The occurrence of groundwater in Antarctica, particularly in the ice-free regions and along the coastal margins is poorly understood. Here we use an airborne transient electromagnetic (AEM) sensor to ...produce extensive imagery of resistivity beneath Taylor Valley. Regional-scale zones of low subsurface resistivity were detected that are inconsistent with the high resistivity of glacier ice or dry permafrost in this region. We interpret these results as an indication that liquid, with sufficiently high solute content, exists at temperatures well below freezing and considered within the range suitable for microbial life. These inferred brines are widespread within permafrost and extend below glaciers and lakes. One system emanates from below Taylor Glacier into Lake Bonney and a second system connects the ocean with the eastern 18 km of the valley. A connection between these two basins was not detected to the depth limitation of the AEM survey (∼350 m).
Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines ...through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.
Observational studies have suggested that low blood pressure and blood pressure variability may partially explain adverse neurological outcome after endovascular therapy with general anaesthesia (GA) ...for acute ischaemic stroke. The aim of this study was to further examine whether blood pressure related parameters during endovascular therapy are associated with neurological outcome.
The GOLIATH trial randomised 128 patients to either GA or conscious sedation for endovascular therapy in acute ischaemic stroke. The primary outcome was 90 day modified Rankin Score. The haemodynamic protocol aimed at keeping the systolic blood pressure >140 mm Hg and mean blood pressure >70 mm Hg during the procedure. Blood pressure related parameters of interest included 20% reduction in mean blood pressure; mean blood pressure <70 mm Hg, <80 mm Hg, and <90 mm Hg, respectively; time with systolic blood pressure <140 mm Hg; procedural minimum and maximum mean and systolic blood pressure; mean blood pressure at the time of groin puncture; postreperfusion mean blood pressure; blood pressure variability; and use of vasopressors. Sensitivity analyses were performed in the subgroup of reperfused patients.
Procedural average mean and systolic blood pressures were higher in the conscious sedation group (P<0.001). The number of patients with mean blood pressure <70–90 mm Hg and systolic blood pressure <140 mm Hg, blood pressure variability, and use of vasopressors were all higher in the GA group (P<0.001). There was no statistically significant association between any of the examined blood pressure related parameters and the modified Rankin Score in the overall patient population, and in the subgroup of patients with full reperfusion.
We found no statistically significant association between blood pressure related parameters during endovascular therapy and neurological outcome.
NCT 02317237.
An unanticipated difficult airway may arise during rapid sequence induction and intubation (RSII). The aim of the trial was to assess how rapidly spontaneous ventilation could be re-established after ...RSII. We hypothesized that the time period from tracheal intubation to spontaneous ventilation would be shorter with rocuronium–sugammadex than with succinylcholine.
This randomized and patient- and observer-blinded trial was approved by the regional Ethics Committee and the Danish Medicines Agency. We included elective surgical patients undergoing general anaesthesia for RSII using alfentanil (10 µg kg−1), propofol (2 mg kg−1), and either succinylcholine (1 mg kg−1) or rocuronium (1 mg kg−1). Sugammadex (16 mg kg−1) was given in the rocuronium group after tracheal intubation. The primary endpoint was the time from correct placement of the tracheal tube to spontaneous ventilation, defined as a respiratory rate of more than 8 bpm and a tidal volume of at least 3 ml kg−1 for 30 s.
We included 61 patients; of whom, 55 were evaluated for the primary endpoint. The median time from tracheal intubation to spontaneous ventilation was 406 s with succinylcholine and 216 s with rocuronium–sugammadex (P = 0.002). The median time from tracheal intubation to 90% recovery of the first twitch in train-of-four (T1 90%) was 518 s with succinylcholine and 168 s with rocuronium–sugammadex (P < 0.0001). Intubation conditions and time to tracheal intubation were not significantly different.
RSII with rocuronium followed by reversal with sugammadex allowed earlier re-establishment of spontaneous ventilation than with succinylcholine.
Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP‐AMP synthase (cGAS) recognizes cytoplasmic DNA ...and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length‐dependent manner. This is observed over a wide length‐span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length‐dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections.
Synopsis
Cytosolic DNA stimulates innate immunity via cGAS‐STING signaling. The response to dsDNA depends on DNA length at physiological DNA concentrations. Activation of cGAS occurs more efficiently with long DNA. This preference is an intrinsic property of cGAS.
cGAS‐mediated type I IFN production is dependent on DNA length.
The length‐dependency is seen at low DNA concentrations comparable with infections.
Recombinant human cGAS produces cGAMP in a DNA length‐dependent manner in vitro.
Cytosolic DNA stimulates innate immunity via cGAS‐STING signaling. The response to dsDNA depends on DNA length at physiological DNA concentrations. Activation of cGAS occurs more efficiently with long DNA. This preference is an intrinsic property of cGAS.
Anti-Müllerian hormone (AMH), which is secreted by immature Sertoli cells, triggers the involution of the fetal Müllerian ducts. AMH is a testis-specific marker used for diagnosis in infants with ...ambiguous genitalia or bilateral cryptorchidism.
The aim of the study was to describe the ontogeny of AMH secretion through life in healthy males.
This was a population-based study of healthy volunteers.
PARTICIPANTS included 1027 healthy males from birth (cord blood) to 69 yr. A subgroup was followed up longitudinally through the infantile minipuberty (in cord blood, and at 3 and 12 months), n=55 and another group through puberty (biannual measurements), n=83.
Serum AMH was determined by a sensitive immunoassay. Serum testosterone, LH, and FSH were measured, and pubertal staging was performed in boys aged 6 to 20 yr (n=616).
