Abstract
Sudden steam-driven eruptions strike without warning and are a leading cause of fatalities at touristic volcanoes. Recent deaths following the 2019 Whakaari eruption in New Zealand expose a ...need for accurate, short-term forecasting. However, current volcano alert systems are heuristic and too slowly updated with human input. Here, we show that a structured machine learning approach can detect eruption precursors in real-time seismic data streamed from Whakaari. We identify four-hour energy bursts that occur hours to days before most eruptions and suggest these indicate charging of the vent hydrothermal system by hot magmatic fluids. We developed a model to issue short-term alerts of elevated eruption likelihood and show that, under cross-validation testing, it could provide advanced warning of an unseen eruption in four out of five instances, including at least four hours warning for the 2019 eruption. This makes a strong case to adopt real-time forecasting models at active volcanoes.
The use of a novel ammonium ion-specific copper-polyaniline nano-composite as transducer for hydrolase-based biosensors is proposed. In this work, a combination of creatinine deaminase and urease has ...been chosen as a model system to demonstrate the construction of urea and creatinine biosensors to illustrate the principle. Immobilisation of enzymes was shown to be a crucial step in the development of the biosensors; the use of glycerol and lactitol as stabilisers resulted in a significant improvement, especially in the case of the creatinine, of the operational stability of the biosensors (from few hours to at least 3 days). The developed biosensors exhibited high selectivity towards creatinine and urea. The sensitivity was found to be 85±3.4mAM−1cm−2 for the creatinine biosensor and 112±3.36mAM−1cm−2 for the urea biosensor, with apparent Michaelis–Menten constants (KM,app), obtained from the creatinine and urea calibration curves, of 0.163mM for creatinine deaminase and 0.139mM for urease, respectively. The biosensors responded linearly over the concentration range 1–125µM, with a limit of detection of 0.5µM and a response time of 15s.
The performance of the biosensors in a real sample matrix, serum, was evaluated and a good correlation with standard spectrophotometric clinical laboratory techniques was found.
•Ammonium sensitive copper-polyaniline nano-composite for amperometric biosensing.•Amperometric ammonium based Creatinine and Urea biosensor.•Stable immobilisation of creatinine deaminase.•Sensitive and fast detection of creatinine and urea.•Detection of creatinine and urea in real patient serum samples.
AbstractIntroductionPrior research has found that psychopathology constructs such as depression and anxiety are associated with problematic use of Facebook (PFU). In the present study, we examined a ...structural equation model whereby depression, social anxiety and lower life satisfaction predicted PFU severity, while analyzing mediating variables including rumination, fear of missing out (FoMO), and frequency of Facebook use, as well as age and gender as covariates. MethodParticipants were 296 college students administered a web survey of instruments measuring these constructs. ResultsModeling results demonstrate that FoMO and rumination were significantly related to PFU severity. Facebook use frequency was related to PFU severity. FoMO and rumination each mediated relations between social anxiety and PFU severity. ConclusionsResults are discussed in the context of prior work on FoMO and excessive technology use, as well as several relevant theoretical frameworks.
Air‐sea gas exchange is an important part of the biogeochemical cycles of many climatically and biologically relevant gases including CO2, O2, dimethyl sulfide and CH4. Here we use a three year ...observational time series of five noble gases (He, Ne, Ar, Kr, and Xe) at the Bermuda Atlantic Time series Study (BATS) site in tandem with a one‐dimensional upper ocean model to develop an improved parameterization for air‐sea gas exchange that explicitly includes separate components for diffusive gas exchange and bubble processes. Based on seasonal timescale noble gas data, this parameterization, which has a 1σ uncertainty of ±14% for diffusive gas exchange and ±29% for bubble fluxes, is more tightly constrained than previous parameterizations. Although the magnitude of diffusive gas exchange is within errors of that of Wanninkhof (1992), a commonly used parameterization, we find that bubble‐mediated exchange, which is not explicitly included by Wanninkhof (1992) or many other formulations, is significant even for soluble gases. If one uses observed saturation anomalies of Ar (a gas with similar characteristics to O2) and a parameterization of gas exchange to calculate gas exchange fluxes, then the calculated fluxes differ by ∼240% if the parameterization presented here is used compared to using the Wanninkhof (1992) parameterization. If instead one includes the gas exchange parameterization in a model, then the calculated fluxes differ by ∼35% between using this parameterization and that of Wanninkhof (1992). These differences suggest that the bubble component should be explicitly included in a range of marine biogeochemical calculations that incorporate air‐sea gas fluxes.
