Mitochondrial Localized STAT3 Is Involved in NGF Induced Neurite Outgrowth

Background: Signal transducer and activator of transcription 3 (STAT3) plays critical roles in neural development and is increasingly recognized as a major mediator of injury response in the nervous system. Cytokines and growth factors are known to phosphorylate STAT3 at tyrosine 705 with or without the concomitant phosphorylation at serine 727, resulting in the nuclear localization of STAT3 and subsequent transcriptional activation of genes. Recent evidence suggests that STAT3 may control cell function via alternative mechanisms independent of its transcriptional activity. Currently, the involvement of STAT3 mono-phosphorylated at residue serine 727 (P-Ser-STAT3) in neurite outgrowth and the underlying mechanism is largely unknown. Principal Findings: In this study, we investigated the role of nerve growth factor (NGF) induced P-Ser-STAT3 in mediating neurite outgrowth. NGF induced the phosphorylation of residue serine 727 but not tyrosine 705 of STAT3 in PC12 and primary cortical neuronal cells. In PC12 cells, serine but not tyrosine dominant negative mutant of STAT3 was found to impair NGF induced neurite outgrowth. Unexpectedly, NGF induced P-Ser-STAT3 was localized to the mitochondria but not in the nucleus. Mitochondrial STAT3 was further found to be intimately involved in NGF induced neurite outgrowth and the production of reactive oxygen species (ROS). Conclusion: Taken together, the findings herein demonstrated a hitherto unrecognized novel transcription independen

Identification of novel small molecules that inhibit STAT3-dependent transcription and function

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents

Anuran responses to spatial patterns of agricultural landscapes in Argentina

Context: Amphibians are declining worldwide and land use change to agriculture is recognized as a leading cause. Argentina is undergoing an agriculturalization process with rapid changes in landscape structure. Objectives: We evaluated anuran response to landscape composition and configuration in two landscapes of east-central Argentina with different degrees of agriculturalization. We identified sensitive species and evaluated landscape influence on communities and individual species at two spatial scales. Methods: We compared anuran richness, frequency of occurrence, and activity between landscapes using call surveys data from 120 sampling points from 2007 to 2009. We evaluated anuran responses to landscape structure variables estimated within 250 and 500-m radius buffers using canonical correspondence analysis and multimodel inference from a set of candidate models. Results: Anuran richness was lower in the landscape with greater level of agriculturalization with reduced amount of forest cover and stream length. This pattern was driven by the lower occurrence and calling activity of seven out of the sixteen recorded species. Four species responded positively to the amount of forest cover and stream habitat. Three species responded positively to forest cohesion and negatively to rural housing. Two responded negatively to crop area and diversity of cover classes. Conclusions: Anurans within agricultural landscapes of east-central Argentina are responding to landscape structure. Responses varied depending on species and study scale. Life-history traits contribute to responses differences. Our study offers a better understanding of landscape effects on anurans and can be used for land management in other areas experiencing a similar agriculturalization process.Facultad de Ciencias ExactasCentro de Investigaciones del Medioambient

Low Reproductive Rate Predicts Species Sensitivity to Habitat Loss: A Meta-Analysis of Wetland Vertebrates

<div><p>We tested the hypotheses that species with greater mobility and/or higher reproductive rates are less sensitive to habitat loss than species with lower mobility and/or reproductive rates by conducting a meta-analysis of wetland vertebrate responses to wetland habitat loss. We combined data from 90 studies conducted worldwide that quantified the relationship between wetland amount in a landscape and population abundance of at least one wetland species to determine if mobility (indexed as home range size and body length) and annual reproductive rate influence species responses to wetland loss. When analyzed across all taxa, animals with higher reproductive rates were less sensitive to wetland loss. Surprisingly, we did not find an effect of mobility on response to wetland loss. Overall, wetland mammals and birds were more sensitive to wetland loss than were reptiles and amphibians. Our results suggest that dispersal between habitat patches is less important than species’ reproductive rates for population persistence in fragmented landscapes. This implies that immigration and colonization rate is most strongly related to reproduction, which determines the total number of potential colonists.</p></div

