Regional distribution of the leucine-rich glioma inactivated (LGI) gene family transcripts in the adult mouse brain

25 p., figuras y bibliografíaThe leucine-rich glioma inactivated (LGI) gene subfamily contains four highly conserved members (LGI1, 2, 3 and 4), which have been described in human, mouse and other mammalians. Although their main roles remain unknown, LGI1 gene mutations have been found in human partial temporal lobe epilepsy. Moreover, previous studies showed that the products of these genes exert their function in the nervous system. The anatomical distribution of these gene transcripts in the brain might give some insight to elucidate their possible function. In this study, the pattern of expression of the four LGI genes was assessed in the brain of C57BL/6J adult mice by in situ hybridization. We found that the LGI1 transcript is mainly expressed in the dentate gyrus and CA3 field of the hippocampus. LGI2 and LGI4 genes, which showed a similar pattern of distribution with minor differences, were mostly expressed in the medial septal area, thalamic reticular nucleus and substantia nigra pars compacta. LGI3-expressing cells were distributed widespread, but were more consistently observed in the hippocampal formation, thalamic and hypothalamic nuclei, substantia nigra and reticular formation. In summary, LGI1 gene expression is very restricted to intrahippocampal circuitry, which might be related to its involvement in temporal lobe epilepsy. The patterns of expression of LGI2 and LGI4 genes are very similar and their distribution in the vertical limb of the diagonal band and in putative hippocampal interneurons, suggest that the function of these genes might be related to the generation of hippocampal theta rhythm. Finally, LGI3 gene widespread expression in the brain suggests that its transcripts might be involved in a common cellular process present in different neuronal types.This work was supported by a grant from the Ministerio de Educación y Ciencia (SAF2006-00724) to J. P-T. Part of F. O-B. work has been supported by the Spanish Health Department (FIS 06-1816).Peer reviewe

A decision support system for on-line leakage localization

This paper describes a model-driven decision-support system (software tool) implementing a model-based methodology for on-line leakage detection and localization which is useful for a large class of water distribution networks. Since these methods present a certain degree of complexity which limits their use to experts, the proposed software tool focuses on the integration of a method emphasizing its use by water network managers as a decision support system. The proposed software tool integrates a model-based leakage localization methodology based on the use of on-line telemetry information, as well as a water network calibrated hydraulic model. The application of the resulting decision support software tool in a district metered area (DMA) of the Barcelona distribution network is provided and discussed. The obtained results show that the leakage detection and localization may be performed efficiently reducing the required time. © 2014 Elsevier Ltd.The authors wish to thank the support received by the AM0901 project funded by R+i Alliance (Suez Environnement) and by the EFFINET grant FP7-ICT-2012-318556 of the European Commission.Peer Reviewe

Compressibility effects on the wake dynamics of a circular cylinder

Compressible large-eddy simulations of the flow past a circular cylinder at Reynolds numbers Re = 104 and Mach numbers in the range M = 0.2-1.2 are performed. Changes in the wake dynamics, coherent structures and flow topology brought about compressibility effects are discussed and analysed in detail.This work has been partially financially supported by the Ministerio de Economía y Competitividad, Secretaría de Estado de Investigación, Desarrollo e Innovación, Spain (ref. PID2020-116937RB-C21 and PID2020-116937RB-C22). O.L. has been partially supported by a Ramon y Cajal postdoctoral contract (Ref: RYC2018-025949-I). I.R. also acknowledges fundings by AGAUR (Ref. 2021 SGR 01051).Peer ReviewedPostprint (published version

Effect of OAS genes on SARS-CoV-2 infection and the induction of innate immune responses

Resumen del trabajo presentado en el 8th European Congress of Virology, celebrado en Gdańsk (Polonia), del 4 al 7 de mayo de 2023Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) infections cause different clinical symptoms ranging from asymptomatic patients to patients suffering severe respiratory disease leading to death in some of them. Genetic and functional studies have shown inborn-errors of interferon (IFN)-related genes in severe COVID-19 patients explaining why some young patients devoid of co-morbidities succumbed to infection. In addition, very large genomic studies identified common genetic variants affecting the expression and splicing of IFN-stimulated genes (ISGs) of the 2",5"- oligoadenylate (2-5A) synthetase (OAS) family associated with COVID-19 severity. We have sequenced the whole genome of 274 patients who required hospitalization after SARS-CoV-2 infection, finding ultrarare mutations in OAS1 and OAS3 genes. Upon double-stranded (ds)RNA binding, the OAS1, OAS2, and OAS3 proteins synthetize 2¿- 5¿olygoadenylates which activate the endonuclease RNAseL. This endonuclease degrades viral and cellular RNAs, inhibiting viral replication. We have analyzed the effect of OAS1 and OAS3 genetic variants identified in our patients, and found that some of them impair the RNAseL activation. In addition, by using OAS3 knock-out cells generated in our laboratory and performing overexpression experiments, we have shown that OAS3 negatively modulates proinflammatory responses induced by immune challenges, and that the activation of the RNAseL activity seems necessary for this function. In addition, by using OAS3 knock-out mice infected with SARS-CoV-2 or treated with the double-stranded RNA analog poly(I:C), we have shown that OAS3 deficiency leads to a higher mouse susceptibility to SARS-CoV-2 infection and that OAS3 counteracts the induction of innate immune responses in the mouse infectedlungs, leading to a higher inflammatory response in OAS3 knock-out mice, compared to the parental mice. Given the contribution of exacerbated inflammatory responses to COVID-19 disease severity, our results suggest that OAS1/OAS3 could play a role limiting the severity of the clinical symptoms after SARS-CoV-2 infection

