The near-surface electron radiation environment of Saturn's moon Mimas

Saturn's inner mid-size moons are exposed to a number of external weathering processes, including charged particle bombardment and UV photolysis, as well as deposition of E-ring grains and interplanetary dust. While optical remote sensing observations by several instruments onboard the Cassini spacecraft have revealed a number of weathering patterns across the surfaces of these moons, it is not entirely clear which external process is responsible for which observed weathering pattern. Here we focus on Saturn's moon Mimas and model the effect of energetic electron bombardment across its surface. By using a combination of a guiding center, bounce-averaged charged particle tracing approach and a particle physics code, we investigate how the radiation dose due to energetic electrons is deposited with depth at different locations. We predict a lens-shaped electron energy deposition pattern that extends down to ∼cm depths at low latitudes centered around the apex of the leading hemisphere (90° W). These results are consistent with previous remote sensing observations of a lens-shaped color anomaly observed by the Imaging Science Subsystem (ISS) instrument as well as a thermal inertia anomaly observed by the Visual and Infrared Mapping Spectrometer (VIMS) and the Composite Infrared Spectrometer (CIRS). Our results confirm that these features are produced by MeV electrons that have a penetration depth into the surface comparable to the effective sampling depths of these instruments. On the trailing hemisphere we predict a similar lens-shaped electron energy deposition pattern, whose effects have to date not been observed by the Cassini remote sensing instruments. We suggest that no corresponding lens-shaped weathering pattern has been observed on the trailing hemisphere because of the comparatively short range of lower energy (<1 MeV) electrons into surface ice, as well as competing effects from cold plasma, neutral, and dust bombardment

Metalevel algorithms for variant satisfiability

Variant satisfiability is a theory-generic algorithm to decide quantifier-free satisfiability in an initial algebra when its corresponding theory has the finite variant property and its constructors satisfy a compactness condition. This paper: (i) gives a precise definition of several meta-level sub-algorithms needed for variant satisfiability; (ii) proves them correct; and (iii) presents a reflective implementation in Maude 2.7 of variant satisfiability using these sub-algorithms.NSF CNS 13-19109Ope

From presence to consciousness through virtual reality

Immersive virtual environments can break the deep, everyday connection between where our senses tell us we are and where we are actually located and whom we are with. The concept of 'presence' refers to the phenomenon of behaving and feeling as if we are in the virtual world created by computer displays. In this article, we argue that presence is worthy of study by neuroscientists, and that it might aid the study of perception and consciousness

Retinoic Acid Mediates Regulation of Network Formation by COUP-TFII and VE-Cadherin Expression by TGFβ Receptor Kinase in Breast Cancer Cells

Tumor development, growth, and metastasis depend on the provision of an adequate vascular supply. This can be due to regulated angiogenesis, recruitment of circulating endothelial progenitors, and/or vascular transdifferentiation. Our previous studies showed that retinoic acid (RA) treatment converts a subset of breast cancer cells into cells with significant endothelial genotypic and phenotypic elements including marked induction of VE-cadherin, which was responsible for some but not all morphological changes. The present study demonstrates that of the endothelial-related genes induced by RA treatment, only a few were affected by knockdown of VE-cadherin, ruling it out as a regulator of the RA-induced endothelial genotypic switch. In contrast, knockdown of the RA-induced gene COUP-TFII prevented the formation of networks in Matrigel but had no effect on VE-cadherin induction or cell fusion. Two pan-kinase inhibitors markedly blocked RA-induced VE-cadherin expression and cell fusion. However, RA treatment resulted in a marked and broad reduction in tyrosine kinase activity. Several genes in the TGFβ signaling pathway were induced by RA, and specific inhibition of the TGFβ type I receptor blocked both RA-induced VE-cadherin expression and cell fusion. Together these data indicate a role for the TGFβ pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA

The λ Red Proteins Promote Efficient Recombination between Diverged Sequences: Implications for Bacteriophage Genome Mosaicism

Genome mosaicism in temperate bacterial viruses (bacteriophages) is so great that it obscures their phylogeny at the genome level. However, the precise molecular processes underlying this mosaicism are unknown. Illegitimate recombination has been proposed, but homeologous recombination could also be at play. To test this, we have measured the efficiency of homeologous recombination between diverged oxa gene pairs inserted into λ. High yields of recombinants between 22% diverged genes have been obtained when the virus Red Gam pathway was active, and 100 fold less when the host Escherichia coli RecABCD pathway was active. The recombination editing proteins, MutS and UvrD, showed only marginal effects on λ recombination. Thus, escape from host editing contributes to the high proficiency of virus recombination. Moreover, our bioinformatics study suggests that homeologous recombination between similar lambdoid viruses has created part of their mosaicism. We therefore propose that the remarkable propensity of the λ-encoded Red and Gam proteins to recombine diverged DNA is effectively contributing to mosaicism, and more generally, that a correlation may exist between virus genome mosaicism and the presence of Red/Gam-like systems

Congenital Hypothyroidism Long‐Term Follow‐up Project: Navigating the Rough Waters of a Multi‐Center, Multi‐State Public Health Project

The Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin), brought together pediatric endocrinologists, state laboratory experts, public health follow‐up specialists, and parents of children with congenital hypothyroidism (CH) to identify the three‐year follow‐up management and education patterns of primary care clinicians and pediatric endocrinologists in the care of children diagnosed with CH by state newborn screening (NBS) programs. Among a number of challenges, each state had different NBS methods, data systems, public health laws, and institutional review board (IRB) requirements. Furthermore, the diagnosis of CH was complicated by the timing of the NBS sample, the gestational age, weight, and co‐morbidities at delivery. There were 409 children with CH identified through NBS in 2007 in the seven state region. The clinician of record and the parents of these children were invited to participate in a voluntary survey. Approximately 64 % of clinician surveys were collected with responses to questions relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided to children with confirmed CH and their families. Nearly one‐quarter (24 %) of parents surveyed responded to questions relating to treatment, education, genetic counseling, resources, and services they received or would like to receive. De‐identified data from six of the seven states were compiled for analysis, with one state being unable to obtain IRB approval within the study timeline. The data from this collaborative effort will improve state follow‐up programs and aid in developing three‐year follow‐up guidelines for children diagnosed with CH. To aid in the facilitation of similar public health studies, this manuscript highlights the challenges faced, and focuses on the pathway to a successful multi‐state public health endeavor.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147153/1/jgc40464.pd

Linking direct and indirect pathways mediating earthworms, deer, and understory composition in Great Lakes forests

Ahistorical drivers such as nonnative invasive earthworms and high deer densities can have substantial impacts on ecosystem processes and plant community composition in temperate and boreal forests of North America. To assess the roles of earthworm disturbance, deer, and environmental factors in the understory, we sampled 125 mixed temperate-boreal forest sites across the western Great Lakes region. We utilized structural equation modeling (SEM) to address the hypothesis that earthworm disturbance to the upper soil horizons and selective herbivory by deer are associated with depauperate understory plant communities dominated by graminoid and nonnative species. Evidence of earthworm activity was found at 93 % of our sites and 49 % had high to very high severity earthworm disturbance. The SEM fit the data well and indicated that widespread nonnative earthworm disturbance and high deer densities had similar magnitudes of impact on understory plant communities and that these impacts were partially mediated by environmental characteristics. One-third of the variation in earthworm disturbance was explained by soil pH, precipitation, and litter quality. Deer density and earthworm disturbance both increased graminoid cover while environmental variables showed direct and indirect relationships. For example, the positive relationship between temperature and graminoids was indirect through a positive temperature effect on deer density. This research characterizes an integrated set of key environmental variables driving earthworm disturbance and deer impacts on the forest understory, facilitating predictions of the locations and severity of future change in northern temperate and boreal forest ecosystems

A Randomized Trial to Assess Anti-HIV Activity in Female Genital Tract Secretions and Soluble Mucosal Immunity Following Application of 1% Tenofovir Gel

Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.ClinicalTrials.gov NCT00594373

Melanoma Spheroids Grown Under Neural Crest Cell Conditions Are Highly Plastic Migratory/Invasive Tumor Cells Endowed with Immunomodulator Function

International audienceBACKGROUND: The aggressiveness of melanoma tumors is likely to rely on their well-recognized heterogeneity and plasticity. Melanoma comprises multi-subpopulations of cancer cells some of which may possess stem cell-like properties. Although useful, the sphere-formation assay to identify stem cell-like or tumor initiating cell subpopulations in melanoma has been challenged, and it is unclear if this model can predict a functional phenotype associated with aggressive tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic or advanced primary tumors, spheroid cells expressed melanoma-associated markers. They displayed higher capacity to differentiate along mesenchymal lineages and enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not enhanced self-renewal or tumorigenicity when compared to their adherent counterparts. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that spheroids display enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen-dependent T cells activation and proliferation more efficiently than their adherent counterparts. Our findings reveal a novel immune-modulator function of melanoma spheroids and suggest specific roles for spheroids in invasion and in evasion of antitumor immunity. CONCLUSION/SIGNIFICANCE: The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroids reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and suggested that aggressiveness and heterogeneity of melanoma tumors can be supported by subpopulations other than cancer stem cells. Therefore, it could be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability

Tumor Cell Plasticity and Angiogenesis in Human Melanomas

Recent molecular studies provide evidence for a significant transcriptional plasticity of tumor cell subpopulations that facilitate an active contribution to tumor vasculature. This feature is accompanied by morphological changes both in vitro and in vivo. Herein, we investigated the morphological plasticity of tumor cells with special focus on vasculogenic mimicry and neovascularisation in human melanoma and mouse xenografts of human melanoma cell lines. In melanoma xenograft experiments, different vessel markers and green fluorescent protein expression were used to show how melanoma cells contribute to neovascularization. Additionally, we analyzed neovascularization in 49 primary melanomas and 175 melanoma metastases using immunostaining for blood (CD34) and lymphatic (D2–40) vessel-specific markers. We found significantly more lymphatic vessels in primary melanomas than in melanoma metastases (p<0.0001). In contrast to the near absence of lymphatic vessels within metastases, we found extensive blood micro-neovascularization. Blood micro-neovascularization was absent in micro metastases (less than 2 mm). A significant inverse correlation between Glut-1 expression (implying local hypoxia) and the presence of microvessels indicates their functional activity as blood vessels (p<0.0001). We suggest that the hypoxic microenvironment in metastases contributes to a phenotype switch allowing melanoma cells to physically contribute to blood vessel formation