Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

Predator Dispersal Determines the Effect of Connectivity on Prey Diversity

Linking local communities to a metacommunity can positively affect diversity by enabling immigration of dispersal-limited species and maintenance of sink populations. However, connectivity can also negatively affect diversity by allowing the spread of strong competitors or predators. In a microcosm experiment with five ciliate species as prey and a copepod as an efficient generalist predator, we analysed the effect of connectivity on prey species richness in metacommunities that were either unconnected, connected for the prey, or connected for both prey and predator. Presence and absence of predator dispersal was cross-classified with low and high connectivity. The effect of connectivity on local and regional richness strongly depended on whether corridors were open for the predator. Local richness was initially positively affected by connectivity through rescue of species from stochastic extinctions. With predator dispersal, however, this positive effect soon turned negative as the predator spread over the metacommunity. Regional richness was unaffected by connectivity when local communities were connected only for the prey, while predator dispersal resulted in a pronounced decrease of regional richness. The level of connectivity influenced the speed of richness decline, with regional species extinctions being delayed for one week in weakly connected metacommunities. While connectivity enabled rescue of prey species from stochastic extinctions, deterministic extinctions due to predation were not overcome through reimmigration from predator-free refuges. Prey reimmigrating into these sink habitats appeared to be directly converted into increased predator abundance. Connectivity thus had a positive effect on the predator, even when the predator was not dispersing itself. Our study illustrates that dispersal of a species with strong negative effects on other community members shapes the dispersal-diversity relationship. When connections enable the spread of a generalist predator, positive effects of connectivity on prey species richness are outweighed by regional extinctions through predation

Characterization of Clinically-Attenuated Burkholderia mallei by Whole Genome Sequencing: Candidate Strain for Exclusion from Select Agent Lists

is an understudied biothreat agent responsible for glanders which can be lethal in humans and animals. Research with this pathogen has been hampered in part by constraints of Select Agent regulations for safety reasons. Whole genomic sequencing (WGS) is an apt approach to characterize newly discovered or poorly understood microbial pathogens. genome. Therefore, the strain by itself is unlikely to revert naturally to its virulent phenotype. There were other genes present in one strain and not the other and vice-versa. was both avirulent in the natural host ponies, and did not possess T3SS associated genes may be fortuitous to advance biodefense research. The deleted virulence-essential T3SS is not likely to be re-acquired naturally. These findings may provide a basis for exclusion of SAVP1 from the Select Agent regulation or at least discussion of what else would be required for exclusion. This exclusion could accelerate research by investigators not possessing BSL-3 facilities and facilitate the production of reagents such as antibodies without the restraints of Select Agent regulation

Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009). From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27).Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications

Firm insoles effectively reduce hemolysis in runners during long distance running - a comparative study

<p>Abstract</p> <p>Background</p> <p>Shock absorbing insoles are effective in reducing the magnitude and rate of loading of peak impact forces generated at foot strike during running, whereas the foot impact force during running has been considered to be an important cause of intravascular hemolysis in long distance runners. Objective of this study was to evaluate the intravascular hemolysis during running and compare the effect of two different types of insoles (Soft and Firm) on hemolysis.</p> <p>Methods</p> <p>Twenty male long and middle distance runners volunteered to participate in this study. We selected two insoles (Soft and Firm) according to their hardness level (SHORE 'A' scale). Participants were randomly assigned to the soft insole (group 1) and firm insole (group 2) group with ten athletes in each group. Each athlete completed one hour of running at the calculated target heart rate (60-70%). Venous blood samples were collected before and immediately after running. We measured unconjucated bilirubin (mg/dl), lactate dehydrogenase (μ/ml), hemoglobin (g/l) and serum ferritin (ng/ml) as indicators of hemolysis.</p> <p>Results</p> <p>Our study revealed a significant increase in the mean values of unconjucated bilirubin (P < 0.05) while running with soft insoles indicating the occurrence of hemolysis in this group of athletes. Graphical analysis revealed an inverse relationship between hardness of insoles and hemolysis for the observed values.</p> <p>Conclusion</p> <p>Our results indicate that intravascular hemolysis occurs in athletes during long distance running and we conclude that addition of firm insoles effectively reduces the amount of hemolysis in runners compared to soft insoles.</p

Expression analysis of Clavata1-like and Nodulin21-like genes from Pinus sylvestris during ectomycorrhiza formation

The ecology and physiology of ectomycorrhizal (EcM) symbiosis with conifer trees are well documented. In comparison, however, very little is known about the molecular regulation of these associations. In an earlier study, we identified three EcM-regulated Pinus expressed sequence tags (EST), two of which were identified as homologous to the Medicago truncatula nodulin MtN21. The third EST was a homologue to the receptor-like kinase Clavata1. We have characterized the expression patterns of these genes and of auxin- and mycorrhiza-regulated genes after induction with indole-3-butyric acid in Pinus sylvestris and in a time course experiment during ectomycorrhizal initiation with the co-inoculation of 2,3,5-triiodobenzoic acid, an auxin transport inhibitor. Our results suggest that different P. sylvestris nodulin homologues are associated with diverse processes in the root. The results also suggest a potential role of the Clv1-like gene in lateral root initiation by the ectomycorrhizal fungus

