A key role for PTP1B in dendritic cell maturation, migration and T cell activation

Acknowledgements We thank the Iain Fraser Flow Cytometry Centre and the Medical Research Facility of the University of Aberdeen. We are grateful to Drs West, Zaru, and Davidson (University of Dundee) for the scientific discussion and technical assistance. Wethank Derek Mitchell (University of Dundee) for aiding with the quantification of focal contacts. Funding This work was supported by Saving Sight in Grampian and the Development Trust of the UoA (both to J.V.F.). Work on this project was partly funded by project grants from British Heart Foundation and European Foundation for the Study of Diabetes/Lilly diabetes programme grant (to M.D.).

A key role for PTP1B in dendritic cell maturation, migration and T cell activation

Acknowledgements We thank the Iain Fraser Flow Cytometry Centre and the Medical Research Facility of the University of Aberdeen. We are grateful to Drs West, Zaru, and Davidson (University of Dundee) for the scientific discussion and technical assistance. Wethank Derek Mitchell (University of Dundee) for aiding with the quantification of focal contacts. Funding This work was supported by Saving Sight in Grampian and the Development Trust of the UoA (both to J.V.F.). Work on this project was partly funded by project grants from British Heart Foundation and European Foundation for the Study of Diabetes/Lilly diabetes programme grant (to M.D.).

Enzymatic transhalogenation of dendritic RGD peptide constructs with the fluorinase

We thank EPSRC and the Scottish Imaging Network (SINAPSE) for grants. DO’H thanks the Royal Society for a Wolfson Research Merit Award and ST is grateful to the John and Kathleen Watson Scholarship for financial support. We are grateful to Dr Catherine Botting and Dr Sally Shirran of the St Andrews Mass Spectrometry Service for MALDI-MS acquisitions. We also thank Dr Sally Pimlott of the University of Glasgow for the use of radiochemistry facilities.

FdDCA : A Novel Fuzzy Deterministic Dendritic Cell Algorithm

Postprint

Characterization of plasmacytoid dendritic cells in the CD4C/HIV transgenic mouse model

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development of a novel approach for brain delivery : dendritic nanocarriers for the enhanced delivery of methotrexate to the brain tumors

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Regulates Dendritic Cells and Myeloid Derived Suppressor Cells Development in the Lymphoma Microenvironment

Calcium (Ca2+) is a known important second messenger. Calcium/Calmodulin (CaM) dependent protein kinase kinase 2 (CaMKK2) is a crucial kinase in the calcium signaling cascade. Activated by Ca2+/CaM, CaMKK2 can phosphorylate other CaM kinases and AMP-activated protein kinase (AMPK) to regulate cell differentiation, energy balance, metabolism and inflammation. Outside of the brain, CaMKK2 can only be detected in hematopoietic stem cells and progenitors, and in the subsets of mature myeloid cells. CaMKK2 has been noted to facilitate tumor cell proliferation in prostate cancer, breast cancer, and hepatic cancer. However, whethter CaMKK2 impacts the tumor microenvironment especially in hematopoietic malignancies remains unknown. Due to the relevance of myeloid cells in tumor growth, we hypothesized that CaMKK2 has a critical role in the tumor microenvironment, and tested this hyopothesis in murine models of hematological and solid cancer malignancies.

We found that CaMKK2 ablation in the host suppressed the growth of E.G7 murine lymphoma, Vk*Myc myeloma and E0771 mammary cancer. The selective ablation of CaMKK2 in myeloid cells was sufficient to restrain tumor growth, of which could be reversed by CD8 cell depletion. In the lymphoma microenvironment, ablating CaMKK2 generated less myeloid-derived suppressor cells (MDSCs) in vitro and in vivo. Mechanistically, CaMKK2 deficient dendritic cells showed higher Major Histocompatibility Class II (MHC II) and costimulatory factor expression, higher chemokine and IL-12 secretion when stimulated by LPS, and have higher potent in stimulating T-cell activation. AMPK, an anti-inflammatory kinase, was found as the relevant downstream target of CaMKK2 in dendritic cells. Treatment with CaMKK2 selective inhibitor STO-609 efficiently suppressed E.G7 and E0771 tumor growth, and reshaped the tumor microenvironment by attracting more immunogenic myeloid cells and infiltrated T cells.

