Limitations to the inference of gene flow at regional geographic scales–an example from the Pieris napi group (Lepidoptera: Pieridae) in Europe

We used hierarchical and pairwise F-statistics to describe genetic differentiation and infer gene flow (M) on local and regional scales within and among parapatric European butterfly taxa in the Pieris napi (L.) group. Within-population allozyme variability is consistently high, and local effective population sizes are inferred to be in the thousands of individuals. The pairwise analysis yields an average neighbourhood area of radius 3.5 km. Among populations within most regions, differentiation is low and M > 2 effective individuals population^-1generation^-1. Pairwise comparisons within the brilannica group show a disjunction indicating that it is out of equilibrium, perhaps as a result of secondary contact between highland and lowland groups. Comparison between meridionalis groups on mainland Italy and Corsica yields M > 12; this is surely loo high and lack of equilibrium resulting from initial colonization is suspected. The hierarchical analysis indicates that 23 ≤0020M≤ 88 among the taxa napi, bryoniae and meridionalis that meet in hybrid zones; no effective gene flow barrier exists among them. This high estimate could also result from recent primary contact, but such a genetic barrier should produce the ‘edge effects' seen in population genetic simulations, and no evidence of this was found among geographically close samples of napi and bryoniae populations from Switzerland. Studies of gene flow among geographic regions are greatly limited by the equilibrium assumption, though studies of local differentiation are much less so. Population studies of gene flow on local scales at regional boundaries provide limited means of testing the equilibrium assumption, and both regional and local analyses provide testable predictions about local population structure. When the equilibrium assumption is not upheld, local patterns at regional boundaries can provide historical information about primary vs. secondary contact.     

Caveolin-1 inhibits epidermal growth factor-stimulated lamellipod extension and cell migration in metastatic mammary adenocarcinoma cells (MTLn3). Transformation suppressor effects of adenovirus-mediated gene delivery of caveolin-1

Caveolin-1 is a principal component of caveolae membranes that may function as a transformation suppressor. For example, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (D7S522; 7q31.1) that is deleted in human cancers, including mammary carcinomas. However, little is known about the role of caveolins in regulating cell movement, a critical parameter in determining metastatic potential. Here, we examine the role of caveolin-1 in cell movement. For this purpose, we employed an established cellular model, MTLn3, a metastatic rat mammary adenocarcinoma cell line. In this system, epidermal growth factor (EGF) stimulation induces rapid lamellipod extension and cell migration. Interestingly, we find that MTLn3 cells fail to express detectable levels of endogenous caveolin-1. To restore caveolin-1 expression in MTLn3 cells efficiently, we employed an inducible adenoviral gene delivery system to achieve tightly controlled expression of caveolin-1. We show here that caveolin-1 expression in MTLn3 cells inhibits EGF-stimulated lamellipod extension and cell migration and blocks their anchorage-independent growth. Under these conditions, EGF-induced activation of the p42/44 mitogen-activated protein kinase cascade is also blunted. Our results suggest that caveolin-1 expression in motile MTLn3 cells induces a non-motile phenotype.     

High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A

Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here we report that in mouse kidney endothelial cells, high glucose causes increased methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc-transferase, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding to a glucose-responsive GC-box in the angiopoietin-2 (Ang-2) promoter, resulting in increased Ang-2 expression. Increased Ang-2 expression induced by high glucose increased expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in cells and in kidneys from diabetic mice and sensitized microvascular endothelial cells to the proinflammatory effects of tumor necrosis factor alpha. This novel mechanism for regulating gene expression may play a role in the pathobiology of diabetic vascular disease.     

The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreatic inflammation

Melanoma differentiation‐associated protein 5 (MDA5) mediates the innate immune response to viral infection. Polymorphisms in IFIH1, the gene coding for MDA5, correlate with the risk of developing type 1 diabetes (T1D). Here, we demonstrate that MDA5 is crucial for the immune response to enteric rotavirus infection, a proposed etiological agent for T1D. MDA5 variants encoded by minor IFIH1 alleles associated with lower T1D risk exhibit reduced activity against rotavirus infection. We find that MDA5 activity limits rotavirus infection not only through the induction of antiviral interferons and pro‐inflammatory cytokines, but also by promoting cell death. Importantly, this MDA5‐dependent antiviral response is specific to the pancreas of rotavirus‐infected mice, similar to the autoimmunity associated with T1D. These findings imply that MDA5‐induced cell death and inflammation in the pancreas facilitate progression to autoimmune destruction of pancreatic β‐cells.