Prions are the transmissible pathogenic agents responsible for diseases such as scrapie and bovine spongiform encephalopathy. In the favoured model of prion replication, direct interaction between ...the pathogenic prion protein (PrPSc) template and endogenous cellular prion protein (PrPC) is proposed to drive the formation of nascent infectious prions. Reagents specifically binding either prion-protein conformer may interrupt prion production by inhibiting this interaction. We examined the ability of several recombinant antibody antigen-binding fragments (Fabs) to inhibit prion propagation in cultured mouse neuroblastoma cells (ScN2a) infected with PrPSc. Here we show that antibodies binding cell-surface PrPC inhibit PrPSc formation in a dose-dependent manner. In cells treated with the most potent antibody, Fab D18, prion replication is abolished and pre-existing PrPSc is rapidly cleared, suggesting that this antibody may cure established infection. The potent activity of Fab D18 is associated with its ability to better recognize the total population of PrPC molecules on the cell surface, and with the location of its epitope on PrPC. Our observations support the use of antibodies in the prevention and treatment of prion diseases and identify a region of PrPC for drug targeting.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Marine debris, directly and indirectly, threatens marine habitat and biota. Fishing activity is generally recognised as a contributor to marine debris, but the relative input from recreational ...fishing remains unassessed. Here we provide the first comprehensive literature review of recreational fishing marine debris (RFMD) on a global scale. A systematic literature review identified 70 studies related to RFMD, and plastic and metal respectively were the dominant debris materials found. Nearshore coastal areas and reefs, acted as both sources and sinks of RFMD and a diverse suite of potential impacts such as ghost fishing and entanglement were identified at local scales. Overall, research of RFMD is lacking globally, however, its role in marine debris input is likely underestimated. We recommend more research on the volumes and risks, using a standardised classification approach. Where intervention is required, we suggest cooperative approaches between the sector and authorities.
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•Research on recreational fishing marine debris is lacking globally.•Plastic was the dominant material found.•Nearshore coastal areas are sources and sinks of recreational fishing debris.•The role of recreational fishing in marine debris input is likely underestimated.•It has diverse impacts on biota and habitat such as entanglement and ghost fishing.
Collaborative Problem Solving (CPS) is an interactive, interdependent, and temporal process. However, current methods for measuring the CPS processes of individuals, such as coding and counting, ...treat these processes as sets of isolated and independent events. In contrast, Epistemic Network Analysis (ENA) models how the contributions of a given individual relate to the contributions of others. This article examines the communications of air defense warfare teams from an experiment comparing two different computer-based decision support systems, using this data to ask whether ENA provides a more ecologically valid quantitative model of CPS than coding and counting. Qualitative analysis showed that commanders using one system asked questions to understand the tactical situation, while commanders using an experimental system focused more on actions in response to the tactical situation. Neither of the coding and counting approaches we tested corroborated these findings with statistically significant results. In contrast, ENA created models of the individual contributions of commanders that (a) showed statistical differences between commanders using the two systems to corroborate the qualitative analysis, and (b) revealed differences in individual performance. This suggests that ENA is a more powerful tool for CPS assessment than coding and counting approaches.
•Coding and counting models CPS processes of individuals as isolated and independent.•ENA models CPS processes of individuals in relation to the processes of others.•ENA found statistically significant differences between individuals in team settings.•ENA found significant differences where coding and counting did not.•Significant ENA differences were aligned with qualitative results.
The Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors have completed their initial upgrade phase and will enter the first observing run in late 2015, with detector ...sensitivity expected to improve in future runs. Through the combined efforts of on-site commissioners and the Detector Characterization Group of the LIGO Scientific Collaboration, interferometer performance, in terms of data quality, at both LIGO observatories has vastly improved from the start of commissioning efforts to present. Advanced LIGO has already surpassed Enhanced LIGO in sensitivity, and the rate of noise transients, which would negatively impact astrophysical searches, has improved. Here we give details of some of the work which has taken place to better the quality of the LIGO data ahead of the first observing run.
Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized ...OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.
