Background
Alzheimer’s disease (AD) patients show sustained levels of inflammation in the brain and the peripheral immune system. It is not known how various peripheral blood mononuclear cells ...(PBMCs) differ in AD patients and whether those differences can act as biomarkers of AD. Here we performed a multi‐omic profiling of PBMCs from AD patients and compared the composition of their cell type and cell state as well as their gene and protein expression to normal controls.
Method
Single‐cell proteogenomics analysis was performed on PBMCs from 20 AD patients and 15 controls using Singleron Biotechnologies’ ESCAPE platform. Seven of the AD and four control samples were additionally analyzed for bulk protein expression using Sciomics’ scioDiscover platform.
Result
Bulk proteomics identified 100 proteins with a significant differential abundance between AD patients and controls. Data point to a higher platelet activation and degranulation, as well as changes in the EGFR / MAPK3 and VEGF signaling in AD. As an individual marker CD163 was identified at a higher abundance in AD PBMCs pointing to an increase in monocyte / macrophage activity.
From the single‐cell analysis we found that AD patients had significantly more CD14+ monocytes. We further found that the CD14+ monocytes could be split into seven clusters based on their gene expression with only two clusters having a significantly higher number of cells in AD patients. One of the overrepresented clusters showed high expression of Alarmin genes, suggesting an increased inflammatory environment, while the other cluster showed a higher level of HLA expression suggesting a state primed for activation.
Conclusion
We found significant changes in both gene and protein expression in PBCMs from AD patients that indicate an increased inflammatory state . While there was a good overlap of findings between gene and protein expression, some of the changes are only seen at the protein level, while others are only observed at the level of gene expression. The combination of the two measurement techniques provides us with additional insights into inflammatory nature of the peripheral immune system in AD patients and provide hints at the mechanisms different cells use to generate those inflammatory signals.
Rimbaud’s relation to religion is particularly complex. Some significant examples from his work allow to grasp the hieratic nature of the poet’s research. Dissatisfied with the existing religion, ...Rimbaud constantly aims to the Absolute and to the Mystery in their purity, complexity and truth, often through a behaviour seemingly opposite to religious sentiment.
Los indicadores sociales y dentro de estos, los laborales, suelen ser los que tienen una menor presencia en las memorias de sostenibilidad de las empresas y en los análisis y políticas de Inversión ...Socialmente Responsable (ISR). Un criterio fundamental para mejorar las condiciones laborales en las empresas es el derecho a la libertad de asociación y la negociación colectiva. Por ello, en este trabajo se trata de analizar cómo informan sobre este derecho una muestra de empresas líderes globales del IBEX 35 y a partir de los mejores ejemplos, se proponen unos indicadores que pueden ser de utilidad para estandarizar la información que se aporta sobre esta cuestión y podrían servir también para homogeneizar los parámetros de análisis y profundizar en la aportación de la negociación colectiva a los objetivos de la ISR y el desarrollo sostenible.
Background
Neurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease ...progression, and studying the impact of therapeutic approaches.
Method
Therefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF‐A), cancer antigen 15‐3 (CA15‐3) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1). Using quantitative ligand‐binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up‐ or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.
Result
The quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF‐A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.
Conclusion
Increased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co‐receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T‐cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF‐A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large‐scale analyses using well characterized samples should be done in the future.
p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown ...to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
