Therapeutic angiogenesis for cardiovascular disease

The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy.     

HLA-DR alpha 2 mediates negative signalling via binding to Tirc7 leading to anti-inflammatory and apoptotic effects in lymphocytes in vitro and in vivo

Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRalpha2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-zeta chain & ZAP70, and inhibition of IFN-gamma and FasL expression. HLA-DRalpha2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRalpha2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway.     

Focal adhesion regulation of cell behavior

Focal adhesions lie at the convergence of integrin adhesion, signaling and the actin cytoskeleton. Cells modify focal adhesions in response to changes in the molecular composition, two-dimensional (2D) vs. three-dimensional (3D) structure, and physical forces present in their extracellular matrix environment. We consider here how cells use focal adhesions to regulate signaling complexes and integrin function. Furthermore, we examine how this regulation controls complex cellular behaviors in response to matrices of diverse physical and biochemical properties. One event regulated by the physical structure of the ECM is phosphorylation of focal adhesion kinase (FAK) at Y397, which couples FAK to several signaling pathways that regulate cell proliferation, survival, migration, and invasion.     

MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 microg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.     

Vibration attraction response is a plastic trait in blind Mexican tetra (Astyanax mexicanus), variable within subpopulations inhabiting the same cave

Animals evolve their sensory systems and foraging behaviours to adapt and colonize new and challenging habitats such as the dark cave environment. Vibration attraction behaviour (VAB) gives fish the ability to locate the source of a water disturbance in the darkness. VAB evolved in the blind Mexican cave tetra, Astyanax mexicanus. VAB is triggered in cavefish by vibration stimuli peaking at 35 Hz, which is within the main spectrum of water fluctuations produced by many prey crustaceans and insects. VAB has a genetic component and is correlated to an increased number of head mechanosensory neuromasts in the eye orbital region when compared to surface fish. Previous competitive prey capture assays have supported the advantage of VAB for foraging in the dark. Despite its putative adaptive function, VAB has been described as absent in some Astyanax cave populations (Tinaja and Molino) but present in others (Pachón, Piedras, Toro and Sabinos). Here we have tested the occurrence of VAB in the field and in multiple cave populations using a vibrating device in natural pools. Our results confirmed the presence of VAB in caves such as Pachón, Toro and Sabinos but showed that VAB is also present in the Tinaja and Molino cave populations, previously reported as VAB-negative in laboratory experiments. Thus, VAB is available throughout the range of hypogean A. mexicanus. However, and most notably, within a given cave the levels of VAB were highly variable among different pools. Fish at one pool may express no VAB, while fish at another nearby pool of the same cave may actively show VAB. While a variety of environmental conditions may foster this diversity, we found that individuals inhabiting pools with a high abundance of organic matter have reduced expression of VAB. In contrast, in pools with little organic debris where fish probably depend more on hunting than on scavenging, VAB is enhanced. Our results suggest that expression of VAB is a plastic trait whose variability can depend on local conditions. Such plasticity may be required within and among caves where high environmental variability between pools results in a diverse availability of food.     

Modeling the Growth/No-Growth Boundaries of Postprocessing Listeria monocytogenes Contamination on Frankfurters and Bologna Treated with Lactic Acid

This study developed models to predict lactic acid concentration, dipping time, and storage temperature combinations determining growth/no-growth interfaces of Listeria monocytogenes at desired probabilities on bologna and frankfurters. L. monocytogenes was inoculated on bologna and frankfurters, and 75 combinations of lactic acid concentrations, dipping times, and storage temperatures were tested. Samples were stored in vacuum packages for up to 60 days, and bacterial populations were enumerated on tryptic soy agar plus 0.6% yeast extract and Palcam agar on day zero and at the end point of storage. The combinations that allowed L. monocytogenes increases of ≥1 log CFU/cm² were assigned the value of 1 (growth), and the combinations that had increases of <l log CFU/cm² were given the value of 0 (no growth). These binary growth response data were fitted to logistic regression to develop a model predicting probabilities of growth. Validation with existing data and various indices showed acceptable model performance. Thus, the models developed in this study may be useful in determining probabilities of growth and in selecting lactic acid concentrations and dipping times to control L. monocytogenes growth on bologna and frankfurters, while the procedures followed may also be used to develop models for other products, conditions, or pathogens.