p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor.

Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiologic inhibitor TFPI, would allow us to understand the critical step that control many different processes. From a gene profiling study aimed to identify differentially regulated genes between wild type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in comparison to wild-type MEFs. Based on these findings, we further investigated in the present study the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase. We found that PAK1/c-Jun complex stimulates the transcription of TF and consequently, its procoagulant activity. Moreover, PAK1 negatively regulates the expression of TFPI and thus, additionally, contributes to increased TF activity. For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor

Gradient induced artifacts in simultaneous EEG-fMRI: Effect of synchronization on spiral and EPI k-space trajectories

The nature of the gradient induced electroencephalography (EEG) artifact is analyzed and compared for two functional magnetic resonance imaging (fMRI) pulse sequences with different k-space trajectories: echo planar imaging (EPI) and spiral. Furthermore, the performance of the average artifact subtraction algorithm (AAS) to remove the gradient artifact for both sequences is evaluated. The results show that the EEG gradient artifact for spiral sequences is one order of magnitude higher than for EPI sequences due to the chirping spectrum of the spiral sequence and the dB/dt of its crusher gradients. However, in the presence of accurate synchronization, the use of AAS yields the same artifact suppression efficiency for both pulse sequences below 80 Hz. The quality of EEG signal after AAS is demonstrated for phantom and human data. EEG spectrogram and visual evoked potential (VEP) are compared outside the scanner and use both EPI and spiral pulse sequences. MR related artifact residues affect the spectra over 40 Hz (less than 0.2 μV up to 120 Hz) and modify the amplitude of P1, N2 and P300 in the VEP. These modifications in the EEG signal have to be taken into account when interpreting EEG data acquired in simultaneous EEG-fMRI experiments

The reference site collaborative network of the european innovation partnership on active and healthy ageing

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs

Cytosolic functions of MORC2 in lipogenesis and adipogenesis

AbstractMicrorchidia (MORC) family CW-type zinc finger 2 (MORC2) has been shown to be involved in several nuclear processes, including transcription modulation and DNA damage repair. However, its cytosolic function remains largely unknown. Here, we report an interaction between MORC2 and adenosine triphosphate (ATP)-citrate lyase (ACLY), an enzyme that catalyzes the formation of acetyl-coA and plays a central role in lipogenesis, cholesterogenesis, and histone acetylation. Furthermore, we demonstrate that MORC2 promotes ACLY activation in the cytosol of lipogenic breast cancer cells and plays an essential role in lipogenesis, adipogenesis and differentiation of 3T3-L1 preadipocytic cells. Consistently, the expression of MORC2 is induced during the process of 3T3-L1 adipogenic differentiation and mouse mammary gland development at a stage of increased lipogenesis. This observation was accompanied by a high ACLY activity. Together, these results demonstrate a cytosolic function of MORC2 in lipogenesis, adipogenic differentiation, and lipid homeostasis by regulating the activity of ACLY

Differential Effect of Cytomegalovirus Infection with Age on the Expression of CD57, CD300a, and CD161 on T-Cell Subpopulations

Immunosenescence is a progressive deterioration of the immune system with aging. It affects both innate and adaptive immunity limiting the response to pathogens and to vaccines. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, and its persistent infection results in functional and phenotypic changes to the T-cell repertoire, the aim of this study was to analyze the effect of CMV-seropositivity and aging on the expression of CD300a and CD161 inhibitory receptors, along with the expression of CD57 marker on CD4+, CD8+, CD8+CD56+ (NKT-Like) and CD4−CD8− (DN) T-cell subsets. Our results showed that, regardless of the T-cell subset, CD57−CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals, whereas CD57−CD161+CD300a+ T-cells decrease. Similarly, CD57+CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals in all subsets except in DN cells and CD57−CD161+CD300a− T-cells decrease in all T-cell subsets except in CD4+ T-cells. Besides, in young individuals, CMV latent infection associates with the expansion of CD57+CD161−CD300a+CD4+, CD57−CD161−CD300a+CD4+, CD57+CD161−CD300a+CD8+, CD57−CD161−CD300a+CD8+, CD57+CD161−CD300a+NKT-like, and CD57+CD161−CD300a+DN T-cells. Moreover, in young individuals, CD161 expression on T-cells is not affected by CMV infection. Changes of CD161 expression were only associated with age in the context of CMV latent infection. Besides, CD300a+CD57+CD161+ and CD300a−CD57+CD161+ phenotypes were not found in any of the T-cell subsets studied except in the DN subpopulation, indicating that in the majority of T-cells, CD161 and CD57 do not co-express. Thus, our results show that CMV latent infection impact on the immune system depends on the age of the individual, highlighting the importance of including CMV serology in any study regarding immunosenescence