Highlights • The detection of new vessels is modelled on a dual classification approach. • Morphology, intensity and gradient based features create a 21-D feature set. • A genetic algorithm is used ...for feature selection and SVM parameter selection. • Reduces false responses to bright lesions, dark lesions and reflection artefacts.
This assessment, by the United Nations Environment Programme (UNEP) Environmental Effects Assessment Panel (EEAP), one of three Panels informing the Parties to the Montreal Protocol, provides an ...update, since our previous extensive assessment (Photochem. Photobiol. Sci., 2019, 18, 595-828), of recent findings of current and projected interactive environmental effects of ultraviolet (UV) radiation, stratospheric ozone, and climate change. These effects include those on human health, air quality, terrestrial and aquatic ecosystems, biogeochemical cycles, and materials used in construction and other services. The present update evaluates further evidence of the consequences of human activity on climate change that are altering the exposure of organisms and ecosystems to UV radiation. This in turn reveals the interactive effects of many climate change factors with UV radiation that have implications for the atmosphere, feedbacks, contaminant fate and transport, organismal responses, and many outdoor materials including plastics, wood, and fabrics. The universal ratification of the Montreal Protocol, signed by 197 countries, has led to the regulation and phase-out of chemicals that deplete the stratospheric ozone layer. Although this treaty has had unprecedented success in protecting the ozone layer, and hence all life on Earth from damaging UV radiation, it is also making a substantial contribution to reducing climate warming because many of the chemicals under this treaty are greenhouse gases.
The properties of precessing, coalescing binary black holes are presently inferred through comparison with two approximate models of compact binary coalescence. In this work we show that these two ...models often disagree substantially when binaries have modestly large spins (a≳0.4) and modest mass ratios (q≳2). We demonstrate these disagreements using standard figures of merit and the parameters inferred for recent detections of binary black holes. By comparing to numerical relativity, we confirm that these disagreements reflect systematic errors. We provide concrete examples to demonstrate that these systematic errors can significantly impact inferences about astrophysically significant binary parameters. For the immediate future, parameter inference for binary black holes should be performed with multiple models (including numerical relativity), and carefully validated by performing inference under controlled circumstances with similar synthetic events.
The Environmental Effects Assessment Panel of the Montreal Protocol under the United Nations Environment Programme evaluates effects on the environment and human health that arise from changes in the ...stratospheric ozone layer and concomitant variations in ultraviolet (UV) radiation at the Earth’s surface. The current update is based on scientific advances that have accumulated since our last assessment (Photochem and Photobiol Sci 20(1):1–67, 2021). We also discuss how climate change affects stratospheric ozone depletion and ultraviolet radiation, and how stratospheric ozone depletion affects climate change. The resulting interlinking effects of stratospheric ozone depletion, UV radiation, and climate change are assessed in terms of air quality, carbon sinks, ecosystems, human health, and natural and synthetic materials. We further highlight potential impacts on the biosphere from extreme climate events that are occurring with increasing frequency as a consequence of climate change. These and other interactive effects are examined with respect to the benefits that the Montreal Protocol and its Amendments are providing to life on Earth by controlling the production of various substances that contribute to both stratospheric ozone depletion and climate change.
The first detection of a binary neutron star merger, GW170817, and an associated short gamma-ray burst confirmed that neutron star mergers are responsible for at least some of these bursts. The ...prompt gamma-ray emission from these events is thought to be highly relativistically beamed. We present a method for inferring limits on the extent of this beaming by comparing the number of short gamma-ray bursts (SGRBs) observed electromagnetically with the number of neutron star binary mergers detected in gravitational waves. We demonstrate that an observing run comparable to the expected Advanced LIGO (aLIGO) 2016-2017 run would be capable of placing limits on the beaming angle of approximately , given one binary neutron star detection, under the assumption that all mergers produce a gamma-ray burst, and that SGRBs occur at an illustrative rate of . We anticipate that after a year of observations with aLIGO at design sensitivity in 2020, these constraints will improve to , under the same efficiency and SGRB rate assumptions.
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