. In this paper we focus specifically on the "locutorios" (call centers), places of access to ICT and also to conventional telephony. Users are mostly the migrant and in motion population. We conducted a qualitative ethnographic study, which have applied techniques of participant observation, interviews and discussion groups. The results show that call centers are not only spaces to enable the establishment and maintenance of links to distance, but also allow space for relationships in situ. This makes the "locutorios" (call centers) meeting places, that is, associations stations. We present the "locutorios" (call centres) as a metaphor for immigration, because it allows us to account for their national and transnational character. It also allows us to account for the family networks and social practices that are generated in these sociotechnical spaces

Interference of non-specific detergents in microbial inhibitor test results for screening antibiotics in goat s milk

[EN] Cleaning and disinfection of dairy equipment is essential to ensure the hygienic quality of milk. Occasionally, some farmers use washing-up liquids and disinfectants for home use, especially when cleaning procedures are carried out manually. Residues of detergents and disinfectants in milk may interfere with the response of microbial inhibitor tests used for screening antibiotics in milk. Therefore, the aim of this study was to evaluate the interference of non-specific detergents in screening tests (BRT MRL; Delvotest SP-NT MCS; Eclipse 100) for goat s milk. Twelve replicates of eight concentrations of five washing-up liquids (0 1%) and one disinfectant (0 1%) were analysed. The results showed that the presence of washing-up liquids at concentrations of ≥1 ml/l leads to positive results in microbial tests. In particular, the product containing sodium laureth sulphate and ethanol produced the largest number of positive outcomes. The presence of disinfectant based on sodium hypochlorite did not affect the test response. The detection capabilities of microbial inhibitor tests for penicillins were also studied in milk with and without cleaning products, calculating the dose response curve with eight concentrations of amoxicillin, ampicillin, benzylpenicillin and cloxacillin, respectively. The detection limits of the screening tests for penicillins were not modified substantially by the cleaning product based on sodium laureth sulphate and ethanol. Residues of cleaning agents in milk can be avoided when specific detergents and disinfectants for milking equipment are used and good cleaning practices are applied.This work forms part of the Project AGL 2009-11524 financed by the Ministry of Science and Innovation (Madrid, Spain).Romero Rueda, T.; Beltrán Martínez, MC.; Althaus, RL.; Molina Pons, MP. (2016). Interference of non-specific detergents in microbial inhibitor test results for screening antibiotics in goat s milk. Journal of Applied Animal Research. 45(1):159-163. https://doi.org/10.1080/09712119.2015.1129341S159163451Beltrán, M. C., Berruga, M. I., Molina, A., Althaus, R. L., & Molina, M. P. (2015). Performance of current microbial tests for screening antibiotics in sheep and goat milk. International Dairy Journal, 41, 13-15. doi:10.1016/j.idairyj.2014.09.007Carlsson, Å., Björck, L., & Persson, K. (1989). Lactoferrin and Lysozyme in Milk During Acute Mastitis and Their Inhibitory Effect in Delvotest P. Journal of Dairy Science, 72(12), 3166-3175. doi:10.3168/jds.s0022-0302(89)79475-3Dubeuf, J.-P., de A. Ruiz Morales, F., & Castel Genis, J. M. (2010). Initiatives and projects to promote the Mediterranean local cheeses and their relations to the development of livestock systems and activities. Small Ruminant Research, 93(2-3), 67-75. doi:10.1016/j.smallrumres.2010.03.001LÓOPEZ, M. B., JORDÁN, M. J., GRANADOS, M. V., FERNÁNDEZ, J. C., CASTILLO, M., & LAENCINA, J. (1999). Viscosity changes during rennet coagulation of Murciano-Granadina goat milk. International Journal of Dairy Technology, 52(3), 102-106. doi:10.1111/j.1471-0307.1999.tb02081.xMERIN, U., ROSENTHAL, I., BERNSTEIN, S., & POPEL, G. (1985). The effect of residues of detergents and detergents-sanitizers on the performance of antibiotic test and the organoleptic quality of milk. Le Lait, 65(649-650), 163-167. doi:10.1051/lait:1985649-65011Oh, D.-H., & Marshall, D. L. (1993). Antimicrobial activity of ethanol, glycerol monolaurate or lactic acid against Listeria monocytogenes. International Journal of Food Microbiology, 20(4), 239-246. doi:10.1016/0168-1605(93)90168-gPontefract, R. D. (1991). Bacterial Adherence: Its Consequences in Food Processing. Canadian Institute of Food Science and Technology Journal, 24(3-4), 113-117. doi:10.1016/s0315-5463(91)70033-3Romero, T., Beltrán, M. C., Althaus, R. L., & Molina, M. P. (2014). Detection of antibiotics in goat’s milk: effect of detergents on the response of microbial inhibitor tests. Journal of Dairy Research, 81(3), 372-377. doi:10.1017/s0022029914000259Romero, T., Beltrán, M. C., Pérez-Baena, I., Rodríguez, M., & Molina, M. P. (2014). Effect of the presence of colostrum on microbial screening methods for antibiotic detection in goats’ milk. Small Ruminant Research, 121(2-3), 376-381. doi:10.1016/j.smallrumres.2014.07.007ROMERO, T., BELTRÁN, M. C., REYBROECK, W., & MOLINA, M. P. (2015). Effect In Vitro of Antiparasitic Drugs on Microbial Inhibitor Test Responses for Screening Antibiotic Residues in Goat’s Milk. Journal of Food Protection, 78(9), 1756-1759. doi:10.4315/0362-028x.jfp-15-020Sierra, D., Sánchez, A., Contreras, A., Luengo, C., Corrales, J. C., Morales, C. T., … Gonzalo, C. (2009). Detection limits of four antimicrobial residue screening tests for β-lactams in goat’s milk. Journal of Dairy Science, 92(8), 3585-3591. doi:10.3168/jds.2008-1981Valladao, M., & Sandine, W. E. (1994). Quaternary Ammonium Compounds in Milk: Detection by Reverse-Phase High Performance Liquid Chromatography and Their Effect on Starter Growth. Journal of Dairy Science, 77(6), 1509-1514. doi:10.3168/jds.s0022-0302(94)77090-9Zeng, S. S., Escobar, E. N., & Brown-Crowder, I. (1996). Evaluation of screening tests for detection of antibiotic residues in goat milk. Small Ruminant Research, 21(2), 155-160. doi:10.1016/0921-4488(95)00822-