The noble gas signature of incoming Pacific Bottom Water (PBW), when compared to North Atlantic Deep Water, indicates the addition of 450 ± 70 GT a−1 glacial melt water to form AABW and subsequently ...PBW. The downstream evolution of this signature between the southern (20°S to equator) and northern (25°–45°N) bottom waters indicates a decrease in sea level pressure around Antarctica over the past two millennia. Vertical profiles of noble gases in the deep Pacific show exponential relationships with depth with scale heights identical to temperature and salinity. Unlike the other noble gases, helium isotopes show evidence of mid‐depth injection of non‐atmospheric helium. Using observed deviations from exponential behavior, we quantify its magnitude and isotope ratio. There is a clear latitude trend in the isotope ratio of this added helium that decreases from a high exceeding 9 RA (atmospheric 3He/4He ratio) in the south to around 8 RA near the equator. North of 30–40°N, it systematically decreases northward to a low of ∼2 RA north of 50°N. This decline results from a combination of northward decline in seafloor spreading, release of radiogenic helium from increased sediment thickness, and the possible emission of radiogenic helium through cold seeps along the Alaskan and North American margins. Finally, we derive an improved method of computing the excess helium isotope concentrations and that the distributions of bottom water 3HeXS/4HeXS are consistent with what is known about bottom water flow patterns and the input of low 3He/4He sedimentary helium.
Plain Language Summary
Dissolved noble gases, because they are inert and span a range of physical characteristics, uniquely record conditions at the sea surface when water masses are formed and sink from polar regions to fill the abyssal ocean. These signatures can be used not only to deduce past changes in sea level pressure and rates of glacial melting but also to disentangle air‐sea exchange and in situ physical processes that affect all gases from subsurface external sources that are unique for helium isotopes. The distribution of helium isotopes in the deep ocean can be used to constrain the patterns and magnitudes of hydrothermal sources at the sea floor as well as the input of sedimentary radiogenic helium and cold seeps to Pacific bottom water. We use these tools to study the various sources of helium isotopes in the abyssal Northeast Pacific.
Key Points
Noble gases constrain the rate of basal melting of Antarctic Glaciers
Noble gases allow us to constrain the isotopic composition of helium being added to deep waters
The distribution of helium isotopes mirrors important geological and geophysical processes in the Pacific
Interleukin (IL)‐33 cytokine plays a critical role in allergic diseases and cancer. IL‐33 also has a nuclear localization signal. However, the nuclear function of IL‐33 and its impact on cancer is ...unknown. Here, we demonstrate that nuclear IL‐33‐mediated activation of SMAD signaling pathway in epithelial cells is essential for cancer development in chronic inflammation. Using RNA and ChIP sequencing, we found that nuclear IL‐33 repressed the expression of an inhibitory SMAD, Smad6, by interacting with its transcription factor, RUNX2. IL‐33 was highly expressed in the skin and pancreatic epithelial cells in chronic inflammation, leading to a markedly repressed Smad6 expression as well as dramatically upregulated p‐SMAD2/3 and p‐SMAD1/5 in the epithelial cells. Blocking TGF‐β/SMAD signaling attenuated the IL‐33‐induced cell proliferation in vitro and inhibited IL‐33‐dependent epidermal hyperplasia and skin cancer development in vivo. IL‐33 and SMAD signaling were upregulated in human skin cancer, pancreatitis, and pancreatitis‐associated pancreatic cancer. Collectively, our findings reveal that nuclear IL‐33/SMAD signaling is a cell‐autonomous tumor‐promoting axis in chronic inflammation, which can be targeted by small‐molecule inhibitors for cancer treatment and prevention.
