Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling

Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate. Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals’ short-term health trajectories. <p<Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11 242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants. Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches

A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes

Changes in the endothelium of the cerebral vasculature can contribute to inflammatory, thrombotic, and malignant disorders. The importance of defining cell-type-specific genes and their modification in disease is increasingly recognized. Here, we develop a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNA sequencing (RNA-seq) data from 238 normal human cortex samples from 2 independent cohorts. We compare endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte, neuron, and microglial cell profiles. Endothelial changes in malignant disease are explored using RNA-seq data from 516 lower-grade gliomas and 401 glioblastomas. Lower-grade gliomas appear to be an “endothelial intermediate” between normal brain and glioblastoma. We apply our method for the prediction of glioblastoma-specific endothelial biomarkers, providing potential diagnostic or therapeutic targets. In summary, we provide a roadmap of endothelial cell identity in normal and malignant brain, using a method developed to resolve bulk RNA-seq into constituent cell-type-enriched profiles

Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.

Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS).To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches--gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response

Dal Global Reporting Initiative (GRI) all'Integrated Reporting. Alcune applicazioni in Italia.

Il suddetto elaborato viene incentrato sull’evoluzione della sostenibilità e su i suoi strumenti. In particolare, l’attenzione è posta sul Global Reporting Initiative (GRI) e sull’Integrated Reporting(IR), citando alcune casi italiani che adottano tali strumenti per la propria rendicontazione. Nel primo capitolo, l’attenzione è rivolta al passaggio segnato dalla finanza etica prima, fino all’attuale finanza sostenibile, cercando di esporre quali siano stati i motivi che hanno spinto gli economisti a intraprendere tale scelta. Si sottolinea l’importanza degli Investimenti Socialmente Responsabili (SRI) e come questi vengono adoperati sia dalle Organizzazioni Aziendali che dalle Banche. Infine, si parla della Corporate Social Responsibility (CSR) e dell’impatto che questa ha all’interno di un’Organizzazione, ponendosi come elemento decisivo nelle scelte strategiche delle stesse. Il secondo capitolo è incentrato sul Global Reporting Initiaitive, dalla nascita all’attuale utilizzo, le procedure adottate per la scelta degli indici per la rendicontazione. Il terzo capitolo si occupa dell’Integrated Reporting (IR) e sull’impatto che questo sta avendo negli ultimi anni. Viene esplicitato il ruolo che l’IR ha nelle Organizzazioni e nelle Banche e come viene adottato tale strumento. Infine, il quarto capitolo, cita alcune applicazioni italiane che adottano il GRI e l’IR: caso “BANCA ETICA” e il caso del gruppo bancario “CREVAL”

Inflammation related genes without histone acetylation in their annotated promoters.

<p>Listed are representative genes of the results from the integration of gene expression and ChIP-seq data.</p><p>Table shows <b>gene</b> name and <b>chromosome position</b> (Chr.Pos); <b>TSS position</b>, annotated transcription start site (hg19); <b>P-value</b> (Student's t- test) and <b>fold change</b> due to LPS stimulation; <b>H3Ac peaks</b> presence in annotated promoter (−2 Kb/+1 Kb of TSS, hg19); the effect of LPS, <b>Peak extension</b>; direction of chromatin expansion (→, upstream only; ←, downstream only; -, no expansion); S5P RNAPII peaks (MACS) in annotated promoters (−2 Kb/+1 Kb of TSS in hg19); Sp1 peaks (MACS) in annotated promoters (−2 Kb/+1 Kb of TSS in hg19); <b>CpG island</b> presence in annotated promoter (−2 Kb/+1 Kb of TSS); <b>TATA box</b><i>in silico</i> finding (−150 bp/+50 bp of TSS) (Δ; TATA box <i>in silico</i> finding downstream of the TSS).</p

Distribution of H3Ac peaks across the macrophage genome.

<p>Graph (A) shows a summary of the expected distribution of genomic features of the whole human genome (2.9 billion base pairs). Graph (B) shows the location of common H3Ac peaks from the macrophage genome. (C) & (D) show the location of unique H3Ac peaks in macrophages during the experimental conditions, unstimulated (−LPS) and LPS-stimulated (+LPS), respectively.</p

LPS treatment and the appearance of unique H3Ac peaks.

<p><i>NFKBIL1</i> and <i>NFATC1</i> are examples of genes having common H3Ac peaks in both +/−LPS conditions. They also have unique H3Ac peaks that appear upon LPS stimulation (indicated with red arrows). (2A) A unique H3Ac peak appears at the 3′ end of <i>NFKBIL1</i> after LPS stimulation. (2B) For <i>NFATC1</i> two unique H3Ac peaks appear, these are located at the intronic and 3′end region, respectively. Genes identified by RefSeq using the UCSC browser are shown with blue arrows indicating TSSs locations and directions (GRCh37/hg19).</p

Inflammation gene members with histone acetylation in their annotated promoters.

<p>Listed are representative genes of the results from the integration of gene expression and ChIP-seq data.</p><p>Table shows <b>gene name</b> and <b>chromosome position</b> (Chr.Pos); <b>TSS position</b>, annotated transcription start site (hg19); <b>P-value</b> (Student's t- test) and <b>fold change</b> due to LPS stimulation; <b>H3Ac peaks</b> presence in annotated promoter (−2 Kb/+1 Kb of TSS, hg 19); the effect of LPS, <b>Peak extension</b>; direction of chromatin expansion (→, upstream only; ←, downstream only; ↔ up- and downstream; -, no expansion); P5S RNAPII peaks (MACS) in annotated promoters (−2 Kb/+1 Kb of TSS in hg19); Sp1 peaks (MACS) in annotated promoters (−2 Kb/+1 Kb of TSS in hg19); <b>CpG island</b> presence in promoter (−2 Kb/+1 Kb of TSS); <b>TATA box</b><i>in silico</i> finding (−150 bp/+50 bp of TSS).</p

Summary of Sp1 ChIP-seq identified peaks and their locations.

<p>Average peaks length for Sp1 showed in brackets for each group of peaks.(n/a), not applicable; the common peaks represent those that are present in both −LPS and +LPS, and the average length of these are shown in the −LPS and +LPS peaks columns.</p