Mussel production and Water Framework Directive targets in the Limfjord, Denmark: an integrated assessment for use in system-based management

Growth of human activities often conflict with nature conservation requirements and integrated assessments are necessary to build reliable scenarios for management. In the Limfjord, Denmark's largest estuary, nutrient loading reductions are necessary to fulfill EU regulations criteria, such as the Water Framework Directive (WFD). Cuts in nutrient loadings do not necessarily result in corresponding reductions in eutrophication impacts or in improving primary and higher trophic-level production. Similarly, the socioeconomic consequences of a mussel fishery and aquaculture production are complex and hard to predict. This study focuses on the usefulness of a System Approach Framework (SAF) implementation for stakeholder understanding of complex systems and development of sustainable management. Ecological-social-economic (ESE) model simulations clearly demonstrated the potential problems of WFD implementation for mussel fishers and mussel farmers. Simulation of mussel fishery closures resulted in a tenfold increase in the hitherto fishable mussel biomass and a similar decrease in the biomass of shallow-water mussels and medium-sized ones in deep water. A total closure of the mussel fishery could result in an annual profit loss of ~6.2 million. Scenario simulation of the introduction of one, two, three, and four mussel culture farms of ~19 ha showed that the introduction of line-mussels would decrease the biomass of wild mussels both in shallow and deep waters, affecting the catch and profit of fishers. The SAF, which included consultation with stakeholders at all stages, differs from the traditional public consultation process in that (1) communication was verbal and multilateral, (2) discussion among stakeholders was facilitated, and (3) stakeholder opinions and priorities formed the focus of the ESE assessment

Combination Treatment of Withalongolide a Triacetate with Cisplatin Induces Apoptosis by Targeting Translational Initiation, Migration, and Epithelial to Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Treatment regimens for head and neck squamous cell carcinoma (HNSCC) typically include cisplatin and radiotherapy and are limited by toxicities. We have identified naturally derived withalongolide A triacetate (WGA-TA) from Physalis longifolia as a lead compound for targeting HNSCC. We hypothesized that combining WGA-TA with cisplatin may allow for lower, less toxic cisplatin doses. HNSCC cell lines were treated with WGA-TA and cisplatin. After treatment with the drugs, the cell viability was determined by MTS assay. The combination index was calculated using CompuSyn. The expression of proteins involved in the targeting of translational initiation complex, epithelial to mesenchymal transition (EMT), and apoptosis were measured by western blot. Invasion and migration were measured using the Boyden-chamber assay. Treatment of MDA-1986 and UMSCC-22B cell lines with either WGA-TA or cisplatin alone for 72 h resulted in a dose dependent decrease in cell viability. Cisplatin in combination with WGA-TA resulted in significant synergistic cell death starting from 1.25 μM cisplatin. Combination treatment with WGA-TA resulted in lower cisplatin dosing while maintaining the downregulation of translational initiation complex proteins, the induction of apoptosis, and the blockade of migration, invasion, and EMT transition. These results suggest that combining a low concentration of cisplatin with WGA-TA may provide a safer, more effective therapeutic option for HNSCC that warrants translational validation

Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO) are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in RO but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multi-omic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in RO. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and RO and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy

New procedures for testing whether stock price processes are martingales

We propose procedures for testing whether stock price processes are martingales based on limit order type betting strategies. We first show that the null hypothesis of martingale property of a stock price process can be tested based on the capital process of a betting strategy. In particular with high frequency Markov type strategies we find that martingale null hypotheses are rejected for many stock price processes

Si and Fe depletion in Galactic star-forming regions observed by the Spitzer Space Telescope

We report the results of the mid-infrared spectroscopy of 14 Galactic star-forming regions with the high-resolution modules of the Infrared Spectrograph (IRS) on board the Spitzer Space Telescope. We detected [SiII] 35um, [FeII] 26um, and [FeIII] 23um as well as [SIII] 33um and H2 S(0) 28um emission lines. Using the intensity of [NII] 122um or 205um and [OI] 146um or 63um reported by previous observations in four regions, we derived the ionic abundance Si+/N+ and Fe+/N+ in the ionized gas and Si+/O0 and Fe+/O0 in the photodissociation gas. For all the targets, we derived the ionic abundance of Si+/S2+ and Fe2+/S2+ for the ionized gas. Based on photodissociation and HII region models the gas-phase Si and Fe abundance are suggested to be 3-100% and <8% of the solar abundance, respectively, for the ionized gas and 16-100% and 2-22% of the solar abundance, respectively, for the photodissociation region gas. Since the [FeII] 26um and [FeIII] 23um emissions are weak, the high sensitivity of the IRS enables to derive the gas-phase Fe abundance widely in star-forming regions. The derived gas-phase Si abundance is much larger than that in cool interstellar clouds and that of Fe. The present study indicates that 3-100% of Si atoms and <22% of Fe atoms are included in dust grains which are destroyed easily in HII regions, probably by the UV radiation. We discuss possible mechanisms to account for the observed trend; mantles which are photodesorbed by UV photons, organometallic complexes, or small grains.Comment: 43 pages with 7 figures, accepted in Astrophysical Journa

Quantifying single nucleotide variant detection sensitivity in exome sequencing

BACKGROUND: The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed. RESULTS: Using down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give “power estimates” for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5–15% of heterozygous and 1–4% of homozygous SNVs in the targeted regions will be missed. CONCLUSIONS: Non-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the “missing heritability” of quantitative traits

ISO spectroscopy of gas and dust: from molecular clouds to protoplanetary disks

Observations of interstellar gas-phase and solid-state species in the 2.4-200 micron range obtained with the spectrometers on board the Infrared Space Observatory are reviewed. Lines and bands due to ices, polycyclic aromatic hydrocarbons, silicates and gas-phase atoms and molecules (in particular H2, CO, H2O, OH and CO2) are summarized and their diagnostic capabilities illustrated. The results are discussed in the context of the physical and chemical evolution of star-forming regions, including photon-dominated regions, shocks, protostellar envelopes and disks around young stars.Comment: 56 pages, 17 figures. To appear in Ann. Rev. Astron. Astrophys. 2004. Higher resolution version posted at http://www.strw.leidenuniv.nl/~ewine/araa04.pd

Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing

We have assessed the numbers of potentially deleterious variants in the genomes of apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals in the 1000 Genomes Pilot Project and (2) current predictions and databases of deleterious variants. Each individual carried 281–515 missense substitutions, 40–85 of which were homozygous, predicted to be highly damaging. They also carried 40–110 variants classified by the Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3–24 variants in the homozygous state, and many polymorphisms putatively associated with disease. Whereas many of these DMs are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0–1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance. These analyses emphasize the need for improved annotation of disease alleles both in mutation databases and in the primary literature; some HGMD mutation data have been recategorized on the basis of the present findings, an iterative process that is both necessary and ongoing. Our estimates of deleterious-allele numbers are likely to be subject to both overcounting and undercounting. However, our current best mean estimates of ∼400 damaging variants and ∼2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively and as additional disease alleles are discovered

Management of the vertebrae as an organ at risk in paediatric radiotherapy clinical trials: Initial QUARTET experience

Irradiation of the vertebrae in prepubertal patients, if non-homogenous, can result in future growth deformities including kyphoscoliosis. Vertebral delineation and dosimetry were assessed for 101 paediatric cases reviewed within QUARTET-affiliated trials. Despite the availability of published consensus guidelines, a high variability in vertebral delineation was observed, with impact on dosimetry