In Vitro Culture with Interleukin-15 Leads to Expression of Activating Receptors and Recovery of Natural Killer Cell Function in Acute Myeloid Leukemia Patients

Despite recent progress in the therapeutic approach of malignant hemopathies, their prognoses remain frequently poor. Immunotherapy could open a new window of great interest in this setting. Natural killer (NK) cells constitute an important area of research for hematologic malignancies, because this subpopulation is able to kill target cells spontaneously without previous sensitization, representing a novel tool in the treatment of them. Abnormal NK cytolytic function is observed in several hematological malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes. Several mechanisms are involved in this abnormal function, such as decreased expression of activating receptors, increased expression of inhibitory receptors or defective expression of NK cell ligands on target cells. New immunotherapies are focused in identifying factors that could increase the expression of these activating receptors, to counteract inhibitory receptors expression, and therefore, to improve the NK cell cytotoxic capacities against tumor cells. In this work, we analyze the effect of interleukin (IL)-15 on the expression of NK cell-activating receptors that play a crucial role in the lysis of blasts from AML patients. Our results showed that IL-15 increased the surface expression of NKp30 on NK cells from healthy donors and AML patients with the consequent improvement of NK cell cytotoxicity. Besides, the upregulation of NKp30 induced by IL-15 is associated with an improvement of NK-mediated myeloid dendritic cells (DCs) maturation. NK cells cultured with IL-15 showed an upregulation of NKp30, which is associated with an increase anti-tumor activity and with an improved maturation of immature DCs. In our in vitro model, IL-15 exerted a great activating stimulus that could be used as novel immunotherapy in AML patients

CD8+CD57+ T cell frequency and functionality in healthy individuals.

<p>A) CD57 expression in CD8+ T cells of healthy individuals stratified by CMV serostatus and age. B) Three-function analysis of SEB responses of CD8+CD57– and CD8+CD57+ T cell subsets. Scatter graphs show the magnitude of SEB responses in each functional category, expressed as percentage of CD8+CD57- T cells or CD8+CD57+ T cells. Vertical black lines indicate interquartile ranges, ranging from the 25th to the 75th percentile. The median response for each category is indicated by a horizontal black line. The combination of functions studied is indicated in the table below the scatter graphs.</p

Correlation between tri-functional CD8+ T cells and CD57 expression in the individuals studied (n = 32).

<p>Y axis represents the percentage of CD8+ T cells that express CD57. X axis represents the percentage of tri-functional CD8+ T cells.</p

CD8+ T cells' responses to SEB stimulation, in healthy individuals stratified by CMV serostatus and age.

<p>A) Percentage of CD3+CD8+ T cells that have any studied response to SEB. B) Total degranulation (CD107a) and cytokine production (IFN-gamma, TNF-alpha) by CD3+CD8+ T lymphocytes responding to SEB. Vertical black lines indicate interquartile ranges, ranging from the 25th to the 75th percentile. The median response for each category is indicated by a horizontal black line. C) Three-function analysis of SEB responses. Scatter graphs show the magnitude of SEB responses in each functional category, expressed as percentage of CD3+CD8+ T cells. The combination of functions studied is indicated in the table below the scatter graphs.</p