Prostaglandin E Inhibition of T-Lymphocyte Colony Formation A POSSIBLE MECHANISM OF MONOCYTE MODULATION OF CLONAL EXPANSION

A B S T R A C T Prostaglandin and monocyte modulation ofa T-lymphocyte cell capable ofundergoing clonal expansion was studied. Circulating human mononuclear cells were isolated by density centrifugation. After 24 h in culture with phytohemagglutinin present, the cells were mixed with 0.3% agar and overlayed onto a 0.5% agar layer that contained media and phytohemagglutinin. At day 6, colonies that contained >50 cells were counted. These colonies represented clonal proliferation ofa phytohemagglutinin-responsive T-lymphocyte precursor. This responder cell accounted for <0.3% of the starting cell population. Colonies were comprised ofcells which, when isolated, formed E rosettes. These colony cells could be shown to have helper or suppressor function as measured by their ability to promote or inhibit immunoglobulin synthesis. By these latter criteria the colony cells were considered to be mature T lymphocytes. The addition of prostaglandin E to the cultures demonstrated a linear, r = 0.82, dose-dependent inhibition of colony formation with a 50% point of inhibition (150) = 0.18 uM. Low numbers of normal monocytes when added to the cultures mimicked the effect of synthetic prostaglandin E2. A highly significant correlation could be shown for endogenous prostaglandin E levels and colony counts. It appears that monocytes through their synthesis of prostaglandin E2 can restrict the clonal expansion of a circulating T-lymphocyte precursor

Target Profile Estimation using Haar Functions

An approach to estimating the target acceleration in a maneuvering target model using Haar function partial summations to model the target acceleration is developed. A kinematic constraint is applied to the maneuvering target model and the effects of the use of this constraint are reviewed

Fabrication and characterization of Ag- and Ga-doped mesoporous glass-coated scaffolds based on natural marine sponges with improved mechanical properties

Natural marine sponges were used as sacrificial template for the fabrication of bioactive glassbased scaffolds. After sintering at 1050 ºC, the resulting samples were additionally coated with a sol silicate solution containing biologically active ions (Ag and Ga), well-known for their antibacterial properties in comparison with standard scaffolds made by PU foam templates. The produced scaffolds were characterized by superior mechanical properties (maximum compressive strength of 4 MPa) and total porosity of ~80%. Direct cell culture tests performed on the uncoated and coated samples showed positive results in terms of adhesion, proliferation, and differentiation of MC3T3-E1 cells. Moreover, vascular endothelial growth factor (VEGF) secretion from cells in contact with scaffold dissolution products was measured after 7 and 10 days of incubation, showing promising angiogenic results for bone tissue engineering applications. The antibacterial potential of the produced samples was assessed by performing agar diffusion tests against both Gram-positive and Gram-negative bacteria.EU Horizon 2020 project COACH 64255

Charge Delocalization in Self-Assembled Mixed-Valence Aromatic Cation Radicals

The spontaneous assembly of aromatic cation radicals (D+•) with their neutral counterpart (D) affords dimer cation radicals (D2+•). The intermolecular dimeric cation radicals are readily characterized by the appearance of an intervalence charge-resonance transition in the NIR region of their electronic spectra and by ESR spectroscopy. The X-ray crystal structure analysis and DFT calculations of a representative dimer cation radical (i.e., the octamethylbiphenylene dimer cation radical) have established that a hole (or single positive charge) is completely delocalized over both aromatic moieties. The energetics and the geometrical considerations for the formation of dimer cation radicals is deliberated with the aid of a series of cyclophane-like bichromophoric donors with drastically varied interplanar angles between the cofacially arranged aryl moieties. X-ray crystallography of a number of mixed-valence cation radicals derived from monochromophoric benzenoid donors established that they generally assemble in 1D stacks in the solid state. However, the use of polychromophoric intervalence cation radicals, where a single charge is effectively delocalized among all of the chromophores, can lead to higher-order assemblies with potential applications in long-range charge transport. As a proof of concept, we show that a single charge in the cation radical of a triptycene derivative is evenly distributed on all three benzenoid rings and this triptycene cation radical forms a 2D electronically coupled assembly, as established by X-ray crystallography

Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors

Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic tuberculosis (TB), remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analogue over the corresponding C-2'-β analogue, consistent with their differential whole-cell activity

New Approach for M-Cell-Specific Molecules Screening by Comprehensive Transcriptome Analysis

A minor population of M cells within the follicle-associated epithelium (FAE) of intestinal Peyer's patches (PPs) serves as a major portal for entry of exogenous antigens. Characterization of the mammalian M cells, including identification of M-cell surface molecules used for bacterial uptake, has been hampered by their relative rarity. In contrast, M cells constitute virtually all of the FAE cells in the avian bursa of Fabricius. We therefore performed comparative gene expression profiling of chicken and murine FAE to identify commonly expressed genes by M cells in both species. The comprehensive transcriptome analysis revealed that 28 genes were commonly up-regulated in FAE from both species. In situ hybridization revealed that annexin A10 (Anxa10) mRNA was scattered in FAE, and co-localized with Ulex europaeus agglutinin-1 binding to M cells. Whole-mount immunostaining also revealed that cellular prion protein (PrPC) was expressed on the luminal side of the apical plasma membrane of M cells, and co-localized with grycoprotein 2 that recognizes only M cells in murine PP. Our findings identify new M-cell-specific molecules through using comprehensive transcriptome analysis. These conserved molecules in M cells of mice and chickens may play essential roles in M-cell function and/or differentiation

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes: Interactions With Metformin

ObjectiveWe sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes.Research design and methodsHIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and beta-cell mass, function, and turnover were measured in each group.ResultsSitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis.ConclusionsThe combination of metformin and sitagliptin had synergistic actions to preserve beta-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation

Mononuclear cells modulate the activity of pancreatic stellate cells which in turn promote fibrosis and inflammation in chronic pancreatitis

Background: Interactions between mononuclear cells and activated pancreatic myofibroblasts (pancreatic stellate cells; PSC) may contribute to inflammation and fibrosis in chronic pancreatitis (CP). Methods: Markers of fibrosis and inflammation were concomitantly analysed by immunohistochemistry in chronic pancreatitis tissues. In vitro, PSC were stimulated with TNFalpha and LPS. Primary human blood mononuclear cells (PBMC) and PSC were cocultured, followed by analysis of cytokines and extracellular matrix (ECM) proteins. PBMC were derived from healthy donors and CP and septic shock patients. Results: In areas of mononuclear cell infiltration in chronic pancreatitis tissues, there was decreased immunoreactivity for collagen1 and fibronectin, in contrast to areas with sparse mononuclear cells, although PSC were detectable in both areas. LPS and TNFalpha induced collagen1 and fibronectin levels as well as the matrix degradation enzyme MMP-1. Coculture experiments with PSC and PBMC revealed increased fibronectin secretion induced by PBMC. In addition, donor and CP PBMC significantly induced an increase in IL-6, MCP-1 and TGFbeta levels under coculture conditions. Determination of the source of cytokines and ECM proteins by mRNA expression analysis confirmed PSC as major contributors of ECM production. The increase in cytokine expression was PBMC- and also PSC-derived. Conclusion: Mononuclear cells modulate the activity of pancreatic stellate cells, which may in turn promote fibrosis and inflammation