William H. Sorrell, Attorney General of Vermont, et al. v. IMS Health Inc., et al. - Amicus Brief in Support of Petitioners

On April 26, 2011, the US Supreme Court will hear oral arguments in the Vermont data mining case, Sorrell v. IMS Health Inc. Respondents claim this is the most important commercial speech case in a decade. Petitioner (the State of Vermont) argues this is the most important medical privacy case since Whalen v. Roe. The is an amicus brief supporting Vermont, written by law professors and submitted on behalf of the New England Journal of Medicin

Seeking Evolution of Dark Energy

We study how observationally to distinguish between a cosmological constant (CC) and an evolving dark energy with equation of state $\omega(Z)$. We focus on the value of redshift Z* at which the cosmic late time acceleration begins and $\ddot{a}(Z^{*}) = 0$. Four $\omega(Z)$ are studied, including the well-known CPL model and a new model that has advantages when describing the entire expansion era. If dark energy is represented by a CC model with $\omega \equiv -1$, the present ranges for $\Omega_{\Lambda}(t_0)$ and $\Omega_m(t_0)$ imply that Z* = 0.743 with 4% error. We discuss the possible implications of a model independent measurement of Z* with better accuracy.Comment: 9 pages, LaTeX, 5 figure

Revisiting rho 1 Cancri e: A New Mass Determination Of The Transiting super-Earth

We present a mass determination for the transiting super-Earth rho 1 Cancri e based on nearly 700 precise radial velocity (RV) measurements. This extensive RV data set consists of data collected by the McDonald Observatory planet search and published data from Lick and Keck observatories (Fischer et al. 2008). We obtained 212 RV measurements with the Tull Coude Spectrograph at the Harlan J. Smith 2.7 m Telescope and combined them with a new Doppler reduction of the 131 spectra that we have taken in 2003-2004 with the High-Resolution-Spectrograph (HRS) at the Hobby-Eberly Telescope (HET) for the original discovery of rho 1 Cancri e. Using this large data set we obtain a 5-planet Keplerian orbital solution for the system and measure an RV semi-amplitude of K = 6.29 +/- 0.21 m/s for rho 1 Cnc e and determine a mass of 8.37 +/- 0.38 M_Earth. The uncertainty in mass is thus less than 5%. This planet was previously found to transit its parent star (Winn et al. 2011, Demory et al. 2011), which allowed them to estimate its radius. Combined with the latest radius estimate from Gillon et al. (2012), we obtain a mean density of rho = 4.50 +/- 0.20 g/cm^3. The location of rho 1 Cnc e in the mass-radius diagram suggests that the planet contains a significant amount of volitales, possibly a water-rich envelope surrounding a rocky core.Comment: 16 pages, 5 figures, accepted for publication in the Astrophysical Journal (the 300+ RV measurements will be published as online tables or can be obtained from the author

Phenotopic Plasticity of Leaf Shape Along a Temperature Gradient in \u3cem\u3eAcer Rubrum\u3c/em\u3e

Both phenotypic plasticity and genetic determination can be important for understanding how plants respond to environmental change. However, little is known about the plastic response of leaf teeth and leaf dissection to temperature. This gap is critical because these leaf traits are commonly used to reconstruct paleoclimate from fossils, and such studies tacitly assume that traits measured from fossils reflect the environment at the time of their deposition, even during periods of rapid climate change. We measured leaf size and shape in Acer rubrum derived from four seed sources with a broad temperature range and grown for two years in two gardens with contrasting climates (Rhode Island and Florida). Leaves in the Rhode Island garden have more teeth and are more highly dissected than leaves in Florida from the same seed source. Plasticity in these variables accounts for at least 6–19 % of the total variance, while genetic differences among ecotypes probably account for at most 69–87 %. This study highlights the role of phenotypic plasticity in leaf-climate relationships. We suggest that variables related to tooth count and leaf dissection in A. rubrum can respond quickly to climate change, which increases confidence in paleoclimate methods that use these variables

Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-γ in primary macrophages requires endogenous 25-hydroxycholesterol synthesis (in press)

AbstractInterferons (IFNs) play a central role in immunity and emerging evidence suggests that IFN-signalling coordinately regulates sterol biosynthesis in macrophages, via Sterol Regulatory Element-Binding Protein (SREBP) dependent and independent pathways. However, the precise mechanisms and kinetic steps by which IFN controls sterol biosynthesis are as yet not fully understood. Here, we elucidate the molecular circuitry governing how IFN controls the first regulated step in the mevalonate-sterol pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), through the synthesis of 25-Hydroxycholesterol (25-HC) from cholesterol by the IFN-inducible Cholesterol-25-Hydroxylase (CH25H). We show for the first 30-min of IFN stimulation of macrophages the rate of de novo synthesis of the Ch25h transcript is markedly increased but by 120-min becomes transcriptionally curtailed, coincident with induction of the Activating Transcription Factor 3 (ATF3) repressor. We demonstrate ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling. While the SREBP-pathway dependent rates of de novo transcription of Hmgcr are relatively unchanged in the first 90-min of IFN treatment, we find HMGCR enzyme levels undergo a rapid proteasomal-mediated degradation, defining a previously unappreciated SREBP-independent mechanism for IFN-action. These events precede a sustained marked reduction in Hmgcr RNA levels involving SREBP-dependent mechanisms. We demonstrate that HMGCR proteasomal-degradation by IFN strictly requires the synthesis of endogenous 25-HC and functionally couples HMGCR to CH25H to coordinately suppress sterol biosynthesis. In conclusion, we quantitatively delineate proteomic and transcriptional levels of IFN-mediated control of HMGCR, the primary enzymatic step of the mevalonate-sterol biosynthesis pathway, providing a foundational framework for mathematically modelling the therapeutic outcome of immune-metabolic pathways

A logic-based diagram of signalling pathways central to macrophage activation.