Proyecto CRIDECO: Cribado de deterioro cognitivo en farmacia comunitaria a partir de la queja subjetiva de memoria

Objetivo: desarrollar un programa de cribado de deterioro cognitivo (DC) en mayores de 50 años. Con la finalidad de que el servicio profesional farmacéutico sea más costo-efectivo utilizaremos un árbol de decisión para la selección del paciente.Además, se pretende valorar la importancia de la dieta mediterránea y el consumo de antioxidantes en la prevención del deterioro cognitivo y estudiar marcadores genéticos de riesgo de enfermedad de Alzheimer.Método: para ello se diseña un estudio observacional transversal mediante entrevista personal estructurada en pacientes que muestren indicios de pérdida de memoria. El estudio de captación se realizará en farmacias desde septiembre 2018 hasta septiembre de 2019. Los pacientes con puntuación en los test con posible DC se remitirán a atención primaria, previa presentación del proyecto a coordinación médica. Se perseguirá el resultado del diagnóstico obtenido en atención primaria y/o especializada. Se utilizarán como test de cribado el Memory Impairment Screening (MIS), Short Portable Mental State Questionnaire (SPMSQ) de Pfeiffer, el Fluidez Verbal Semántica (FVS) y siempre que sea posible el Test del Informador (TIN). Se define deterioro cognitivo por MIS ≤4; SPMSQ ≥ 3 (para analfabetos ≥ 4); FVS ≤10 palabras y el valor del TIN >57. A su vez se recogen una muestra de saliva del paciente, para estudio genético, y datos de nutrición para valorar la importancia de la dieta mediterránea y de los alimentos antioxidantes en la prevención del DC

From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic‒Associated Pernio

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets

Editorial: 10 years of Frontiers in genetics: past discoveries, current challenges and future perspectives

3 páginasThis research was supported by the National Institute on Health,grant number R01AG059586, R01AG059586-03S1, and by the University of Connecticut (UConn) Claude D. Pepper Older Americans Independence Center (P30-AG067988). BR is a recipient of a Glenn Award for Research in Biological Mechanisms of Aging. Research in the MR lab is supported by the Canadian Institutes of Health Research (CIHR) Project Grant 202203PJG-482520-CIA-CDAA-111824, CIHR Project Grant 202209PJT-486512-CIA-CDAA-111824, University of Manitoba Collaborative Research Program, Ontario Rett Syndrome Association Hope Fund, Children Hospital Research Institute of Manitoba (CHRIM), and Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN2016-06035. Work at JP-T’s lab was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red-(209), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación.Peer reviewe

Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

4 páginas, 1 figura, a tabla. Los autores pertenecen a The dementia genetic Spanish consortium (DEGESCO).A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3,172 AD and 682 FTD patients and 2,169 healthy controls from Spain. We found that 0.6% of AD cases carried this variant compared to 0.1% of controls (odds ratio [OR]=4.12, 95% confidence interval [CI]: 1.21-14.00, P=0.014). A meta-analysis comprising 32,598 subjects from four previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR=4.11, 95% CI: 2.99-5.68, P=5.27x10-18). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk and suggest that this rare genetic variant is not related to FTD.This study was supported by grants from Instituto de Salud Carlos III (PI12/01311 and 12/00013), grants from the Ministry of Science (SAF2010-15558, SAF2009-10434), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), Consolider (CSD2010-00045), and the Department of Health of the Government of Navarra (refs. 13085 and 3/2008). CR held during the period 2009-2013 a “Torres Quevedo” fellowship from the Spanish Ministry of Science and Technology, co-financed by the European Social Fund. Fundació ACE researchers are indebted to Trinitat Port-Carbó and her family who are supporting Fundació ACE scientific programs.Peer reviewe

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation

Changes in bread consumption and 4-year changes in adiposity in Spanish subjects at high cardiovascular risk

The effects of bread consumption change over time on anthropometric measures have been scarcely studied. We analysed 2213 participants at high risk for CVD from the PREvención con DIeta MEDiterránea (PREDIMED) trial to assess the association between changes in the consumption of bread and weight and waist circumference gain over time. Dietary habits were assessed with validated FFQ at baseline and repeatedly every year during 4 years of follow-up. Using multivariate models to adjust for covariates, long-term weight and waist circumference changes according to quartiles of change in energy-adjusted white and whole-grain bread consumption were calculated. The present results showed that over 4 years, participants in the highest quartile of change in white bread intake gained 0·76 kg more than those in the lowest quartile (P for trend = 0·003) and 1·28 cm more than those in the lowest quartile (P for trend 2 kg) and gaining waist circumference (>2 cm) during follow-up was not associated with increase in bread consumption, but participants in the highest quartile of changes in white bread intake had a reduction of 33 % in the odds of losing weight (>2 kg) and a reduction of 36 % in the odds of losing waist circumference (>2 cm). The present results suggest that reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat