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

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

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

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

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

An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels

<p>Abstract</p> <p>Background</p> <p>Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia.</p> <p>Results</p> <p>In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups.</p> <p>Conclusion</p> <p>These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.</p

IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren's syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions.PRECISESADS Clinical Consortium Members: Te research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115565, resources of which are composed of fnancial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution. Swedish Heart Lung foundation and Swedish Rheumatism Association also contributed to fnancing. Open access funding provided by Karolinska Institute.Ye

Association of systemic lupus erythematosus associates with decreased immunosuppressive potential of the IgG glycome

Objective: Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation. Methods: Using ultra-performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China). Results: Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N-acetylglucosamine (which affect antibody-dependent cell-mediated cytotoxicity). Conclusion: The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE