Role of aberrant PI3K pathway activation in gallbladder tumorigenesis

The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations

Community dynamics of Pleistocene coral reefs during alternative climatic regimes

Reef ecosystems built during successive periods of Pleistocene sea level rise have shown remarkable persistence in coral community structure, but little is known of the ecological characteristics of reef communities during periods of low sea stands or sea level falls. We sampled the relative species abundance of coral, benthic foraminifera, and calcareous red algae communities from eight submerged coral reefs in the Huon Gulf, Papua New Guinea, which formed during successive sea level fall and lowstand periods over the past 416 kyr. We found that dissimilarity in coral species composition increased significantly with increasing time between reef-building events. However, neither coral diversity nor the taxonomic composition of benthic foraminifera and calcareous red algae assemblages varied significantly over time. The taxonomic composition of coral communities from lowstand reefs was significantly different from that of highstand reefs previously reported from the nearby Huon Peninsula. We interpret the community composition and temporal dynamics of lowstand reefs as a result of shifting energy regimes in the Huon Gulf, and differences between low and highstand reefs as a result of differences in the interaction between biotic and environmental factors between the Huon Gulf and Huon Peninsula. Regardless of the exact processes driving these trends, our study represents the first glimpse into the ecological dynamics of coral reefs during low sea level stands when climatic conditions for reef growth were much different and less optimal than during previously studied highstand periods. Copyright ESA. All rights reserved

Evolutionary impacts of fishing: overfishing's ‘Darwinian debt’

Human harvesting of fish results in far greater mortality than natural causes, with enormous potential to affect the phenotypic traits of fish populations, even after exploitation stops. Central to understanding these effects is the untangling of the genetic versus environmental components of phenotypic response. Evolutionary consequences of harvesting must be incorporated into conservation and management strategies

SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer

The RNA Binding Protein ESRP1 Fine-Tunes the Expression of Pluripotency-Related Factors in Mouse Embryonic Stem Cells

In pluripotent stem cells, there is increasing evidence for crosstalk between post-transcriptional and transcriptional networks, offering multifold steps at which pluripotency can be controlled. In addition to well-studied transcription factors, chromatin modifiers and miRNAs, RNA-binding proteins are emerging as fundamental players in pluripotency regulation. Here, we report a new role for the RNA-binding protein ESRP1 in the control of pluripotency. Knockdown of Esrp1 in mouse embryonic stem cells induces, other than the well-documented epithelial to mesenchymal-like state, also an increase in expression of the core transcription factors Oct4, Nanog and Sox2, thereby enhancing self-renewal of these cells. Esrp1-depleted embryonic stem cells displayed impaired early differentiation in vitro and formed larger teratomas in vivo when compared to control embryonic stem cells. We also show that ESRP1 binds to Oct4 and Sox2 mRNAs and decreases their polysomal loading. ESRP1 thus acts as a physiological regulator of the finely-tuned balance between self-renewal and commitment to a restricted developmental fate. Importantly, both mouse and human epithelial stem cells highly express ESRP1, pinpointing the importance of this RNA-binding protein in stem cell biology

Instability in a marginal coral reef: the shift from natural variability to a human-dominated seascape

As global climate change drives the demise of tropical reef ecosystems, attention is turning to the suitability o refuge habitat. For the Great Barrier Reef, are there historically stable southern refugia where corals from th north might migrate as climate changes? To address this question, we present a precise chronology of margina coral reef development from Moreton Bay, southeast Queensland, Australia. Our chronology shows that ree growth was episodic, responding to natural environmental variation throughout the Holocene, and tha Moreton Bay was inhospitable to corals for about half of the past 7000 years. The only significant change ii coral species composition occurred between similar to 200 and similar to 50 years ago, following anthropogenic alterations of th, bay and its catchments. Natural historical instability of reefs, coupled with environmental degradation sinc, European colonization, suggests that Moreton Bay offers limited potential as refuge habitat for reef species or human time scales

Influence of local habitat on the physiological responses of large benthic foraminifera to temperature and nutrient stress

Large benthic foraminifera (LBF) are important for reef sediment formation, but sensitive to elevated temperature and nutrients. However, it is possible that conspecific foraminifera living in different reef sites present divergent response to environmental shifts. We investigated how populations of Amphistegina lobifera from reef sites located along a temperature and nutrient gradient of the northern Great Barrier Reef respond and acclimate to elevated temperature and nitrate under lab-controlled conditions. Generalized linear mixed models showed that interaction between reef sites and temperature or nitrate conditions had a significant effect on survivorship, bleaching frequency and growth rates of A. lobifera. Further physiological analyses of antioxidant capacity and Ca-ATPase activity showed that populations collected from the inner-shelf sites (highest nutrient levels, largest temperature variation) were consistently able to acclimate to both parameters after 30 days. In contrast, foraminifera collected from the reef sites located in the mid- and outer-shelfs were significantly more sensitive to elevated temperatures and nitrate. Our results highlight the importance of local habitat in shaping the tolerance of LBF to changing environmental conditions; populations that live in stable environments are more sensitive to elevated temperature and nitrate, even within their fundamental tolerance range, than those that experience fluctuating conditions

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns