A non-conserved amino acid variant regulates differential signalling between human and mouse CD28

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P212 in human vs. A210 in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this Y209APP212 sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside

The influence of abiotic and biotic conditions on lifecycle stages is critical for estuarine seagrass resilience

Abiotic and biotic factors influence seagrass resilience, but the strength and relative importance of the effects are rarely assessed over the complete lifecycle. This study examined the effects of abiotic (salinity, temperature, water depth) and biotic (grazing by black swans) factors on Ruppia spp. over the complete lifecycle. Structures were set up in two estuaries ( – 33.637020, 115.412608) that prevented and allowed natural swan grazing of the seagrasses in May 2019, before the start of the growing season. The density of life stage(s) was measured from June 2019 when germination commenced through to January 2020 when most of the seagrass senesced. Our results showed that swans impacted some but not all life stages. Seedling densities were significantly higher in the plots that allowed natural grazing compared to the exclusion plots (e.g. 697 versus 311 seedlings per m-2), revealing an apparent benefit of swans. Swans removed ≤ 10% of seagrass vegetation but a dormant seedbank was present and new propagules were also observed. We conclude that grazing by swans provides some benefit to seagrass resilience by enhancing seedling recruitment. We further investigated the drivers of the different lifecycle stages using general additive mixed models. Higher and more variable salinity led to increased seed germination whilst temperature explained variation in seedling density and adult plant abundance. Bet-hedging strategies of R. polycarpa were revealed by our lifecycle assessment including the presence of a dormant seedbank, germinated seeds and seedlings over the 8-month study period over variable conditions (salinity 2–42 ppt; temperatures 11–28 °C). These strategies may be key determinants of resilience to emerging salinity and temperature regimes from a changing climate

Evaluation of WRF model configurations for dynamic downscaling of tropical cyclones activity over the North Atlantic basin for Lagrangian moisture tracking analysis in future climate

This study assessed five well-established physics suites of the Weather Research and Forecasting (WRF) model in operational forecasting systems in the North Atlantic (NATL) basin or from previous sensitive experiments for dynamic downscaling tropical cyclone (TC) activity. We performed long-term simulations for the 2020 TC season in the NATL and compared the WRF tracks against the HURDAT2 dataset from the US National Hurricane Center. Among the tested configurations, the analysis revealed that the Kain-Fritsch, Purdue Lin, BouLac and revised MM5 schemes for cumulus, microphysics, planetary boundary layer and surface layer, respectively (hereafter WT), outperformed all four others in terms of TC frequency, track density and intensity and showed good performance in the cyclone accumulated energy and TC landfalling locations. In addition, WT well-captured the spatial distribution of accumulated TC precipitation and moisture uptake patterns, although it overestimated the precipitation maxima. Likewise, it agreed on the relative moisture contribution from fixed moisture sources (i.e., Gulf of Mexico, Caribbean Sea, tropical NATL, and western NATL) in the NATL basin. Overall, this study highlighted the high potential of using the WT physics suite in WRF for downscaling TC activity over the NATL basin, which will be useful for TC Lagrangian moisture sources analysis in future climate.Agencia Estatal de Investigación | Ref. PID2021-122314OB-I00Xunta de Galicia | Ref. ED431C 2021/44Xunta de Galicia | Ref. ED481B-2023/016Xunta de Galicia | Ref. ED481D 2022/020Universidade de Vigo/CISU