Nasotracheal enterococcal carriage and resistomes: detection of optrA-, poxtA- and cfrD-carrying strains in migratory birds, livestock, pets, and in-contact humans in Spain

This study determined the carriage rates and antimicrobial resistance (AMR) genes of enterococci from nasotracheal samples of three healthy animal species and in-contact humans. Nasal samples were collected from 27 dog-owning households (34 dogs, 41 humans) and 4 pig-farms (40 pigs, 10 pig-farmers), and they were processed for enterococci recovery (MALDI-TOF–MS identification). Also, a collection of 144 enterococci previously recovered of tracheal/nasal samples from 87 white stork nestlings were characterized. The AMR phenotypes were determined in all enterococci and AMR genes were studied by PCR/sequencing. MultiLocus-Sequence-Typing was performed for selected isolates. About 72.5% and 60% of the pigs and pig-farmers, and 29.4% and 4.9%, of healthy dogs and owners were enterococci nasal carriers, respectively. In storks, 43.5% of tracheal and 69.2% of nasal samples had enterococci carriages. Enterococci carrying multidrug-resistance phenotype was identified in 72.5%/40.0%/50.0%/23.5%/1.1% of pigs/pig-farmers/dogs/dogs’ owners/storks, respectively. Of special relevance was the detection of linezolid-resistant enterococci (LRE) in (a) 33.3% of pigs (E. faecalis-carrying optrA and/or cfrD of ST59, ST330 or ST474 lineages; E. casseliflavus-carrying optrA and cfrD); (b) 10% of pig farmers (E. faecalis-ST330-carrying optrA); (c) 2.9% of dogs (E. faecalis-ST585-carrying optrA); and (d) 1.7% of storks (E. faecium-ST1736-carrying poxtA). The fexA gene was found in all optrA-positive E. faecalis and E. casseliflavus isolates, while fexB was detected in the poxtA-positive E. faecium isolate. The enterococci diversity and AMR rates from the four hosts reflect differences in antimicrobial selection pressure. The detection of LRE carrying acquired and transferable genes in all the hosts emphasizes the need to monitor LRE using a One-Health approach

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and A?, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, A? load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.This work was supported by the Jerome Lejeune Foundation, Fundación Tatiana Pérez de Guzmán el Bueno and the Spanish Ministry of Economy and Competitiveness (PSI-2016-76194-R, AEI/FEDER, EU). The authors wish to express their gratitude to Mariona Arbonés for providing Dyrk1A +/− KO mice and to Eva García Iglesias for technical assistance

Nuclear Reorganization in Hippocampal Granule Cell Neurons from a Mouse Model of Down Syndrome: Changes in Chromatin Configuration, Nucleoli and Cajal Bodies

Down syndrome (DS) or trisomy of chromosome 21 (Hsa21) is characterized by impaired hippocampal-dependent learning and memory. These alterations are due to defective neurogenesis and to neuromorphological and functional anomalies of numerous neuronal populations, including hippocampal granular cells (GCs). It has been proposed that the additional gene dose in trisomic cells induces modifications in nuclear compartments and on the chromatin landscape, which could contribute to some DS phenotypes. The Ts65Dn (TS) mouse model of DS carries a triplication of 92 genes orthologous to those found in Hsa21, and shares many phenotypes with DS individuals, including cognitive and neuromorphological alterations. Considering its essential role in hippocampal memory formation, we investigated whether the triplication of this set of Hsa21 orthologous genes in TS mice modifies the nuclear architecture of their GCs. Our results show that the TS mouse presents alterations in the nuclear architecture of its GCs, affecting nuclear compartments involved in transcription and pre-rRNA and pre-mRNA processing. In particular, the GCs of the TS mouse show alterations in the nucleolar fusion pattern and the molecular assembly of Cajal bodies (CBs). Furthermore, hippocampal GCs of TS mice present an epigenetic dysregulation of chromatin that results in an increased heterochromatinization and reduced global transcriptional activity. These nuclear alterations could play an important role in the neuromorphological and/or functional alterations of the hippocampal GCs implicated in the cognitive dysfunction characteristic of TS mice