The interleukin-1 family members, IL-1β and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that ...mediate IL-1β processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.
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•AFS-D successfully deposited layers wider than the diameter of the tool offering a new path for large scale AM components.•Aluminum oxide films were dispersed by tool features and ...provided increased interlayer mixing.•More homogenous grain structures occurring from repeated stirring in overlapping region.•As-deposited tensile strength was unaffected by the overlapping region compared to similar AFS-D AA6061 single row studies.•Undispersed oxides dominated the fracture surface in place of typical secondary phase continuative particles.
In this paper, the effect of overlapping parallel additive depositions on microstructure and mechanical properties in Additive Friction Stir Deposition (AFS-D) was examined. In particular, the AFS-D process was employed to make parallel depositions of AA6061 with a 6.35 mm overlap to effectively bond the two parallel layers. The AFS-D process draws on similar physics to friction stir welding in that frictional heat and plastic deformation is exploited to deposit metallic materials from the center of a hollow rotating tool as it traverses across the build table to produce consecutive metallurgically bonded layers. In this work, the microstructural aspects of the 6.35 mm overlapping raster interface were characterized using optical and scanning electron microscopy. Aluminum oxide particles were observed at the raster interface, which were located at layer boundaries. Additional grain refinement was also apparent as a direct result of multiple stirring passes within the overlapping deposition region. Mechanical characterization via microindentation and monotonic tensile testing observed a hardness gradient in the overlapping region, but the parallel deposition layers exhibited comparable tensile strength to a single row of deposited AA6061. The influence of existing oxides on the mechanical results was observed to have limited effect on the properties longitudinally across the raster. This study determined that parallel layers of AA6061 can be successfully deposited via the AFS-D technique. The resulting deposit exhibited a strong metallurgical bond across the parallel layers despite the presence of surface oxidation on the unprepared feedstock and substrate.
Changes in temperature, CO2, and precipitation under the scenarios of climate change for the next 30 yr present a challenge to crop production. This review focuses on the impact of temperature, CO2, ...and ozone on agronomic crops and the implications for crop production. Understanding these implications for agricultural crops is critical for developing cropping systems resilient to stresses induced by climate change. There is variation among crops in their response to CO2, temperature, and precipitation changes and, with the regional differences in predicted climate, a situation is created in which the responses will be further complicated. For example, the temperature effects on soybean Glycine max (L.) Merr. could potentially cause yield reductions of 2.4% in the South but an increase of 1.7% in the Midwest. The frequency of years when temperatures exceed thresholds for damage during critical growth stages is likely to increase for some crops and regions. The increase in CO2 contributes significantly to enhanced plant growth and improved water use efficiency (WUE); however, there may be a downscaling of these positive impacts due to higher temperatures plants will experience during their growth cycle. A challenge is to understand the interactions of the changing climatic parameters because of the interactions among temperature, CO2, and precipitation on plant growth and development and also on the biotic stresses of weeds, insects, and diseases. Agronomists will have to consider the variations in temperature and precipitation as part of the production system if they are to ensure the food security required by an ever increasing population.
Key points
The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia ...whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing.
We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus.
This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations.
The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.
Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean PaO2 levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Δ: 4.8 ± 1.6 vs. 0.5 ± 1.4 μmol l−1, P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase‐derived reactive oxygen species.
Key points
The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing.
We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus.
This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations.
The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.
Coronal mass ejection driven sheath regions are one of the key drivers of drastic outer radiation belt responses. The response can however be significantly different based on the sheath properties ...and the associated inner magnetospheric wave activity. We performed two case studies on the effects of sheaths on outer belt electrons of various energies using data from the Van Allen Probes. One sheath caused a major geomagnetic disturbance and the other had only a minor impact. We especially investigated the phase space density (PSD) of seed, core, and ultrarelativistic electrons to determine the dominant energization and loss processes taking place during the events. Both sheaths produced substantial variation in the electron fluxes from tens of kiloelectronvolts up to ultrarelativistic energies. The responses were however the opposite: the geoeffective sheath mainly led to enhancement, while the nongeoeffective one caused a depletion throughout most of the outer belt. The case studies highlight that both inward and outward radial transport driven by ultra‐low frequency waves played an important role in both electron energization and loss. Additionally, PSD radial profiles revealed a local peak that indicated significant acceleration to core energies by chorus waves during the geoeffective event. The distinct responses and different mechanisms in action during these events were related to the timing of the peaked solar wind dynamic pressure causing magnetopause compression, and the differing levels of substorm activity. The most remarkable changes in the radiation belt system occurred in key sheath sub‐regions near the shock and the ejecta leading edge.