The cell‐autonomous functions of cytokines and their impact on cancer promotion are unclear. Here, we demonstrate that nuclear IL‐33 promotes epithelial carcinogenesis in chronic inflammation independent of its cytokine function.
IL‐33 is highly induced and localized in the epithelial cell nuclei of the skin and pancreas affected by chronic inflammation.
Nuclear IL‐33 upregulates SMAD signaling in epithelial cells by repressing the expression of Smad6 (an inhibitory SMAD).
Nuclear IL‐33 binds to the RUNX2 transcription factor to block Smad6 expression.
Nuclear IL‐33 promotes epithelial cell proliferation and tumor development by upregulating SMAD signaling in cancer‐prone chronic inflammation of skin and pancreas.
Tumor‐promoting activities of interleukin‐33 are independent of its cytokine function, but instead involve direct regulation of RUNX2‐dependent Smad6 expression in the cell nucleus.
Aim
Antimicrobial stewardship plays an important role in ensuring that the appropriate drug, dose, route and duration are employed to provide adequate treatment while minimising the risks of ...unnecessary antibiotic use. Surveillance of antibiotic use with prescriber feedback is recommended as a high‐impact stewardship intervention. The aim of this study was to reduce unnecessary antimicrobial use in a neonatal unit.
Methods
A prospective audit was performed to assess compliance with antimicrobial guidelines. Following this, educational interventions were applied, electronic prescribing was introduced to the neonatal unit, and re‐audit was performed. The primary outcome was a reduction in days of therapy (DOT).
Results
There were 312 neonatal admissions. There was a significant overall reduction in the primary outcome of DOT/1000 patient days from 572 to 417 DOT. This represents a 27% reduction in total antibiotic use. Prolonged antibiotic treatment courses >36 hours in negative sepsis evaluations were reduced from 82 DOT to 7.5 DOT. Similarly, treatment courses greater than five days for culture‐negative sepsis were reduced from 46.5 DOT to 7 DOT.
Conclusion
Monitoring antibiotic prescribing data can provide useful insights into the trends of antibiotic use and also inform clinicians of potential areas where antibiotic use may be safely reduced.
Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the ...unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD.
Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ...ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.
An Update on the Structure of hERG Butler, Andrew; Helliwell, Matthew V; Zhang, Yihong ...
Frontiers in pharmacology,
01/2020, Letnik:
10
Journal Article
Recenzirano
Odprti dostop
The human voltage-sensitive K
channel hERG plays a fundamental role in cardiac action potential repolarization, effectively controlling the QT interval of the electrocardiogram. Inherited loss- or ...gain-of-function mutations in hERG can result in dangerous "long" (LQTS) or "short" QT syndromes (SQTS), respectively, and the anomalous susceptibility of hERG to block by a diverse range of drugs underlies an acquired LQTS. A recent open channel cryo-EM structure of hERG should greatly advance understanding of the molecular basis of hERG channelopathies and drug-induced LQTS. Here we describe an update of recent research that addresses the nature of the particular gated state of hERG captured in the new structure, and the insight afforded by the structure into the molecular basis for high affinity drug block of hERG, the binding of hERG activators and the molecular basis of hERG's peculiar gating properties. Interpretation of the pharmacology of natural SQTS mutants in the context of the structure is a promising approach to understanding the molecular basis of hERG inactivation, and the structure suggests how voltage-dependent changes in the membrane domain may be transmitted to an extracellular "turret" to effect inactivation through aromatic side chain motifs that are conserved throughout the KCNH family of channels.
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