In conclusion, we demonstrate that CaMKK2 expressed in myeloid cells is an important checkpoint in tumor microenvironment. Ablating CaMKK2 suppresses lymphoma growth by promoting myeloid cells development thereby decreasing MDSCs while enhancing the anti-tumor immune response. CaMKK2 inhibition is an innovative strategy for cancer therapy through reprogramming the tumor microenvironment.

Spatiotemporal Dynamics of CaMKI During Structural Plasticity of Single Dendritic Spines

Multifunctional calcium/calmodulin dependent protein kinases (CaMKs) are key regulators of spine structural plasticity and long-term potentiation (LTP) in neurons. CaMKs have promiscuous and overlapping substrate recognition motifs, and are distinguished in their regulatory role based on differences in the spatiotemporal dynamics of activity. While the function and activity of CaMKII in synaptic plasticity has been extensively studied, that of CaMKI, another major class of CaMK required for LTP, still remain elusive.

Here, we develop a Förster’s Resonance Energy Transfer (FRET) based sensor to measure the spatiotemporal activity dynamics of CaMK1. We monitored CaMKI activity using 2-photon fluorescence lifetime imaging, while inducing LTP in single dendritic spines of rat (Rattus Norvegicus, strain Sprague Dawley) hippocampal CA1 pyramidal neurons using 2-photon glutamate uncaging. Using RNA-interference and pharmacological means, we also characterize the role of CaMKI during spine structural plasticity.

We found that CaMKI was rapidly and transiently activated with a rise time of ~0.3 s and decay time of ~1 s in response to each uncaging pulse. Activity of CaMKI spread out of the spine. Phosphorylation of CaMKI by CaMKK was required for this spreading and for the initial phase of structural LTP. Combined with previous data showing that CaMKII is restricted to the stimulated spine and required for long-term maintenance of structural LTP, these results suggest that CaMK diversity allows the same incoming signal – calcium – to independently regulate distinct phases of LTP by activating different CaMKs with distinct spatiotemporal dynamics.

Characterization of plasmacytoid dendritic cells in the CD4C/HIV transgenic mouse model

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development of a novel approach for brain delivery : dendritic nanocarriers for the enhanced delivery of methotrexate to the brain tumors

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Multiples in the Newborn Intensive Care Unit: parents' and nurses' perspectives

This paper discusses the issues of parents and nurses when mulitples are admitted to busy NICU's

The role of the Midwife in the Final Examination of the Newborn

This poster illustrated the role of the midiwfe in the final examination and discharge of the newborn baby.

The effect of garlic extract on growth, haematology and cell-mediated immune response of newborn goat kids

The present study was carried out to evaluate the effect of different levels of garlic extract supplemented in milk on growth rate, haematology and cell–mediated immune response of Markhoz newborn goat kids. Twenty four newborn goat kids (aged 7+/-3days) were randomly assigned to four groups. The groups consisted of control (received milk without garlic extract), T1, T2 and T3 which received milk supplemented with 62.5, 125 and 250 mg aqueous garlic extract per kg live weight per day for 42 days, respectively. Body weights were measured weekly throughout the experimental period. At day 42, about 10 ml blood samples were collected from each kid via the jugular vein for haematological study. Cell–mediated immune response was evaluated through double skin thickness after intradermal injection of phyto-hematogglutinin (PHA) at day 21 and 42. Total gain was significantly higher for kids in T3 (P<0.05) compared with the control group. Average daily gain (ADG) in T3 group in week 4–5 was higher (P<0.05). Significant differences in globulin (P<0.01), hemoglobin (Hb; P<0.001), hematocrit (PCV; P<0.001), erythrocyte (RBC; P<0.001), neutrophil (P<0.001), lymphocyte (P<0.001) and leukocyte (WBC; P<0.001) were observed among groups. Hb, PCV, RBC, lymphocytes and WBC were higher in kids given garlic extract supplementation. There was a significant difference of double skin thickness among the groups at day 42 (P<0.01). In conclusion, this study indicated that milk supplemented with aqueous garlic extract improved growth rate and immunity of newborn goat kids.

Evaluation of a Quality Improvement (QI) Intervention for Maternal, Newborn, and Child Health (MNCH) in Colombia: The Mil Días Intervention of SINERGIAS in the Department of Bolívar

Thesis (Master's)--University of Washington, 2016-06