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Aortic aneurysm; Marfan syndrome; VersicanAneurisma aòrtic; Síndrome de Marfan; VersicanAneurisma aortico; Síndrome de Marfan; VersicanThoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), the CBMSO is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid. CBMSO and CNIC are Severo Ochoa Centers of Excellence (grants CEX2021-001154-S and CEX2020-001041-S, respectively) funded by MICIN/AEI/10.13039/501100011033. The project leading to these results has received funding from “La Caixa” Banking Foundation under project codes HR18-00068 (to MRC and JMR); Spanish Ministerio de Ciencia e Innovación grant RTI2018-099246-B-I00 (MICIU/AEI/FEDER, UE) to JMR, and grants PID2020-115217RB-100 and PID2021-122388OB-100 to MRC and JMR, respectively, funded by MCIN/AEI/10.13039/501100011033; Instituto de Salud Carlos III (CIBER-CV CB16/11/00264 and CB16/11/00479; and grants PI17/00381 to GT-T and PI21/00084 (co-funded by Fondo Europeo de Desarrollo Regional (FEDER)) to JFN); Fundacio La Marato TV3 (20151330 to JMR); Instituto de Investigación Sanitaria Marqués de Valdecilla (IDIVAL) (INNVAL 21/24) to JFN; The Marfan Foundation USA Faculty grant 2017 MRF/1701 (to JMR); Fundación MERCK-Fundación Española de Enfermedades Raras 2022 and V-Ayudas “Muévete por los que no pueden 2021” (to JO); and Spanish Ministerio de Ciencia e Innovación contracts FPI (BES-2016-077649) to MJR-R; Sara Borrell (CD18/00028) and Juan de la Cierva (IJC2020-044581-I) to MT; Ramón y Cajal (RYC2021-033343-I) to JO; and FPU (20/04814) to IA-R

Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases

Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Due to its low prevalence, this disease has been very poorly studied at the molecular level. We performed for the first time an epigenome-wide association study interrogating DNA methylation data obtained with the Infinium MethylationEPIC array from whole blood samples in 31 patients diagnosed with MCTD and 255 healthy subjects. We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. We mostly identified epigenetic signals at genes previously implicated in other SADs, for example MX1, PARP9, DDX60, or IFI44L, for which we also observed that MCTD patients exhibit higher DNA methylation variability compared with controls, suggesting that these sites might be involved in plastic immune responses that are relevant to the disease. Through methylation quantitative trait locus (meQTL) analysis we identified widespread local genetic effects influencing DNA methylation variability at MCTD-associated sites. Interestingly, for IRF7, IFI44 genes, and the HLA region we have evidence that they could be exerting a genetic risk on MCTD mediated through DNA methylation changes. Comparison of MCTD-associated epigenome with patients diagnosed with SLE, or Sjogren's Syndrome, reveals a common interferon-related epigenetic signature, however we find substantial epigenetic differences when compared with patients diagnosed with rheumatoid arthritis and systemic sclerosis. Furthermore, we show that MCTD-associated CpGs are potential epigenetic biomarkers with high diagnostic value. Our study serves to reveal new genes and pathways involved in MCTD, to illustrate the important role of epigenetic modifications in MCTD pathology, in mediating the interaction between different genetic and environmental MCTD risk factors, and as potential biomarkers of SADs

Technological aspects of functional foods containing probiotics

Os alimentos funcionais constituem hoje prioridade de pesquisa em todo mundo com a finalidade de elucidar as propriedades e os efeitos que estes produtos podem apresentar na promoção da saúde. As bactérias probióticas são microrganismos vivos que, quando consumidos, exercem efeitos benéficos sobre o hospedeiro conferindo propriedades à microbiota endógena. Algumas propriedades benéficas atribuídas às culturas probióticas necessitam de estudos mais controlados para serem definitivamente esclarecidas. Neste artigo são enfocados os aspectos tecnológicos dos probióticos, os efeitos associados ao consumo de produtos contendo probióticos e as principais cepas empregadas. São apresentados resultados experimentais originais para ilustrar os aspectos tecnológicos da fabricação de alimentos contendo probióticos buscando descrever suas limitações e alternativas.Functional food science is being considered priority of research nowadays and studies are directed towards attempts to elucidate their proprieties and effects in promoting health. Probiotics are viable microbial dietary supplements that have beneficial effects over the health of the host by means of modulation of the intestinal microflora. Some beneficial properties attributed to probiotic microorganisms still need more controlled studies to be definitely established. This article deals with technology aspects related to probiotics, the effects associated with the consumption of food products containing these microorganisms and the main strains employed for that purpose. Experimental data are also presented in order to illustrate technological aspects of the manufacture of food products containing probiotics, intending to describe their limitations and alternatives