GC Content Increased at CpG Flanking Positions of Fish Genes Compared with Sea Squirt Orthologs as a Mechanism for Reducing Impact of DNA Methylation

Background: Fractional DNA methylation in sea squirts evolved to global DNA methylation in fish. The impact of global DNA methylation is reflected by more CpG depletions and/or more A/T to G/C changes at CpG flanking positions due to context-dependent mutations of methylated CpG sites. Methods and Findings: In this report, we demonstrate that the sea squirt genes have undergone more CpG to TpG/CpA substitutions than the fish orthologs using homologous fragments from orthologous genes among Ciona intestinalis, Ciona savignyi, fugufish and zebrafish. To avoid premature transcription, the TGA sites derived from CGA were largely converted to TGG in sea squirt genes. By contrast, a significant increment of GC content at CpG flanking positions was shown in fish genes. The positively selected A/T to G/C substitutions, in combination with the CpG to TpG/CpA substitutions, are the sources of the extremely low CpG observed/expected ratios in vertebrates. The nonsynonymous substitutions caused by the GC content increase have resulted in frequent amino acid replacements in the directions that were not noticed previously. Conclusion: The increased GC content at CpG flanking positions can reduce CpG loss in fish genes and attenuate the impact of DNA methylation on CpG-containing codons, probably accounting for evolution towards vertebrates. © 2008 Wang, Leung.published_or_final_versio

The logic-bias effect: The role of effortful processing in the resolution of belief-logic conflict.

According to the default interventionist dual-process account of reasoning, belief-based responses to reasoning tasks are based on Type 1 processes generated by default, which must be inhibited in order to produce an effortful, Type 2 output based on the validity of an argument. However, recent research has indicated that reasoning on the basis of beliefs may not be as fast and automatic as this account claims. In three experiments, we presented participants with a reasoning task that was to be completed while they were generating random numbers (RNG). We used the novel methodology introduced by Handley, Newstead & Trippas (Journal of Experimental Psychology: Learning, Memory, and Cognition, 37, 28-43, 2011), which required participants to make judgments based upon either the validity of a conditional argument or the believability of its conclusion. The results showed that belief-based judgments produced lower rates of accuracy overall and were influenced to a greater extent than validity judgments by the presence of a conflict between belief and logic for both simple and complex arguments. These findings were replicated in Experiment 3, in which we controlled for switching demands in a blocked design. Across all three experiments, we found a main effect of RNG, implying that both instructional sets require some effortful processing. However, in the blocked design RNG had its greatest impact on logic judgments, suggesting that distinct executive resources may be required for each type of judgment. We discuss the implications of our findings for the default interventionist account and offer a parallel competitive model as an alternative interpretation for our findings

The behaviour of inositol 1,3,4,5,6-pentakisphosphate in the presence of the major biological metal cations

The inositol phosphates are ubiquitous metabolites in eukaryotes, of which the most abundant are inositol hexakisphosphate (InsP6) and inositol 1,3,4,5,6-pentakisphosphate [Ins(1,3,4,5,6)P5)]. These two compounds, poorly understood functionally, have complicated complexation and solid formation behaviours with multivalent cations. For InsP6, we have previously described this chemistry and its biological implications (Veiga et al. in J Inorg Biochem 100:1800, 2006; Torres et al. in J Inorg Biochem 99:828, 2005). We now cover similar ground for Ins(1,3,4,5,6)P5, describing its interactions in solution with Na+, K+, Mg2+, Ca2+, Cu2+, Fe2+ and Fe3+, and its solid-formation equilibria with Ca2+ and Mg2+. Ins(1,3,4,5,6)P5 forms soluble complexes of 1:1 stoichiometry with all multivalent cations studied. The affinity for Fe3+ is similar to that of InsP6 and inositol 1,2,3-trisphosphate, indicating that the 1,2,3-trisphosphate motif, which Ins(1,3,4,5,6)P5 lacks, is not absolutely necessary for high-affinity Fe3+ complexation by inositol phosphates, even if it is necessary for their prevention of the Fenton reaction. With excess Ca2+ and Mg2+, Ins(1,3,4,5,6)P5 also forms the polymetallic complexes [M4(H2L)] [where L is fully deprotonated Ins(1,3,4,5,6)P5]. However, unlike InsP6, Ins(1,3,4,5,6)P5 is predicted not to be fully associated with Mg2+ under simulated cytosolic/nuclear conditions. The neutral Mg2+ and Ca2+ complexes have significant windows of solubility, but they precipitate as [Mg4(H2L)]·23H2O or [Ca4(H2L)]·16H2O whenever they exceed 135 and 56 μM in concentration, respectively. Nonetheless, the low stability of the [M4(H2L)] complexes means that the 1:1 species contribute to the overall solubility of Ins(1,3,4,5,6)P5 even under significant Mg2+ or Ca2+ excesses. We summarize the solubility behaviour of Ins(1,3,4,5,6)P5 in straightforward plots