BACKGROUND: The complex yet flexible cellular response to pathogens is orchestrated by the interaction of multiple signalling and metabolic pathways. The molecular regulation of this response has been studied in great detail but comprehensive and unambiguous diagrams describing these events are generally unavailable. Four key signalling cascades triggered early-on in the innate immune response are the toll-like receptor, interferon, NF-kappaB and apoptotic pathways, which co-operate to defend cells against a given pathogen. However, these pathways are commonly viewed as separate entities rather than an integrated network of molecular interactions. RESULTS: Here we describe the construction of a logically represented pathway diagram which attempts to integrate these four pathways central to innate immunity using a modified version of the Edinburgh Pathway Notation. The pathway map is available in a number of electronic formats and editing is supported by yEd graph editor software. CONCLUSION: The map presents a powerful visual aid for interpreting the available pathway interaction knowledge and underscores the valuable contribution well constructed pathway diagrams make to communicating large amounts of molecular interaction data. Furthermore, we discuss issues with the limitations and scalability of pathways presented in this fashion, explore options for automated layout of large pathway networks and demonstrate how such maps can aid the interpretation of functional studies

Managing disease outbreaks: The importance of vector mobility and spatially heterogeneous control

This work is licensed under a Creative Commons Attribution 4.0 International License.Management strategies for control of vector-borne diseases, for example Zika or dengue, include using larvicide and/or adulticide, either through large-scale application by truck or plane or through door-to-door efforts that require obtaining permission to access private property and spray yards. The efficacy of the latter strategy is highly dependent on the compliance of local residents. Here we develop a model for vector-borne disease transmission between mosquitoes and humans in a neighborhood setting, considering a network of houses connected via nearest-neighbor mosquito movement. We incorporate large-scale application of adulticide via aerial spraying through a uniform increase in vector death rates in all sites, and door-to-door application of larval source reduction and adulticide through a decrease in vector emergence rates and an increase in vector death rates in compliant sites only, where control efficacies are directly connected to real-world experimentally measurable control parameters, application frequencies, and control costs. To develop mechanistic insight into the influence of vector motion and compliance clustering on disease controllability, we determine the basic reproduction number R0 for the system, provide analytic results for the extreme cases of no mosquito movement, infinite hopping rates, and utilize degenerate perturbation theory for the case of slow but non-zero hopping rates. We then determine the application frequencies required for each strategy (alone and combined) in order to reduce R0 to unity, along with the associated costs. Cost-optimal strategies are found to depend strongly on mosquito hopping rates, levels of door-to-door compliance, and spatial clustering of compliant houses, and can include aerial spray alone, door-to-door treatment alone, or a combination of both. The optimization scheme developed here provides a flexible tool for disease management planners which translates modeling results into actionable control advice adaptable to system-specific details.Simons Foundation (426126)University of Kansas General Research Grant (2301-2105075)Department of Defense SERDP contract (W912HQ-16-C-0054

Functional Characterization of a Novel Family of Acetylcholine-Gated Chloride Channels in Schistosoma mansoni

Acetylcholine is the canonical excitatory neurotransmitter of the mammalian neuromuscular system. However, in the trematode parasite Schistosoma mansoni, cholinergic stimulation leads to muscle relaxation and a flaccid paralysis, suggesting an inhibitory mode of action. Information about the pharmacological mechanism of this inhibition is lacking. Here, we used a combination of techniques to assess the role of cholinergic receptors in schistosome motor function. The neuromuscular effects of acetylcholine are typically mediated by gated cation channels of the nicotinic receptor (nAChR) family. Bioinformatics analyses identified numerous nAChR subunits in the S. mansoni genome but, interestingly, nearly half of these subunits carried a motif normally associated with chloride-selectivity. These putative schistosome acetylcholine-gated chloride channels (SmACCs) are evolutionarily divergent from those of nematodes and form a unique clade within the larger family of nAChRs. Pharmacological and RNA interference (RNAi) behavioral screens were used to assess the role of the SmACCs in larval motor function. Treatment with antagonists produced the same effect as RNAi suppression of SmACCs; both led to a hypermotile phenotype consistent with abrogation of an inhibitory neuromuscular mediator. Antibodies were then generated against two of the SmACCs for use in immunolocalization studies. SmACC-1 and SmACC-2 localize to regions of the peripheral nervous system that innervate the body wall muscles, yet neither appears to be expressed directly on the musculature. One gene, SmACC-1, was expressed in HEK-293 cells and characterized using an iodide flux assay. The results indicate that SmACC-1 formed a functional homomeric chloride channel and was activated selectively by a panel of cholinergic agonists. The results described in this study identify a novel clade of nicotinic chloride channels that act as inhibitory modulators of schistosome neuromuscular function. Additionally, the iodide flux assay used to characterize SmACC-1 represents a new high-throughput tool for drug screening against these unique parasite ion channels

Nuclear Physics Neutrino PreTown Meeting: Summary and Recommendations

In preparation for the nuclear physics Long Range Plan exercise, a group of 104 neutrino physicists met in Seattle September 21-23 to discuss both the present state of the field and the new opportunities of the next decade. This report summarizes the conclusions of that meeting and presents its recommendations. Further information is available at the workshop's web site. This report will be further reviewed at the upcoming Oakland Town Meeting.Comment: Latex, 31 pages. This version has been updated to include final Comments from the working group