Serum AMH was above the detection limit in all samples with a marked variation according to age and pubertal status. The median AMH level in cord blood was 148 pmol/liter and increased significantly to the highest observed levels at 3 months (P<0.0001). AMH declined at 12 months (P<0.0001) and remained at a relatively stable level throughout childhood until puberty, when AMH declined progressively with adults exhibiting 3-4% of infant levels.
Based on this extensive data set, we found detectable AMH serum levels at all ages, with the highest measured levels during infancy. At the time of puberty, AMH concentrations declined and remained relatively stable throughout adulthood. The potential physiological role of AMH and clinical applicability of AMH measurements remain to be determined.
Discrete Element Method (DEM) simulations are a promising approach to accurately predict agglomeration and deposition of micron-sized adhesive particles. However, the mechanistic models in DEM ...combined with high particle stiffness for most common materials require time step sizes in the order of nanoseconds, which makes DEM simulations impractical for more complex applications.
In this study, analytically derived guidelines on how to reduce computational time by using a reduced particle stiffness are given. The guidelines are validated by comparing simulations of particles with and without reduced particle stiffness to experimental data. Then two well-defined test cases are investigated to show the applicability of the guidelines.
When introducing a reduced particle stiffness in DEM simulations by reducing the effective Young's modulus from E to Emod, the surface energy density γ in the adhesive Johnson-Kendall-Roberts (JKR) model by Johnson et al. 1 should be modified as γmod=γ (Emod/E)2/5. Using this relation, the stick/rebound threshold remains the same but the collision process takes place over a longer time period, which allows for a higher time step size. When rolling motion is important, the commonly used adhesive rolling resistance torque model proposed by Dominik and Tielens 2,3, Krijt et al. 4 can be used by modifying the contact radius ratio (a/a0)3/2 to (amod/a0,mod)3/2, while keeping the other terms unaltered in the description of the rolling resistance torque Mr,mod=−4FC (a/a0)3/2ξ. Furthermore, as the particle stiffness is reduced from E to Emod, the time period for collisions (or oscillations when particles stick upon impact) Δtcol is found to vary as Δtcol,mod=Δtcol(E/Emod)2/5. As the collision duration and the collision time step size are directly related, this criterion can be used to estimate how much the time step size can be changed when a reduced particle stiffness is introduced.
Introducing particles with a reduced particle stiffness has some limitations when strong external forces are acting to break-up formed agglomerates or re-entrain particles deposited on a surface out into the free stream. Therefore, care should be taken in flows with high local shear to make sure that an external force, such as a fluid drag force, acting to separate agglomerated particles, is several orders of magnitude lower than the critical force required to separate particles.
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•Guidelines to reduce computation time of adhesive collisions using JKR model are presented.•Guidelines to modify JKR based rolling resistance models are presented.•The surface energy density should be modified as γmod=γ(Emod/E)2/5.•The computation time can be reduced by a factor (E/Emod)2/5.•Dimensionless map showing borders between sticking, rebounding and rolling behaviour stays the same.
A liquid-chromatography–tandem-mass-spectrometry method using pneumatically assisted electrospray ionisation (LC–ESI-MS/MS) was developed for the simultaneous determination of cathinone, ...methcathinone, ethcathinone, amfepramone, mephedrone, flephedrone, methedrone, methylone, butylone, cathine, norephedrine, ephedrine, pseudoephedrine, methylephedrine and methylpseudoephedrine in human live and post-mortem whole blood. The blood proteins were precipitated by the addition of methanol, and the extract was purified by ultrafiltration. The separation of diastereomeric ephedrines was achieved on an ethyl-linked phenyl column. Matrix-matched calibrants combined with the isotope dilution of selected substances were used for quantitative analysis. The relative intra-laboratory reproducibility standard deviations were generally better than 7% at concentrations of 20
μg/L, and the mean true recoveries were 87–106% in the concentration range of 10–250
μg/L. The detection limits were in the range of 0.5–3
μg/L. The cathinones were unstable in whole blood and sample extracts under neutral conditions, but the stability could be improved by the acidification of the sample matrix.
Osmotic balance in fish is maintained through the coordinated regulation of water and ion transport performed by epithelia in intestine, kidney and gill. In the current study, six aquaporin (AQP) ...isoforms found in Atlantic salmon (Salmo salar) were classified and their tissue specificity and mRNA expression in response to a hyperosmotic challenge and during smoltification were examined. While AQP-1a was generic, AQP-1b had highest expression in kidney and AQP-3 was predominantly found in oesophagus, gill and muscle. Two novel teleost isoforms, AQP-8a and -8b, were expressed specifically in liver and intestinal segments, respectively. AQP-10 was predominantly expressed in intestinal segments, albeit at very low levels. Transfer from freshwater (FW) to seawater (SW) induced elevated levels of intestinal AQP-1a, -1b and -8b mRNA, whereas only AQP-8b was stimulated during smoltification. In kidney, AQP-1a, -3 and -10 were elevated in SW whereas AQP-1b was reduced compared with FW levels. Correspondingly, renal AQP-1a and -10 peaked during smoltification in April and March, respectively, as AQP-1b and AQP-3 declined. In the gill, AQP-1a and AQP-3 declined in SW whereas AQP-1b increased. Gill AQP-1a and -b peaked in April, whereas AQP-3 declined through smoltification. These reciprocal isoform shifts in renal and gill tissues may be functionally linked with the changed role of these organs in FW compared with SW. The presence and observed dynamics of the AQP-8b isoform specifically in intestinal sections suggest that this is a key water channel responsible for water uptake in the intestinal tract of seawater salmonids.
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