A modified hyperbolic tangent equation to determine equilibrium shape of headland bay beaches

When designing any artificial beach, it’s desirable to avoid (or minimise) future maintenance commitments by arranging the initial beach planshape so that it remains in equilibrium given the incident wave climate. Headlands bays, or embayments, where a sandy beach is held between two erosion resistant headlands, tend to evolve to a stable beach planshape with little movement of the beach contours over time. Several empirical bay shape equations have been derived to fit curves to the shoreline of headland bay beaches. One of the most widely adopted empirical equations is the parabolic bay shape equation, as it is the only equation that directly links the shoreline positions to the predominant wave direction and the point of diffraction. However, the main limitation with the application of the parabolic bay shape equation is locating the downcoast control point. As a result of research presented in this paper a new equation, based on the hyperbolic tangent shape equation was developed, which eliminates the requirement of placing the down coast control point and relies on defining a minimum beach width instead. This modified equation was incorporated into a new ArcGIS tool

Impact of cyclosporine dosing regimen and infection on voriconazole pharmacodynamics in an experimental model of cerebral scedosporiosis

International audienc

Impact of infection status and cyclosporine on voriconazole pharmacokinetics in an experimental model of cerebral scedosporiosis

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near-drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barriers in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole were assessed in the plasma, cerebrospinal fluid (CSF), and brain, in an experimental model of cerebral scedosporiosis in rats receiving or not cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administrated to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose or three doses 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using UPLC-MS/MS and HPLC-UV methods and documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a non-compartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and the brain in all groups studied. Voriconazole Cmax and AUC0=>48h were significantly higher in the plasma than in the CSF (CSF/plasma ratio, median [range] = 0.5 [0.39-0.55] for AUC0=>48h and 0.47 [0.35 and 0.75] for Cmax). Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together these results emphasize the impact of cyclosporine on the brain voriconazole exposure

Gene Disruption in Scedosporium aurantiacum: Proof of Concept with the Disruption of SODC Gene Encoding a Cytosolic Cu,Zn-Superoxide Dismutase

Scedosporium species are opportunistic pathogens responsible for a large variety of infections in humans. An increasing occurrence was observed in patients with underlying conditions such as immunosuppression or cystic fibrosis. Indeed, the genus Scedosporium ranks the second among the filamentous fungi colonizing the respiratory tracts of the CF patients. To date, there is very scarce information on the pathogenic mechanisms, at least in part because of the limited genetic tools available. In the present study, we successfully developed an efficient transformation and targeted gene disruption approach on the species Scedosporium aurantiacum. The disruption cassette was constructed using double-joint PCR procedure, and resistance to hygromycin B as the selection marker. This proof of concept was performed on the functional gene SODC encoding the Cu,Zn-superoxide dismutase. Disruption of the SODC gene improved susceptibility of the fungus to oxidative stress. This technical advance should open new research areas and help to better understand the biology of Scedosporium species

Genomic Organization and Expression of Iron Metabolism Genes in the Emerging Pathogenic Mold

The ubiquitous mold is increasingly recognized as an emerging pathogen, especially among patients with underlying disorders such as immunodeficiency or cystic fibrosis (CF). Indeed, it ranks the second among the filamentous fungi colonizing the respiratory tract of CF patients. However, our knowledge about virulence factors of this fungus is still limited. The role of iron-uptake systems may be critical for establishment of infections, notably in the iron-rich environment of the CF lung. Two main strategies are employed by fungi to efficiently acquire iron from their host or from their ecological niche: siderophore production and reductive iron assimilation (RIA) systems. The aim of this study was to assess the existence of orthologous genes involved in iron metabolism in the recently sequenced genome of . At first, a tBLASTn analysis using iron-related proteins as query revealed orthologs of almost all relevant loci in the genome. Whereas the genes putatively involved in RIA were randomly distributed, siderophore biosynthesis and transport genes were organized in two clusters, each containing a non-ribosomal peptide synthetase (NRPS) whose orthologs in have been described to catalyze hydroxamate siderophore synthesis. Nevertheless, comparative genomic analysis of siderophore-related clusters showed greater similarity between and phylogenetically close molds than with species. The expression level of these genes was then evaluated by exposing conidia to iron starvation and iron excess. The expression of several orthologs of genes involved in siderophore-based iron uptake or RIA was significantly induced during iron starvation, and conversely repressed in iron excess conditions. Altogether, these results indicate that possesses the genetic information required for efficient and competitive iron uptake. They also suggest an important role of the siderophore production system in iron uptake by

Application of genetics and genomics to aquaculture development: current and future directions

Global aquaculture production continues to grow rapidly yet a small proportion of the animals and plants being used come from managed breeding and improvement programmes. The biology of aquatic organisms offer many opportunities for rapid genetic gains as new genetic and genomic techniques make the management of improvement programmes feasible in a wider range of species. The current paper describes the application of a wide range of techniques, many unique to aquatic organisms, and their potential to secure aquaculture production in the future

Draft Genome Sequence of the Human-Pathogenic Fungus Scedosporium boydii

The opportunistic fungal pathogen Scedosporium boydii is the most common Scedosporium species in French patients with cystic fibrosis. Here we present the first genome report for S. boydii, providing a resource which may enable the elucidation of the pathogenic mechanisms in this species

HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-κB pathway in a transcription-independent manner

HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-κB signaling pathway. Here, we reveal a strong positive correlation between expression of HOXA1 and of members of the TNF/NF-κB pathway in breast tumor datasets. Functionally, we demonstrate that HOXA1 can activate NF-κB and operates upstream of the NF-κB inhibitor IκB. Consistently, we next demonstrate that the HOXA1-mediated activation of NF-κB is non-transcriptional and that RBCK1 and TRAF2 influences on NF-κB are epistatic to HOXA1. We also identify an 11 Histidine repeat and the homeodomain of HOXA1 to be required both for RBCK1 and TRAF2 interaction and NF-κB stimulation. Finally, we highlight that activation of NF-κB is crucial for HOXA1 oncogenic activity

Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.

PURPOSE: Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma. METHODS: cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated RASSF1A (RASSF1A-M). Correlation with outcome was studied by combining cfDNA RASSF1A-M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients. RESULTS: At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. RASSF1A-M was detected in 21 of 57 patients. The presence of RASSF1A-M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 RASSF1A-M‒positive patients, compared with 84.9% for 36 RASSF1A-M‒negative patients [P < .001]). RASSF1A-M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for RASSF1A-M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, P < .001). CONCLUSION: Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring RASSF1A-M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel