The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells

INTRODUCTION: Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. METHOD: A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor. RESULTS: In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous. CONCLUSION: Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor

Nestedness of Ectoparasite-Vertebrate Host Networks

Determining the structure of ectoparasite-host networks will enable disease ecologists to better understand and predict the spread of vector-borne diseases. If these networks have consistent properties, then studying the structure of well-understood networks could lead to extrapolation of these properties to others, including those that support emerging pathogens. Borrowing a quantitative measure of network structure from studies of mutualistic relationships between plants and their pollinators, we analyzed 29 ectoparasite-vertebrate host networks—including three derived from molecular bloodmeal analysis of mosquito feeding patterns—using measures of nestedness to identify non-random interactions among species. We found significant nestedness in ectoparasite-vertebrate host lists for habitats ranging from tropical rainforests to polar environments. These networks showed non-random patterns of nesting, and did not differ significantly from published estimates of nestedness from mutualistic networks. Mutualistic and antagonistic networks appear to be organized similarly, with generalized ectoparasites interacting with hosts that attract many ectoparasites and more specialized ectoparasites usually interacting with these same “generalized” hosts. This finding has implications for understanding the network dynamics of vector-born pathogens. We suggest that nestedness (rather than random ectoparasite-host associations) can allow rapid transfer of pathogens throughout a network, and expand upon such concepts as the dilution effect, bridge vectors, and host switching in the context of nested ectoparasite-vertebrate host networks

Super-Genotype: Global Monoclonality Defies the Odds of Nature

The ability to respond to natural selection under novel conditions is critical for the establishment and persistence of introduced alien species and their ability to become invasive. Here we correlated neutral and quantitative genetic diversity of the weed Pennisetum setaceum Forsk. Chiov. (Poaceae) with differing global (North American and African) patterns of invasiveness and compared this diversity to native range populations. Numerous molecular markers indicate complete monoclonality within and among all of these areas (FST = 0.0) and is supported by extreme low quantitative trait variance (QST = 0.00065–0.00952). The results support the general-purpose-genotype hypothesis that can tolerate all environmental variation. However, a single global genotype and widespread invasiveness under numerous environmental conditions suggests a super-genotype. The super-genotype described here likely evolved high levels of plasticity in response to fluctuating environmental conditions during the Early to Mid Holocene. During the Late Holocene, when environmental conditions were predominantly constant but extremely inclement, strong selection resulted in only a few surviving genotypes

Increasing Potential Risk of a Global Aquatic Invader in Europe in Contrast to Other Continents under Future Climate Change

BACKGROUND: Anthropogenically-induced climate change can alter the current climatic habitat of non-native species and can have complex effects on potentially invasive species. Predictions of the potential distributions of invasive species under climate change will provide critical information for future conservation and management strategies. Aquatic ecosystems are particularly vulnerable to invasive species and climate change, but the effect of climate change on invasive species distributions has been rather neglected, especially for notorious global invaders. METHODOLOGY/PRINCIPAL FINDINGS: We used ecological niche models (ENMs) to assess the risks and opportunities that climate change presents for the red swamp crayfish (Procambarus clarkii), which is a worldwide aquatic invasive species. Linking the factors of climate, topography, habitat and human influence, we developed predictive models incorporating both native and non-native distribution data of the crayfish to identify present areas of potential distribution and project the effects of future climate change based on a consensus-forecast approach combining the CCCMA and HADCM3 climate models under two emission scenarios (A2a and B2a) by 2050. The minimum temperature from the coldest month, the human footprint and precipitation of the driest quarter contributed most to the species distribution models. Under both the A2a and B2a scenarios, P. clarkii shifted to higher latitudes in continents of both the northern and southern hemispheres. However, the effect of climate change varied considerately among continents with an expanding potential in Europe and contracting changes in others. CONCLUSIONS/SIGNIFICANCE: Our findings are the first to predict the impact of climate change on the future distribution of a globally invasive aquatic species. We confirmed the complexities of the likely effects of climate change on the potential distribution of globally invasive species, and it is extremely important to develop wide-ranging and effective control measures according to predicted geographical shifts and changes

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity

A New Threat to Honey Bees, the Parasitic Phorid Fly Apocephalus borealis

Honey bee colonies are subject to numerous pathogens and parasites. Interaction among multiple pathogens and parasites is the proposed cause for Colony Collapse Disorder (CCD), a syndrome characterized by worker bees abandoning their hive. Here we provide the first documentation that the phorid fly Apocephalus borealis, previously known to parasitize bumble bees, also infects and eventually kills honey bees and may pose an emerging threat to North American apiculture. Parasitized honey bees show hive abandonment behavior, leaving their hives at night and dying shortly thereafter. On average, seven days later up to 13 phorid larvae emerge from each dead bee and pupate away from the bee. Using DNA barcoding, we confirmed that phorids that emerged from honey bees and bumble bees were the same species. Microarray analyses of honey bees from infected hives revealed that these bees are often infected with deformed wing virus and Nosema ceranae. Larvae and adult phorids also tested positive for these pathogens, implicating the fly as a potential vector or reservoir of these honey bee pathogens. Phorid parasitism may affect hive viability since 77% of sites sampled in the San Francisco Bay Area were infected by the fly and microarray analyses detected phorids in commercial hives in South Dakota and California's Central Valley. Understanding details of phorid infection may shed light on similar hive abandonment behaviors seen in CCD

Consistent Pattern of Local Adaptation during an Experimental Heat Wave in a Pipefish-Trematode Host-Parasite System

Extreme climate events such as heat waves are expected to increase in frequency under global change. As one indirect effect, they can alter magnitude and direction of species interactions, for example those between hosts and parasites. We simulated a summer heat wave to investigate how a changing environment affects the interaction between the broad-nosed pipefish (Syngnathus typhle) as a host and its digenean trematode parasite (Cryptocotyle lingua). In a fully reciprocal laboratory infection experiment, pipefish from three different coastal locations were exposed to sympatric and allopatric trematode cercariae. In order to examine whether an extreme climatic event disrupts patterns of locally adapted host-parasite combinations we measured the parasite's transmission success as well as the host's adaptive and innate immune defence under control and heat wave conditions. Independent of temperature, sympatric cercariae were always more successful than allopatric ones, indicating that parasites are locally adapted to their hosts. Hosts suffered from heat stress as suggested by fewer cells of the adaptive immune system (lymphocytes) compared to the same groups that were kept at 18°C. However, the proportion of the innate immune cells (monocytes) was higher in the 18°C water. Contrary to our expectations, no interaction between host immune defence, parasite infectivity and temperature stress were found, nor did the pattern of local adaptation change due to increased water temperature. Thus, in this host-parasite interaction, the sympatric parasite keeps ahead of the coevolutionary dynamics across sites, even under increasing temperatures as expected under marine global warming

Fluctuating Environments, Sexual Selection and the Evolution of Flexible Mate Choice in Birds

Environmentally-induced fluctuation in the form and strength of natural selection can drive the evolution of morphology, physiology, and behavior. Here we test the idea that fluctuating climatic conditions may also influence the process of sexual selection by inducing unexpected reversals in the relative quality or sexual attractiveness of potential breeding partners. Although this phenomenon, known as ‘ecological cross-over’, has been documented in a variety of species, it remains unclear the extent to which it has driven the evolution of major interspecific differences in reproductive behavior. We show that after controlling for potentially influential life history and demographic variables, there are significant positive associations between the variability and predictability of annual climatic cycles and the prevalence of infidelity and divorce within populations of a taxonomically diverse array of socially monogamous birds. Our results are consistent with the hypothesis that environmental factors have shaped the evolution of reproductive flexibility and suggest that in the absence of severe time constraints, secondary mate choice behaviors can help prevent, correct, or minimize the negative consequences of ecological cross-overs. Our findings also illustrate how a basic evolutionary process like sexual selection is susceptible to the increasing variability and unpredictability of climatic conditions that is resulting from climate change

Primary Human mDC1, mDC2, and pDC Dendritic Cells Are Differentially Infected and Activated by Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ∼6.8% of mDC1 and ∼0.9% pDCs were infected. We extended these studies to include CD1c−CD141+ mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity

Environmental Enrichment Preceding Early Adulthood Methylphenidate Treatment Leads to Long Term Increase of Corticosterone and Testosterone in the Rat

Attention-deficit/hyperactivity disorder (ADD/ADHD) has been emerging as a world-wide psychiatric disorder. There appears to be an increasing rate of stimulant drug abuse, specifically methylphenidate (MPH) which is the most common treatment for ADHD, among individuals who do not meet the criteria for ADHD and particularly for cognitive enhancement among university students. However, the long term effects of exposure to MPH are unknown. Thus, in light of a developmental approach in humans, we aimed to test the effects of adolescence exposure to enriched environment (EE) followed by MPH administration during early adulthood, on reactions to stress in adulthood. Specifically, at approximate adolescence [post natal days (PND) 30–60] rats were reared in EE and were treated with MPH during early adulthood (PND 60–90). Adult (PND 90–92) rats were exposed to mild stress and starting at PND 110, the behavioral and endocrine effects of the combined drug and environmental conditions were assessed. Following adolescence EE, long term exposure to MPH led to decreased locomotor activity and increased sucrose preference. EE had a beneficial effect on PPI (attentive abilities), which was impaired by long term exposure to MPH. Finally, the interaction between EE and, exposure to MPH led to long-term elevated corticosterone and testosterone levels. In view of the marked increase in MPH consumption over the past decade, vigilance is crucial in order to prevent potential drug abuse and its long term detrimental consequences