Key Points
Opposite outer belt response caused by two sheaths: mainly enhancement by geoeffective sheath and depletion by nongeoeffective sheath
Phase space density analyses of seed, core, and ultrarelativistic electrons reveal importance of ultra‐low frequency‐driven diffusion and chorus acceleration
Major variations in wave activity and electron fluxes occur during key sub‐regions near the start and end of a sheath
The energetic electron content in the Van Allen radiation belts surrounding the Earth can vary dramatically at several timescales, and these strong electron fluxes present a hazard for spacecraft ...traversing the belts. The belt response to solar wind driving is, however, largely unpredictable, and the direct response to specific large-scale heliospheric structures has not been considered previously. We investigate the immediate response of electron fluxes in the outer belt that are driven by sheath regions preceding interplanetary coronal mass ejections and the associated wave activity in the inner magnetosphere. We consider the events recorded from 2012 to 2018 in the Van Allen Probes era to utilise the energy- and radial-distance-resolved electron flux observations of the twin spacecraft mission. We perform a statistical study of the events by using the superposed epoch analysis in which the sheaths are superposed separately from the ejecta and resampled to the same average duration. Our results show that the wave power of ultra-low frequency Pc5 and electromagnetic ion cyclotron waves, as measured by a Geostationary Operational Environmental Satellite (GOES), is higher during the sheath than during the ejecta. However, the level of chorus wave power, as measured by the Van Allen Probes, remains approximately the same due to similar substorm activity during the sheath and ejecta. Electron flux enhancements are common at low energies (<1 MeV) throughout the outer belt (L = 3–6), whereas depletion predominantly occurs at high energies for high radial distances (L>4). It is distinctive that the depletion extends to lower energies at larger distances. We suggest that this L-shell and energy-dependent depletion results from the magnetopause shadowing that dominates the losses at large distances, while the wave–particle interactions dominate closer to the Earth. We also show that non-geoeffective sheaths cause significant changes in the outer belt electron fluxes.
Key points
Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms ...by which FHRV is reduced in the chronically hypoxic fetus have yet to be established.
The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV.
In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy.
We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans.
Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected.
Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In this study, we present a longitudinal study of the development of autonomic control of FHRV, assessed by indirect indices, time domain and power spectral analysis, in normoxic and chronically hypoxic, chronically catheterised, singleton fetal sheep over the last third of gestation. We used isobaric chambers able to maintain pregnant sheep for prolonged periods in hypoxic conditions (stable fetal femoral arterial PO2 10–12 mmHg), and a customised wireless data acquisition system to record beat‐to‐beat variation in the fetal heart rate. We determined in vivo longitudinal changes in overall FHRV and the sympathetic and parasympathetic contribution to FHRV in hypoxic (n = 6) and normoxic (n = 6) ovine fetuses with advancing gestational age. Normoxic fetuses show gestational age‐related increases in overall indices of FHRV, and in the sympathetic nervous system contribution to FHRV (P < 0.001). Conversely, gestational age‐related increases in overall FHRV were impaired by exposure to chronic hypoxia, and there was evidence of suppression of the sympathetic nervous system control of FHRV after 72 h of exposure to hypoxia (P < 0.001). This demonstrates that exposure to late gestation isolated chronic fetal hypoxia has the potential to alter the development of the autonomic nervous system control of FHRV in sheep. This presents a potential mechanism by which a reduction in indices of FHRV in human fetuses affected by uteroplacental dysfunction can predict fetuses at increased risk.
Key points
Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established.
The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV.
In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy.
We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans.
Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected.
Dr Peter Henriksen (consultant cardiologist and honorary senior lecturer, Edinburgh Heart Centre, NHS Lothian, University Hospitals Division), Professor C P Day (Professor of Liver Medicine, ...Institute of Cellular Medicine, Newcastle University), Dr D Thorburn (consultant hepatologist, Liver Unit, Royal Free Hospital, London), Mr D F Mirza (consultant hepatobiliary and transplant surgeon, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr J W Ferguson (consultant hepatologist and honorary senior lecturer, Liver Unit, University Hospital Birmingham NHS Foundation Trust), Dr G Auzinger (consultant intensive care medicine, Liver Intensive Therapy Unit, King's College Hospital London NHS Foundation Trust), Dr M Allison (consultant hepatologist, Liver Unit, Department of Medicine, Cambridge University Hospital NHS Foundation Trust), Dr J W Tomlinson (reader in endocrinology, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham), H Manley (British Liver Trust), Dr K J Simpson (senior lecturer in hepatology, University of Edinburgh and honorary consultant physician, Scottish Liver Transplantation Unit, Royal Infirmary Edinburgh), Professor S G Hubscher (Leith Professor and Professor of Hepatic Pathology, University of Birmingham, and consultant histopathologist, University Hospital Birmingham NHS Foundation Trust), Dr C Millson (consultant hepatologist, St James's University Hospital, Leeds), Dr J Oben (Wellcome Trust senior lecturer and consultant hepatologist, University College London, Centre for Hepatology, Royal Free Hospital, London), Professor J M Neuberger (Associate Medical Director for Organ Donation and Transplantation, NHS Blood and Transplant and honorary consultant physician, Queen Elizabeth Hospital, Birmingham), Dr P J McKiernan (consultant paediatrician, Liver Unit, Birmingham Children's Hospital) and Dr J I Wyatt (consultant histopathologist, St James's University Hospital, Leeds). Criteria for diagnosis of NASH group should include an established clinical and histological diagnosis of NASH on liver biopsy, or a histological diagnosis of cryptogenic cirrhosis with a clinical phenotype compatible with underlying NASH, as defined by the presence of three or more components of the metabolic syndrome prior to liver transplant (LT).
Atomic-Scale Visualization of Inertial Dynamics Lindenberg, A. M; Larsson, J; Sokolowski-Tinten, K ...
Science (American Association for the Advancement of Science),
04/2005, Volume:
308, Issue:
5720
Journal Article
Peer reviewed
Open access
The motion of atoms on interatomic potential energy surfaces is fundamental to the dynamics of liquids and solids. An accelerator-based source of femtosecond x-ray pulses allowed us to follow ...directly atomic displacements on an optically modified energy landscape, leading eventually to the transition from crystalline solid to disordered liquid. We show that, to first order in time, the dynamics are inertial, and we place constraints on the shape and curvature of the transition-state potential energy surface. Our measurements point toward analogies between this nonequilibrium phase transition and the short-time dynamics intrinsic to equilibrium liquids.
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