Eficacia de los talleres infantiles del proyecto de prevención “Creando conciencia sobre el abuso sexual en la infancia”

Los menores están expuestos a diferentes riesgos y situaciones en su etapa evolutiva. La literatura científica pone de manifiesto la importancia del trabajo preventivo en el contexto educativo para abordar las dificultades en la etapa de la infancia. Con este objetivo se desarrolló el proyecto de la Asociación Con.Ciencia, que pretende ofrecer recursos y conciencia sobre el abuso sexual infantil (ASI), financiado en convocatoria competitiva por la Diputación de Málaga. En este estudio se presentan los resultados del análisis de la eficacia de una parte de este proyecto, los talleres a estudiantes de primaria con cuatro ejes fundamentales: la intuición, el reconocimiento de las sensaciones corporales, los secretos y las personas de confianza. Método: Participaron un total de 87 niños y niñas de 3º de primaria de tres centros educativos de la provincia de Málaga con edades comprendidas entre 8 y 10 años (M=8,21). Todos participaban en el programa de prevención del ASI de la Asociación Con.Ciencia. Se diseñó una evaluación específica para analizar los efectos de los talleres llevados a cabo con preguntas sobre las 4 áreas trabajadas. Se realizó el cuestionario antes y después de cada taller de forma colectiva y anónima. Resultados: Los resultados apuntan a que existen diferencias significativas en tres de las cuatro preguntas evaluadas antes y después de recibir el taller de prevención. No se obtuvieron diferencias entre géneros. Discusión: El objetivo de esta comunicación es presentar datos sobre el proyecto de prevención “creando Conciencia sobre el abuso sexual en la infancia” a la comunidad científica, exponiendo los resultados de los talleres donde los menores aprenden herramientas para detectar y pedir ayuda en una situación problemática. Se pone de manifiesto la importancia de la labor preventiva en un importante contexto de referencia para los menores como es el escolar.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

C/EBPβ Regulates TFAM Expression, Mitochondrial Function and Autophagy in Cellular Models of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPβ was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPβ overexpression increased TFAM promoter activity. However, downregulation of C/EBPβ in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPβ. Then, we concluded that C/EBPβ is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.This research was supported by the “MINECO” (SAF2017-85199-P to A.P.C.), UCM-Santander (PR44/21-29931 to J.A.M.-G.) and the Health Institute “Carlos III” ( PI18/00118 to E.C. and PI21/00183 to F.B.). CIBERNED is funded by the Health Institute “Carlos III”. F.B. is a Miguel Servet Fellow (CP20/0007)

Neuroprotective and anti-inflammatory effects of linoleic acid in models of parkinson’s disease: the implication of lipid droplets and lipophagy

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.This research was supported by the Health Institute “Carlos III”-CIBERNED (CB06/05/0041 and 2015/03), “MINECO” (SAF2014-52940-R, SAF2017-85199-P and SAF 2016-78666-R), “Comunidadde Madrid” (PEJ-2019-AI/SAL-12877), “Erasmus+ funding programme”, UCM-Santander (PR44/21-29931 to J.A.M.-G.), and partially supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Inhibidor de MNK1; OncologíaInhibidor de MNK1; OncologiaMNK1 inhibitor; OncologyTargeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.This work was supported by the Instituto de Salud Carlos III (PI17/02247), (PI20/01687), and CIBERONC (CB16/12/00363). S.R.y.C. acknowledges support from the Generalitat de Catalunya (2017-9015-385045). E. Bou-Petit thanks the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017 FI_B2 00139) and the European Social Funds for her predoctoral fellowship