Isolation-by-distance in landscapes: considerations for landscape genetics.

In landscape genetics, isolation-by-distance (IBD) is regarded as a baseline pattern that is obtained without additional effects of landscape elements on gene flow. However, the configuration of suitable habitat patches determines deme topology, which in turn should affect rates of gene flow. IBD patterns can be characterized either by monotonically increasing pairwise genetic differentiation (for example, FST) with increasing interdeme geographic distance (case-I pattern) or by monotonically increasing pairwise genetic differentiation up to a certain geographical distance beyond which no correlation is detectable anymore (case-IV pattern). We investigated if landscape configuration influenced the rate at which a case-IV pattern changed to a case-I pattern. We also determined at what interdeme distance the highest correlation was measured between genetic differentiation and geographic distance and whether this distance corresponded to the maximum migration distance. We set up a population genetic simulation study and assessed the development of IBD patterns for several habitat configurations and maximum migration distances. We show that the rate and likelihood of the transition of case-IV to case-I FST-distance relationships was strongly influenced by habitat configuration and maximum migration distance. We also found that the maximum correlation between genetic differentiation and geographic distance was not related to the maximum migration distance and was measured across all deme pairs in a case-I pattern and, for a case-IV pattern, at the distance where the FST-distance curve flattens out. We argue that in landscape genetics, separate analyses should be performed to either assess IBD or the landscape effects on gene flow.

Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages.

Neuroinflammation, as defined by activation of local glial cells and production of various inflammatory mediators, is an important feature of many neurological disorders. Expression of pro-inflammatory mediators produced by glial cells in the central nervous system (CNS) is considered to contribute to the neuropathology observed in those diseases. To diminish the production or action of pro-inflammatory mediators, we have used lentiviral (LV) vector-mediated encoding rat interleukin-10 (rIL-10) or rat interleukin-1 receptor antagonist (rIL-1ra) to direct the local, long-term expression of these anti-inflammatory cytokines in the CNS. We have shown that cultured macrophages or astroglia transduced with LV-rIL-10 or LV-rIL-1ra produced far less tumor necrosis factor (TNF)alpha or IL-6, respectively in response to pro-inflammatory stimuli. Moreover, intracerebroventricular (i.c.v.) administration of LV-rIL-10 or LV-rIL-1ra resulted in transduction of glial cells and macrophages and, subsequently reduced TNFalpha, IL-6 and inducible nitric oxide synthase (iNOS) expression in various brain regions induced by inflammatory stimuli, whereas peripheral expression of these mediators remained unaffected. In addition, expression levels of the anti-inflammatory cytokines IL-4 and transforming growth factor-beta were not altered in either brain or pituitary gland. Furthermore, i.c.v. administration of LV-rIL-10 or LV-rIL-1ra given during the remission phase of chronic-relapsing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, improved the clinical outcome of the relapse phase. Thus, local application of LV vectors expressing anti-inflammatory cytokines could be of therapeutic interest to counteract pro-inflammatory processes in the brain without interfering with the peripheral production of inflammatory mediators.

Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy.

Multiple Sclerosis (MS) is an autoimmune inflammatory disease that presents clinically with a range of symptoms including motor, sensory, and cognitive dysfunction as well as demyelination and lesion formation in brain and spinal cord. A variety of animal models of MS have been developed that share many of the pathological hallmarks of MS including motor deficits (ascending paralysis), demyelination and axonal damage of central nervous system (CNS) tissue. In recent years, neuropathic pain has been recognized as a prevalent symptom of MS in a majority of patients. To date, there have been very few investigations into sensory disturbances in animal models of MS. The current work contains the first assessment of hind paw mechanical allodynia (von Frey test) over the course of a relapsing-remitting myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE) rat model of MS and establishes the utility of this model in examining autoimmune induced sensory dysfunction. We demonstrate periods of both decreased responsiveness to touch that precedes the onset of hind limb paralysis, and increased responsiveness (allodynia) that occurs during the period of motor deficit amelioration traditionally referred to as symptom remission. Furthermore, we tested the ability of our recently characterized anti-inflammatory IL-10 gene therapy to treat the autoimmune inflammation induced behavioral symptoms and tissue histopathological changes. This therapy is shown here to reverse inflammation induced paralysis, to reduce disease associated reduction in sensitivity to touch, to prevent the onset of allodynia, to reverse disease associated loss of body weight, and to suppress CNS glial activation associated with disease progression in this model.

Inhibition of osteoclastic bone resorption by mechanical stimulation in vitro.

The influence of mechanical stimulation by intermittent compressive force (ICF) of physiologic magnitude on osteoclastic bone resorption was investigated in cultures of fetal mouse cartilaginous long bones. Exposure to ICF resulted in a significant decrease in mineral resorption, as indicated by the decreased release of 45Ca and a decreased number of osteoclasts in the diaphysis. Conditioned medium (CM) from ICF-exposed periosteum-free cultures (ICF-CM), but not from control cultures (Co-CM), inhibited mineral resorption in fresh bones cultured under control conditions. Co-CM increased, but ICF-CM decreased, the number of tartrate-resistant acid phosphatase-positive cells in 7-day bone marrow cultures. Direct exposure of bone marrow cultures to ICF yielded the same results. Thus, osteoclastic bone resorption in cartilaginous long bones is inhibited by ICF in vitro. A soluble factor(s) acting on tartrate-resistant acid phosphatase-positive, osteoclast precursor-like cells seems to play a role in this effect.

Perilobular fibrosis in chronic bovine fascioliasis.

The character, extent, and localization of perilobular fibrosis were studied in cattle experimentally infected with Fasciola hepatica. Such fibrosis is indirectly due to the liver flukes. The regionally localized fibrosis results from cholestasis due to transient occlusion of branches of the biliary tree. In periobular fibrosis it is possible to distinguish a florid, an intermediate, and an uncomplicated form. The florid phase is marked by proliferation of the biliary epithelium and is followed by infiltration of inflammatory cells.

Perilobular fibrosis in chronic bovine fascioliasis.

Summary The character, extent, and localization of perilobular fibrosis were studied in cattle experimentally infected with Fasciola hepatica. Such fibrosis is indirectly due to the liver flukes. The regionally localized fibrosis results from cholestasis due to transient occlusion of branches of the biliary tree. In perilobular fibrosis it is possible to distinguish a florid, an intermediate, and an uncomplicated form. The florid phase is marked by proliferation of the biliary epithelium and is followed by infiltration of inflammatory cells.