Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

Pigment epithelium-derived factor protects retinal ganglion cells

BACKGROUND: Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors. RESULTS: Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC(50 )= 31 μM). In the presence of 100 μM glutamate, RGC number decreased to 55 ± 4% of control (mean ± SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 ± 4%, n = 60, P < 0.001). PEDF protected against both insults with EC(50 )values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor κB (NFκB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF. CONCLUSION: We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFκB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma

The genome-wide dynamics of purging during selfing in maize

Self-fertilization (also known as selfing) is an important reproductive strategy in plants and a widely applied tool for plant genetics and plant breeding. Selfing can lead to inbreeding depression by uncovering recessive deleterious variants, unless these variants are purged by selection. Here we investigated the dynamics of purging in a set of eleven maize lines that were selfed for six generations. We show that heterozygous, putatively deleterious single nucleotide polymorphisms are preferentially lost from the genome during selfing. Deleterious single nucleotide polymorphisms were lost more rapidly in regions of high recombination, presumably because recombination increases the efficacy of selection by uncoupling linked variants. Overall, heterozygosity decreased more slowly than expected, by an estimated 35% to 40% per generation instead of the expected 50%, perhaps reflecting pervasive associative overdominance. Finally, three lines exhibited marked decreases in genome size due to the purging of transposable elements. Genome loss was more likely to occur for lineages that began with larger genomes with more transposable elements and chromosomal knobs. These three lines purged an average of 398 Mb from their genomes, an amount equivalent to three Arabidopsis thaliana genomes per lineage, in only a few generations

The relationship between doses of mindfulness-based programs and depression, anxiety, stress, and mindfulness: a dose-response meta-regression of randomized controlled trials

Abstract Objectives: Research with mindfulness-based programs (MBPs) has found participating in an MBP to predict beneficial outcomes, however, there is currently mixed research regarding the most helpful dose. This review aimed to determine whether different doses related to MBPs significantly predict outcomes. Methods: Systematic literature searches of electronic databases and trial registration sites for all randomized controlled trials of MBPs identified 203 studies (N=15,971). Depression was the primary outcome at post-program and follow-up, with secondary outcomes being mindfulness, anxiety and stress. Doses examined related to session numbers, duration and length, facilitator contact and practice. Dose-response relationships were analyzed using meta-regression in R with separate analyses for inactive and active controls. Results: Initial meta-analyses found significant between-group differences favoring MBPs for all outcomes. Meta-regression results suggested significant dose-response relationships for the mindfulness outcome for doses relating to face-to-face contact (d=0.211; C.I.[0.064,0.358]), program intensity (d=0.895; C.I.[0.315,1.474]) and actual program use (d=0.013; C.I.[0.001,0.024]). The majority of results for psychological outcomes, including depression, were not significant. Conclusions: This meta-regression examines dose-response relationships for different types and doses relating to MBPs. Considered together, MBPs appeared helpful compared to controls, supporting previous research. Based on meta-regression results, there was no evidence that larger doses are more helpful than smaller doses for predicting psychological outcomes; a finding consistent with some previous research particularly with non-clinical populations. Additionally, greater contact, intensity and actual use of MBPs predicting increased mindfulness corresponds with previous research and theory. Potential limitations and recommendations for future research are explored

Spatial correlation bias in late-Cenozoic erosion histories derived from thermochronology

International audienceThe potential link between erosion rates at the Earth's surface and changes in global climate has intrigued geoscientists for decades1,2 because such a coupling has implications for the influence of silicate weathering3,4 and organic-carbon burial5 on climate and for the role of Quaternary glaciations in landscape evolution1,6. A global increase in late-Cenozoic erosion rates in response to a cooling, more variable climate has been proposed on the basis of worldwide sedimentation rates7. Other studies have indicated, however, that global erosion rates may have remained steady, suggesting that the reported increases in sediment-accumulation rates are due to preservation biases, depositional hiatuses and varying measurement intervals8-10. More recently, a global compilation of thermochronology data has been used to infer a nearly twofold increase in the erosion rate in mountainous landscapes over late-Cenozoic times6. It has been contended that this result is free of the biases that affect sedimentary records11, although others have argued that it contains biases related to how thermochronological data are averaged12 and to erosion hiatuses in glaciated landscapes13. Here we investigate the 30 locations with reported accelerated erosion during the late Cenozoic6. Our analysis shows that in 23 of these locations, the reported increases are a result of a spatial correlation bias—that is, combining data with disparate exhumation histories, thereby converting spatial erosion-rate variations into temporal increases. In four locations, the increases can be explained by changes in tectonic boundary conditions. In three cases, climatically induced accelerations are recorded, driven by localized glacial valley incision. Our findings suggest that thermochronology data currently have insufficient resolution to assess whether late-Cenozoic climate change affected erosion rates on a global scale. We suggest that a synthesis of local findings that include location-specific information may help to further investigate drivers of global erosion rates