An empirical approach to modeling ion production rates in Titan's ionosphere II: Ion production rates on the nightside

Ionization of neutrals by precipitating electrons and ions is the main source of Titan's nightside ionosphere. This paper has two goals: (1) characterization of the role of electron impact ionization on the nightside ionosphere for different magnetospheric conditions and (2) presentation of empirical ion production rates determined using densities measured by the Cassini Ion and Neutral Mass Spectrometer on the nightside. The ionosphere between 1000 and 1400 km is emphasized. We adopt electron fluxes measured by the Cassini Plasma Spectrometer-Electron Spectrometer and the Magnetospheric Imaging Instrument as classified by Rymer et al. (2009). The current paper follows an earlier paper (Paper I), in which we investigated sources of Titan's dayside ionosphere and demonstrated that the photoionization process is well understood. The current paper (Paper II) demonstrates that modeled and empirical ionization rates on the nightside are in agreement with an electron precipitation source above 1100 km. Ion production rate profiles appropriate for different Saturnian magnetospheric conditions, as outlined by Rymer et al., are constructed for various magnetic field topologies. Empirical production rate profiles are generated for deep nightside flybys of Titan. The results also suggest that at lower altitudes (below 1100 km) another source, such as ion precipitation, is probably needed

An empirical approach to modeling ion production rates in Titan’s ionosphere I: Ion production rates on the dayside and globally

Titan's ionosphere is created when solar photons, energetic magnetospheric electrons or ions, and cosmic rays ionize the neutral atmosphere. Electron densities generated by current theoretical models are much larger than densities measured by instruments on board the Cassini orbiter. This model density overabundance must result either from overproduction or from insufficient loss of ions. This is the first of two papers that examines ion production rates in Titan's ionosphere, for the dayside and nightside ionosphere, respectively. The first (current) paper focuses on dayside ion production rates which are computed using solar ionization sources (photoionization and electron impact ionization by photoelectrons) between 1000 and 1400 km. In addition to theoretical ion production rates, empirical ion production rates are derived from CH4, CH3+, and CH4+ densities measured by the INMS (Ion Neutral Mass Spectrometer) for many Titan passes. The modeled and empirical production rate profiles from measured densities of N2+ and CH4+ are found to be in good agreement (to within 20%) for solar zenith angles between 15 and 90°. This suggests that the overabundance of electrons in theoretical models of Titan's dayside ionosphere is not due to overproduction but to insufficient ion losses

Linking Animals Aloft with the Terrestrial Landscape

Despite using the aerosphere for many facets of their life, most flying animals (i.e., birds, bats, some insects) are still bound to terrestrial habitats for resting, feeding, and reproduction. Comprehensive broad-scale observations by weather surveillance radars of animals as they leave terrestrial habitats for migration or feeding flights can be used to map their terrestrial distributions either as point locations (e.g., communal roosts) or as continuous surface layers (e.g., animal densities in habitats across a landscape). We discuss some of the technical challenges to reducing measurement biases related to how radars sample the aerosphere and the flight behavior of animals. We highlight a recently developed methodological approach that precisely and quantitatively links the horizontal spatial structure of birds aloft to their terrestrial distributions and provides novel insights into avian ecology and conservation across broad landscapes. Specifically, we present case studies that (1) elucidate how migrating birds contend with crossing ecological barriers and extreme weather events, (2) identify important stopover areas and habitat use patterns of birds along their migration routes, and (3) assess waterfowl response to wetland habitat management and restoration. These studies aid our understanding of how anthropogenic modification of the terrestrial landscape (e.g., urbanization, habitat management), natural geographic features, and weather (e.g., hurricanes) can affect the terrestrial distributions of flying animals

Linking Animals Aloft with the Terrestrial Landscape

Despite using the aerosphere for many facets of their life, most flying animals (i.e., birds, bats, some insects) are still bound to terrestrial habitats for resting, feeding, and reproduction. Comprehensive broad-scale observations by weather surveillance radars of animals as they leave terrestrial habitats for migration or feeding flights can be used to map their terrestrial distributions either as point locations (e.g., communal roosts) or as continuous surface layers (e.g., animal densities in habitats across a landscape). We discuss some of the technical challenges to reducing measurement biases related to how radars sample the aerosphere and the flight behavior of animals. We highlight a recently developed methodological approach that precisely and quantitatively links the horizontal spatial structure of birds aloft to their terrestrial distributions and provides novel insights into avian ecology and conservation across broad landscapes. Specifically, we present case studies that (1) elucidate how migrating birds contend with crossing ecological barriers and extreme weather events, (2) identify important stopover areas and habitat use patterns of birds along their migration routes, and (3) assess waterfowl response to wetland habitat management and restoration. These studies aid our understanding of how anthropogenic modification of the terrestrial landscape (e.g., urbanization, habitat management), natural geographic features, and weather (e.g., hurricanes) can affect the terrestrial distributions of flying animals

Somatic mutations and clonal dynamics in healthy and cirrhotic human liver.

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.This work was supported by a Wellcome Trust and Cancer Research UK (CRUK) Grand Challenge Award (C98/A24032). P.J.C. is a Wellcome Trust Senior Clinical Fellow (WT088340MA); S.F.B. was supported by the Swiss National Science Foundation (P2SKP3-171753 and P400PB-180790); M.A.S. is supported by a Rubicon fellowship from NWO (019.153LW.038); the Cambridge Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre; and M.H. is supported by a CRUK Clinician Scientist Fellowship (C52489/A19924)

A database of microRNA expression patterns in Xenopus laevis

MicroRNAs (miRNAs) are short, non-coding RNAs around 22 nucleotides long. They inhibit gene expression either by translational repression or by causing the degradation of the mRNAs they bind to. Many are highly conserved amongst diverse organisms and have restricted spatio-temporal expression patterns during embryonic development where they are thought to be involved in generating accuracy of developmental timing and in supporting cell fate decisions and tissue identity. We determined the expression patterns of 180 miRNAs in Xenopus laevis embryos using LNA oligonucleotides. In addition we carried out small RNA-seq on different stages of early Xenopus development, identified 44 miRNAs belonging to 29 new families and characterized the expression of 5 of these. Our analyses identified miRNA expression in many organs of the developing embryo. In particular a large number were expressed in neural tissue and in the somites. Surprisingly none of the miRNAs we have looked at show expression in the heart. Our results have been made freely available as a resource in both XenMARK and Xenbase

Divergent viral presentation among human tumors and adjacent normal tissues

We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup