Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.

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Review for "Tumor necrosis factor receptor family co‐stimulation increases regulatory T cell activation and function via NF‐κB"

10.1002/eji.201948393/v1/review1 ◽

2019 ◽

Keyword(s):

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Activation ◽

Regulatory T Cell ◽

Tumor Necrosis ◽

Cell Activation ◽

Tumor Necrosis Factor Receptor ◽

And Function ◽

Necrosis Factor ◽

Receptor Family

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NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis

Blood ◽

10.1182/blood-2010-12-322701 ◽

2011 ◽

Vol 118 (3) ◽

pp. 795-803 ◽

Cited By ~ 31

Author(s):

Katia Urso ◽

Arantzazu Alfranca ◽

Sara Martínez-Martínez ◽

Amelia Escolano ◽

Inmaculada Ortega ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Target Genes ◽

Gene Knockout ◽

Activated T Cells ◽

Knock Down ◽

And Function

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.

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The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2

Science Signaling ◽

10.1126/scisignal.aao4354 ◽

2018 ◽

Vol 11 (556) ◽

pp. eaao4354 ◽

Cited By ~ 1

Author(s):

Ivana Halova ◽

Monika Bambouskova ◽

Lubica Draberova ◽

Viktor Bugajev ◽

Petr Draber

Keyword(s):

Mast Cell ◽

Mast Cells ◽

T Cell Activation ◽

Cell Activation ◽

Adaptor Protein ◽

Prostaglandin E ◽

Dependent Manner ◽

And Function ◽

Cell Chemotaxis

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.

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Towards a more inclusive and equitable developmental cognitive neuroscience

10.31219/osf.io/wdqvr ◽

2021 ◽

Author(s):

Jazlyn Nketia ◽

Dima Amso ◽

Natalie Hiromi Brito

Keyword(s):

Cognitive Development ◽

Cognitive Neuroscience ◽

Cultural Context ◽

Large Scale ◽

Marginalized Communities ◽

Developmental Science ◽

Science Theory ◽

Brain Structure And Function ◽

Scientific Potential ◽

And Function

Brain and cognitive development is a burgeoning area of scientific inquiry, with tremendous potential to better the lives of children. Large scale longitudinal neuroimaging studies offer opportunities for significant scientific advances in our understanding of developing brain structure and function. The proposed manuscript will focus on the scientific potential of the HEALthy Brain and Cognitive Development (HBCD) Study, highlighting what questions these data can and what they cannot answer about child development. Specifically, we caution against the misuse of these data for advancing de-contextualized and scientifically questionable narratives about the development of children from marginalized communities. We will focus on building and organizing a framework for interpreting HBCD data through the lens of sampling, cultural context, measurement, and developmental science theory. Our goal is to thoughtfully offer the scientific community opportunities to use the large scale and collaborative nature of HBCD to collectively revise practices in developmental science that to-date have not carefully considered their own role in perpetuating narratives that support systemic injustice.

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T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms21197424 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7424

Author(s):

Nicholas J. Chandler ◽

Melissa J. Call ◽

Matthew E. Call

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Immune Cell ◽

Single Chain ◽

Design Work ◽

Cell Therapies ◽

Form And Function ◽

Car T ◽

And Function

The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics.

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Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

International Journal of Molecular Sciences ◽

10.3390/ijms21176118 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6118 ◽

Cited By ~ 1

Author(s):

Marianna Szczypka

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Splice Variants ◽

Cell Activity ◽

Cell Functions ◽

Simultaneous Inhibition ◽

And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

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Unraveling Natalizumab Effects on Deregulated miR-17 Expression in CD4+T Cells of Patients with Relapsing-Remitting Multiple Sclerosis

Journal of Immunology Research ◽

10.1155/2014/897249 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 35

Author(s):

Maria Meira ◽

Claudia Sievers ◽

Francine Hoffmann ◽

Maria Rasenack ◽

Jens Kuhle ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell Activation ◽

Posttranscriptional Regulation ◽

Cell Activation ◽

Target Genes ◽

Regulation Of Gene Expression ◽

Expression Of Genes ◽

Relapsing Remitting

MicroRNAs (miRNAs) are a family of noncoding RNAs that play critical roles in the posttranscriptional regulation of gene expression. Accumulating evidence supports their involvement in the pathogenesis of multiple sclerosis (MS). Here, we compare miR-17 expressions in CD4+T cells from relapsing-remitting (RR) MS patients treated with natalizumab versus untreated patients. miR-17 was downregulated under natalizumab treatment and upregulated during relapse, therefore supporting a possible role of miR-17 in MS immunopathogenesis. Downregulation of miR-17 was associated with upregulation of PTEN, BIM, E2F1, and p21 target genes.In vitromiR-17 inhibition was associated with upregulation of the same targets and resulted in impaired CD4+T cell activation and proliferation. We further describe deregulated TGFBR2 expression in untreated patients versus healthy volunteers (HVs) and confirmin vitrothe link between miR-17 and TGFBR2 expressions. These findings support an effect of natalizumab on expression of specific miRNA and subsequent expression of genes involved in proliferation and control of the cell cycle.

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