Relative effects of landscape-scale wetland amount and landscape matrix quality on wetland vertebrates: A meta-analysis

Conservation management of wetland-dependent species generally focuses on preserving or increasing wetland habitat. However, the quality of the landscape matrix (the intervening non-wetland portion of the landscape) has been shown to be more important than wetland availability for some wetland-dependent species. We used meta-analysis to compare the effects of wetland amount (measured as the area of wetland habitat in a landscape) and matrix quality (measured as the area of forest cover in the same landscape) on the population abundance of wetland-dependent vertebrates. We combined data across 63 studies conducted in forested ecoregions worldwide and extracted 330 population responses for 155 species, at the spatial scale that best predicted the effects of wetland amount and forest amount for each response. In addition, to ensure that our results were not biased by the scale selected, we assessed whether the relative effects of wetland and forest amount were scale dependent. We found that the amount of wetland in a landscape had a larger effect than the amount of forest on the abundance of mammals and birds whereas, surprisingly, for amphibians the amount of forest in a landscape was more important than the amount of wetland. For reptiles, both wetland amount and forest amount showed only weak effects on abundance. These results were not scale dependent, i.e., they were consistent across spatial scales. Our results suggest that the population distribution of wetland-dependent amphibians is more strongly related to landscape matrix quality than to wetland availability in a landscape, likely due to their requirement for access to terrestrial resources. We conclude that conservation policies for wetland biodiversity that focus only on wetland habitat will be ineffective in conserving many of these species. In addition

Effects of habitat loss, habitat configuration and matrix composition on declining wetland species

Worldwide declines in wetland birds and turtles are attributed to landscape-scale habitat loss, habitat fragmentation and anthropogenic land use. However, due to multi-collinearity, the relative importance of these factors is largely unknown. We evaluated the relative effects of wetland amount, wetland configuration (measured as the number of wetland patches), and matrix composition (measured as the amount of forest, cropland and road density) on the occurrence of eight declining wetland bird species and two threatened freshwater turtles across 66-70 landscapes. We selected landscapes to minimize correlations among the landscape-scale predictors and to represent the range of variation in each predictor available in the study region. For wetland birds, we found that the amount of wetland at a landscape-scale was more important than the other landscape variables, whereas surprisingly for turtles, the amount of forest in the surrounding landscape was more important than the other landscape variables. Wetland configuration independent of wetland amount was not an important predictor of any species. This is the first study to assess the relative, independent effects of the landscape-scale factors thought to contribute to wetland bird and turtle declines. Our results confirm that wetland loss is the primary landscape-scale factor of wetland bird declines, but suggest that forest loss may play a greater role in freshwater turtle declines than previously realized; minimizing forest loss will have the most positive outcome for freshwater turtle conservation. Therefore, effective conservation planning requires a multi-taxa approach to meet landscape-scale requirements of all declining wetland fauna

Pearson correlation coefficients (above diagonals) and associated p-values (below diagonals and italicized) between species traits within each vertebrate class.

a<p>home range (ha) = mean annual home range or seasonal migration distance across both sexes.</p>b<p>body length (cm) = average total body length of the two sexes.</p>c<p>reproductive rate = mean litter or clutch size multiplied by the mean number of litters or clutches per year.</p

Effects of species traits on vertebrate response to wetland loss.

<p>Effects of reproductive rate and mobility (indexed as home range size and body length) on population response of wetland vertebrates to wetland habitat loss in a landscape, including mammals, birds, reptiles and amphibians (n  = 137 species). Points represent mean-weighted effect sizes (<i>z</i>-transformed correlation coefficients) from mixed-effects meta-regression and lines indicate 95% confidence intervals.</p

Appendix A. Studies included in the meta-analysis and associated country, species, effect sizes, adjusted sample sizes, and study design categories.

Studies included in the meta-analysis and associated country, species, effect sizes, adjusted sample sizes, and study design categories

Appendix C. Funnel plots to assess publication bias in the meta-analysis.

Funnel plots to assess publication bias in the meta-analysis