Although improving, the mortality from septic shock still remains high despite increased international awareness. As a consequence, much effort has focused on alternative treatment strategies in an ...effort to improve outcomes. The application of blood purification therapies to improve immune homeostasis has been suggested as one such method, but these approaches, such as high-volume continuous haemofiltration or cytokine and/or endotoxin removal, have enjoyed little success to date. More recently, the use of sorbent technologies has attracted much attention. These adsorbers are highly effective at removing inflammatory mediators, in particular, cytokines, from the bloodstream. This narrative review is the executive summary of meetings held throughout the 6th International Fluid Academy Days in Antwerp, Belgium (Nov 23–25, 2017), focusing on the current understanding regarding the use of such adsorbers in humans with septic shock. We followed a modified Delphi approach involving a combination of evidence appraisal together with expert opinion in order to achieve recommendations for practice and, importantly, future research.
1. Animals produce sounds for diverse biological functions such as defending territories, attracting mates, deterring predators, navigation, finding food and maintaining contact with members of their ...social group. Biologists can take advantage of these acoustic behaviours to gain valuable insights into the spatial and temporal scales over which individuals and populations interact. Advances in bioacoustic technology, including the development of autonomous cabled and wireless recording arrays, permit data collection at multiple locations over time. These systems are transforming the way we study individuals and populations of animals and are leading to significant advances in our understandings of the complex interactions between animals and their habitats. 2. Here, we review questions that can be addressed using bioacoustic approaches, by providing a primer on technologies and approaches used to study animals at multiple organizational levels by ecologists, behaviourists and conservation biologists. 3. Spatially dispersed groups of microphones (arrays) enable users to study signal directionality on a small scale or to locate animals and track their movements on a larger scale. 4. Advances in algorithm development can allow users to discriminate among species, sexes, age groups and individuals. 5. With such technology, users can remotely and non-invasively survey populations, describe the soundscape, quantify anthropogenic noise, study species interactions, gain new insights into the social dynamics of sound-producing animals and track the effects of factors such as climate change and habitat fragmentation on phenology and biodiversity. 6. There remain many challenges in the use of acoustic monitoring, including the difficulties in performing signal recognition across taxa. The bioacoustics community should focus on developing a common framework for signal recognition that allows for various species' data to be analysed by any recognition system supporting a set of common standards. 7. Synthesis and applications. Microphone arrays are increasingly used to remotely monitor acoustically active animals. We provide examples from a variety of taxa where acoustic arrays have been used for ecological, behavioural and conservation studies. We discuss the technologies used, the methodologies for automating signal recognition and some of the remaining challenges. We also make recommendations for using this technology to aid in wildlife management.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
First time migrants (juveniles hereafter) of many species migrate without specific knowledge of non-breeding locations, but experience may aid adults in timing and route decisions because they can ...migrate more efficiently to their previous non-breeding sites. Consequently, we expect a transition to more efficient migratory behaviour with age, but when and how this happens is little known. We used light-level geolocator data from Cyprus wheatears Oenanthe cypriaca to compare migration timing and route directness between juveniles and adults, and repeatability of their timing and non-breeding locations. We predicted that juveniles would depart and arrive later than adults for both autumn and spring migration; that duration of migration would be greater for juveniles; that routes taken by juveniles would be less direct than those for adults; and that autumn and spring departure timing, and non-breeding locations, would be more repeatable for adults between two years than for juveniles between their first and subsequent migration. We found that juveniles departed significantly later than adults in autumn but there was no difference in arrival timing, and although spring departure timings did not differ, juveniles arrived on the breeding grounds later than adults. Nevertheless, we found no significant age-related difference in the duration of migration in autumn or spring. Yet, juvenile migrations were less direct than those of adults in autumn, but not spring. We found evidence that spring departure timing and non-breeding locations were repeatable for adults but not juveniles. Our findings show that age-related changes in migratory behaviour begin to occur during the first annual cycle demonstrating the potential for early adaptation to environmental variability within an individual's life.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There are currently no proven or approved treatments for coronavirus disease 2019 (COVID‐19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine ...(HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID‐19 are treated with these agents and more evidence accumulates, there continues to be no high‐quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto‐immune conditions, and provided a component in the original rationale for their use in patients with COVID‐19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID‐19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID‐19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID‐19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case‐by‐case basis after rigorous consideration of the risks and benefits of this therapeutic approach.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and ...prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models.
We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis.
We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ∼5- to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and D-Ala(2), N-MePhe(4), Gly-ol-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage-independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ∼65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis.
Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.
Knowledge of the neutrino flux produced by the Neutrinos at the Main Injector (NuMI) beamline is essential to the neutrino oscillation and neutrino interaction measurements of the MINERvA, MINOS+, ...NOvA and MicroBooNE experiments at Fermi National Accelerator Laboratory. We have produced a flux prediction which uses all available and relevant hadron production data, incorporating measurements of particle production off of thin targets as well as measurements of particle yields from a spare NuMI target exposed to a 120 GeV proton beam. The result is the most precise flux prediction achieved for a neutrino beam in the one to tens of GeV energy region. We have also compared the prediction to in situ measurements of the neutrino flux and find good agreement.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in ...the kidney undergoing fibrosis in a TGF-β/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition. A total of 501 differentially expressed genes associated with macrophage-myofibroblast transition were identified. However, Smad3-knockout largely reduced the transcriptome diversity. More importantly, inhibition of Src largely suppresses ureteral obstruction-induced macrophage-myofibroblast transition in the injured kidney in vivo along with transforming growth factor-β1-induced elongated fibroblast-like morphology, α-smooth muscle actin expression and collagen production in bone marrow derived macrophages in vitro. Unexpectedly, we further uncovered that Src serves as a direct Smad3 target gene and also specifically up-regulated in macrophages during macrophage-myofibroblast transition. Thus, macrophage-myofibroblast transition contributes to Src-mediated tissue fibrosis. Hence, targeting Src may represent as a precision therapeutic strategy for macrophage-myofibroblast transition-driven fibrotic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and ...2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ~2 Myr old classical T Tauri star CI Tau shows periodic variability in its radial velocity (RV) variations measured at infrared (IR) and optical wavelengths. We find that these observations are ...consistent with a massive planet in a ~9 day period orbit. These results are based on 71 IR RV measurements of this system obtained over five years, and on 26 optical RV measurements obtained over nine years. CI Tau was also observed photometrically in the optical on 34 nights over ~one month in 2012. The optical RV data alone are inadequate to identify an orbital period, likely the result of star spot and activity-induced noise for this relatively small data set. The infrared RV measurements reveal significant periodicity at ~9 days. In addition, the full set of optical and IR RV measurements taken together phase coherently and with equal amplitudes to the ~9 day period. Periodic RV signals can in principle be produced by cool spots, hotspots, and reflection of the stellar spectrum off the inner disk, in addition to resulting from a planetary companion. We have considered each of these and find the planet hypothesis most consistent with the data. The RV amplitude yields an M sin i of ~8.1 M sub(Jup); in conjunction with a 1.3 mm continuum emission measurement of the circumstellar disk inclination from the literature, we find a planet mass of ~11.3 M sub(Jup), assuming alignment of the planetary orbit with the disk.
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