BMI and retinal vascular caliber in children

Objective: In adult populations, changes in retinal vascular caliber have been linked with obesity and metabolic syndrome. We examined the association of BMI and weight with retinal vascular caliber in children. Research Methods and Procedures: This was a school‐based, cross‐sectional study of 768 children, 7 to 9 years old, randomly sampled from the Singapore Cohort Study of the Risk Factors for Myopia. Participants had digital retinal photographs. Retinal vascular caliber was measured using a computer‐based program and combined to provide average calibers of arterioles and venules in that eye. Weight and height were measured using standardized protocol. These data were used to calculate BMI. Results: In this population, the mean retinal arteriolar and venular calibers were 156.40 μm [95% confidence interval (CI), 155.44 to 157.36] and 225.43 μm (95% CI, 224.10 to 226.74) respectively. After controlling for age, gender, race, parental monthly income, axial length, birth weight, and birth length, each 3.1 kg/m² (standard deviation) increase in BMI was associated with a 2.55‐μm (95% CI, 1.21 to 3.89; p < 0.001) larger retinal venular caliber. In multivariable analysis, greater weight was also significantly associated with larger retinal venular caliber. BMI and weight were not associated with retinal arteriolar caliber. Height was not significantly associated with retinal arteriolar or venular caliber. Discussion: Greater BMI and weight are associated with larger retinal venular caliber in healthy children.     

Hydrogen sulfide acts as a mediator of inflammation in acute pancreatitis: in vitro studies using isolated mouse pancreatic acinar cells

Hydrogen sulphide (H(2)S) is synthesized from L-cysteine via the action of cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS). We have earlier shown that H(2)S acts as a mediator of inflammation. However the mechanism remains unclear. In this study, we investigated the presence of H(2)S and the expression of H(2)S synthesizing enzymes, CSE and CBS, in isolated mouse pancreatic acini. Pancreatic acinar cells from mice were incubated with or without caerulein (10(-7) M for 30 and 60 min). Caerulein increased the levels of H(2)S and CSE mRNA expression while CBS mRNA expression was decreased. In addition, cells pre-treated with DL-propargylglycine (PAG, 3 mM), a CSE inhibitor, reduced the formation of H(2)S in caerulein treated cells, suggesting that CSE may be the main enzyme involved in H(2)S formation in mouse acinar cells. Furthermore, substance P (SP) concentration in the acini and expression of SP gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for SP, are increased in secretagogue caerulein-treated acinar cells. Inhibition of endogenous production of H(2)S by PAG significantly suppressed SP concentration, PPT-A expression and NK1-R expression in the acini. To determine whether H(2)S itself provoked inflammation in acinar cells, the cells were treated with H(2)S donor drug, sodium hydrosulphide (NaHS), (10, 50 and 100 muM), that resulted in a significant increase in SP concentration and expression of PPT-A and NK1-R in acinar cells. These results suggest that the pro-inflammatory effect of H(2)S may be mediated by SP-NK-1R related pathway in mouse pancreatic acinar cells.     

Effect of mitogen-activated protein kinases on chemokine synthesis induced by substance P in mouse pancreatic acinar cells

Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFκB-driven chemokines. However, the signal transduction pathways by which substance P-NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen-activated protein kinases (MAPKs) in substance P-induced synthesis of pro-inflammatory chemokines, monocyte chemoanractant protein-1 (MCP-I), macrophage inflammatory protein-lα (MIP-lα) and macrophage inflammatory protein-2 (MIP-2), in pancreatic acini. In this study, we observed a time-dependent activation of ERK1/2, c-Jun N-terminal kinase (JNK), NFκB and activator protein-1 (AP-1) when pancreatic acini were stimulated with substance P. Moreover, substance P-induced ERK 1/2, JNK, NFκB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P-induced activation of ERK 112, JNK, NFκB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFκB and AP-1 signalling pathways in mouse pancreatic acini.     

Theoretical insights into the metal chelating and antimicrobial properties of the chalcone based Schiff bases

The emergence of multi-drug resistant pathogens in infectious disease conditions accentuates the need for the design of new classes of antimicrobial agents that could defeat the multidrug resistance problems. As a new class of molecules, the Heterocyclic Schiff base is of considerable interest, owing to their preparative accessibility, structural flexibilities, versatile metal chelating properties, and inherent biological activities. In the present study, CAM-B3LYP/LANL2DZ and M062X/DEF2-TZVP level of density functional method is used to explore the complexation of chalcone based Schiff base derivatives by Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺ metal ions. The HL(1-3)-Co²⁺, HL(1-3)-Ni²⁺ and HL(1-3)-Zn²⁺ complexes formed the distorted tetrahedral geometry. Whereas, the HL(1-3)-Cu²⁺ complexes prefers distorted square-planar geometry. The BSSE corrected interaction energies of the studied complexes reveals that Cu²⁺ ion forms the most stable complexes with all three chalcone based Schiff bases. Of the three Schiff bases studied, the HL2 Schiff base acts as a potent chelating agent and forms the active metal complexes than the HL1 and HL3 Schiff bases. Further, the strength of the interaction follows the order as Cu^2+?>?Ni^2+?>?Co^2+?>?Zn²⁺. The QTAIM analysis reveals that the interaction between the metal ions and coordinating ligand atoms are electrostatic dominant. The metal interaction increases the π-delocalisation of electrons over the entire chelate. Hence, the antimicrobial activity of the metal complexes is more effective than the free Schiff bases. Moreover, the HL(1-3)-Cu²⁺ complexes shows higher antimicrobial activities than the other complexes studied.     

A three-dimensional multiscale model for the prediction of thrombus growth under flow with single-platelet resolution

Modeling thrombus growth in pathological flows allows evaluation of risk under patient-specific pharmacological, hematological, and hemodynamical conditions. We have developed a 3D multiscale framework for the prediction of thrombus growth under flow on a spatially resolved surface presenting collagen and tissue factor (TF). The multiscale framework is composed of four coupled modules: a Neural Network (NN) that accounts for platelet signaling, a Lattice Kinetic Monte Carlo (LKMC) simulation for tracking platelet positions, a Finite Volume Method (FVM) simulator for solving convection-diffusion-reaction equations describing agonist release and transport, and a Lattice Boltzmann (LB) flow solver for computing the blood flow field over the growing thrombus. A reduced model of the coagulation cascade was embedded into the framework to account for TF-driven thrombin production. The 3D model was first tested against in vitro microfluidics experiments of whole blood perfusion with various antiplatelet agents targeting COX-1, P₂Y₁, or the IP receptor. The model was able to accurately capture the evolution and morphology of the growing thrombus. Certain problems of 2D models for thrombus growth (artifactual dendritic growth) were naturally avoided with realistic trajectories of platelets in 3D flow. The generalizability of the 3D multiscale solver enabled simulations of important clinical situations, such as cylindrical blood vessels and acute flow narrowing (stenosis). Enhanced platelet-platelet bonding at pathologically high shear rates (e.g., von Willebrand factor unfolding) was required for accurately describing thrombus growth in stenotic flows. Overall, the approach allows consideration of patient-specific platelet signaling and vascular geometry for the prediction of thrombotic episodes.     

Active cell migration drives the unilateral movements of the anterior visceral endoderm

The anterior visceral endoderm (AVE) of the mouse embryo is a specialised extra-embryonic tissue that is essential for anterior patterning of the embryo. It is characterised by the expression of anterior markers such as Hex, Cerberus-like and Lhx1. At pre-gastrula stages, cells of the AVE are initially located at the distal tip of the embryo, but they then move unilaterally to the future anterior. This movement is essential for converting the existing proximodistal axis into an anteroposterior axis. To investigate this process, we developed a culture system capable of imaging embryos in real time with single cell resolution. Our results show that AVE cells continuously change shape and project filopodial processes in their direction of motion, suggesting that they are actively migrating. Their proximal movement stops abruptly at the junction of the epiblast and extra-embryonic ectoderm, whereupon they move laterally. Confocal microscope images show that AVE cells migrate as a single layer in direct contact with the epiblast, suggesting that this tissue might provide directional cues. Together, these results show that the anteroposterior axis is correctly positioned by the active movement of cells of the AVE in response to cues from their environment, and by a 'barrier' to their movement that provides an endpoint for this migration.     

Bioinformatics and cellular signaling

The understanding of cellular function requires an integrated analysis of context-specific, spatiotemporal data from diverse sources. Recent advances in describing the genomic and proteomic 'parts list' of the cell and deciphering the interrelationship of these parts are described, including genome-wide location analysis, standards for microarray data analysis, and two-hybrid and mass spectrometry approaches. This information is being collected and curated in databases such as the Alliance for Cellular Signaling (AfCS) Molecule Pages, which will serve as vital tools for the reconstruction and analysis of cellular signaling networks.