Efficacy of CMX001 as a Prophylactic and Presymptomatic Antiviral Agent in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination

A genome-wide association study of self-rated health

Self-rated health questions have been proven to be a highly reliable and valid measure of overall health as measured by other indicators in many population groups. It also has been shown to be a very good predictor of mortality, chronic or severe diseases, and the need for services, and is positively correlated with clinical assessments. Genetic factors have been estimated to account for 25-64% of the variance in the liability of self-rated health. The aim of the present study was to identify Single Nucleotide Polymorphisms (SNPs) underlying the heritability of self-rated health by conducting a genome-wide association analysis in a large sample of 6,706 Australian individuals aged 18-92. No genome wide significant SNPs associated with self-rated health could be identified, indicating that self-rated health may be influenced by a large number of SNPs with very small effect size. A very large sample will be needed to identify these SNPs

The reach of citizenship: Locating the politics of industrial air pollution in Durban and beyond

This paper develops a relational understanding of the geographies of citizenship action, using the example of environmental activism in Durban as an empirical reference point. We argue that citizenship involves an interactive dynamic shaped by different actors' capacities to project authority and influence over distance by enacting different modalities of spatial reach. Post-apartheid environmental politics illustrates how the relationship between the subjects of environmental rights and agents of obligation is both de-territorialised and re-territorialised by the activities of environmental activists. We examine the politics of attributing responsibility for urban industrial pollution in Durban, and identify two modalities of spatial reach through which environmental rights have been given weight. We conclude by emphasising that forms of transnational activism, while indicative in some respects of emergent styles of cosmopolitan citizenship, remain oriented by the goals of realizing national citizenship rights

Imaging X-Ray Polarimeter Explorer Systems Engineering Approach and Implementation

The Imaging X-ray Polarimetry Explorer (IXPE) is a NASA Small Explorer x-ray astrophysics mission being implemented by a geographically dispersed team. Each IXPE partner provides unique capabilities and experience which are utilized to design, build and launch the IXPE observator. A rigorous and iterative systems engineering approach is essential to ensuring the successful realization of reliable and cost effective IXPE mission system. The IXPE collaboration and observatory complexity provide both unique challenges and advantages for project systems engineering. The project uses established and tailored systems engineering (SE) methods and teaming approaches to achieve the IXPE mission goals. The IXPE systems engineering team spans all partner organizations. Currently, the project is in system integration and test working through structural environmental testing–vibration testing is just starting. Systems work is now focused on requirements management and maturity assessments, requirements verification and validation via sell-off packages (SOP) and interface control document (ICD) verification while supporting environmental test planning and execution. IXPE verification, validation and characterization (V&V) starts at the component/unit level and rolls up to appropriate higher levels where V&V compliance is assured by collaborative development by the cross-organizational V&V Team. This paper provides a technical summary of the IXPE concept of operations and mission-system (payload, spacecraft, observatory, ground system, launch vehicle), overviews the IXPE systems engineering approach (communications, project reviews, requirements analysis and management, baseline design and design trade studies, interfaces definition and documentation, resource management), describes the verification, validation and characterization activities (requirements validation, models and simulations validation, systems integration and test (I&T), system validation), discusses risk and opportunities philosophy and implementation, outlines COVID 19 accommodations, itemizes some key challenges and lessons-learned followed by the path to launch and conclusions

An upper limit on the electron-neutrino flux from the HiRes detector

Air-fluorescence detectors such as the High Resolution Fly's Eye (HiRes) detector are very sensitive to upward-going, Earth-skimming ultrahigh energy electron-neutrino-induced showers. This is due to the relatively large interaction cross sections of these high-energy neutrinos and to the Landau-Pomeranchuk-Migdal (LPM) effect. The LPM effect causes a significant decrease in the cross sections for bremsstrahlung and pair production, allowing charged-current electron-neutrino-induced showers occurring deep in the Earth's crust to be detectable as they exit the Earth into the atmosphere. A search for upward-going neutrino-induced showers in the HiRes-II monocular dataset has yielded a null result. From an LPM calculation of the energy spectrum of charged particles as a function of primary energy and depth for electron-induced showers in rock, we calculate the shape of the resulting profile of these showers in air. We describe a full detector Monte Carlo simulation to determine the detector response to upward-going electron-neutrino-induced cascades and present an upper limit on the flux of electron-neutrinos.Comment: 13 pages, 3 figures. submitted to Astrophysical Journa

Search for Correlations between HiRes Stereo Events and Active Galactic Nuclei

We have searched for correlations between the pointing directions of ultrahigh energy cosmic rays observed by the High Resolution Fly's Eye experiment and Active Galactic Nuclei (AGN) visible from its northern hemisphere location. No correlations, other than random correlations, have been found. We report our results using search parameters prescribed by the Pierre Auger collaboration. Using these parameters, the Auger collaboration concludes that a positive correlation exists for sources visible to their southern hemisphere location. We also describe results using two methods for determining the chance probability of correlations: one in which a hypothesis is formed from scanning one half of the data and tested on the second half, and another which involves a scan over the entire data set. The most significant correlation found occurred with a chance probability of 24%.Comment: 13 pages, 1 table, 5 figure

Space, state-building and the hydraulic mission: crafting the Mozambican State

This article explores the role of large-scale water infrastructure in the formation of states in sub-Saharan Africa. We examine this through a focus on government agents and their shifting hydro-developmental visions of the state in colonial and post-colonial Mozambique. Over time, the focus, underlying principles, and goals of the hydraulic mission shifted, triggered by contextual factors and historical developments within and outside the country. We identify the making of three hydraulic paradigms, fostering different imaginaries of ‘the state’ and social and spatial engineering of the territory: the ‘Estado Novo’ (1930 - 1974), the socialist post-independence state-space (1974 - 1987) and the neoliberal state (1987 - present). We then conclude by discussing how the shifting discursive justifications for infrastructure projects consolidate different state projects and link these to material re-patterning of hydrosocial territories, showing that whilst promoted as a rupture with the past, emerging projects tend to reaffirm, rather than redistribute, power and water within the country

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.The QIMR Berghofer groups were supported by a Rio Tinto Ride to Conquer Cancer (RTCC)/Weekend to End Women's Cancers (WEWC) Grant and NHMRC project grants 1058415 to SLE and 1031333 to ABS. ABS is supported by an NHMRC Senior Research Fellowship (1061779). DFE is a Principal Research Fellow of CR-UK.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Cell Press