AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric ...restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort.
Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown.
Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation.
We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans.
CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.
Water-air flux of dimethylsulfide McGillis, W. R.; Dacey, J. W. H.; Frew, N. M. ...
Journal of Geophysical Research, Washington, DC,
15 January 2000, Letnik:
105, Številka:
C1
Journal Article
Recenzirano
Odprti dostop
The water‐air exchange of dimethylsulfide (DMS) has been measured in a laboratory wind‐wave tank in fresh and seawater. To understand the transport behavior of DMS, its exchange was measured ...simultaneously with that of O2, SF6, Ne, CH4, and He under varying wind speeds and hydrodynamic conditions. No unpredictable differences between fresh and seawater were found, indicating that DMS surface affinities do not exist in seawater. Results also indicate that Schmidt number corrections can be applied to DMS gas exchange. While the rate of transfer of relatively insoluble or sparingly soluble permanent gases between the ocean and the atmosphere is primarily controlled by the rate of flux through the aqueous boundary layer, interfacial mass balances indicate that increased DMS solubility increases the significance of the airside control of flux. The hypothesis that DMS transport across the water‐air interface is subject to waterside control for moderate environmental conditions is supported. However, for ocean‐atmospheric DMS exchange with low sea surface temperature or moderate wind speeds, there may be a significant influence by the atmospheric mass boundary layer. An atmospheric gradient fraction γa applied to the waterside air‐sea gas transfer velocity will correct for these effects. Estimates of ocean‐atmospheric DMS transfer velocities for these conditions are provided.
Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience ...and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impairment.
The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated.
In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/.
Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.
The flow in the human trachea is turbulent. Thus, the tracheal resistance (R) and the pressure gradient (ΔP) required to maintain a given flow across the trachea is inversely related to its radius ...raised to the fifth power. If the caliber reduction ratio (X) after endotracheal intubation is calculated as X = radius of the endotracheal tube (rETT)/radius of the trachea (rT), then ΔP and/or R will be increased by (1/X)5.
To measure the actual ratio between rETT and rT following endotracheal intubation of pediatric patients with respiratory failure and to calculate the resulting increase in the tracheal R and ΔP for a given inspiratory flow rate.
Retrospective chart review.
Pediatric ICU in a tertiary-care teaching children's medical center.
Twenty consecutive pediatric patients (mean ± SD age, 6.4 ± 7.2 years) whose tracheas had been intubated for various causes of respiratory failure, and who had received a CT scan, were included in our study. All patients received an endotracheal tube the size of which was derived from the following formula: (age in years/4) + 4.
rT and rETT were measured from CT scan sections at and around the level of the thoracic inlet, and the average values were used to calculate X. These values ranged from 0.33 to 0.65 (mean, 0.55 ± 0.8). The factor (1/X)5 was calculated for each patient and then was multiplied by the known normal value for tracheal R for adolescents and adults (0.07 cm H2O/L/s) to obtain the value of R resulting from the artificial airway, (1/X)5 × 0.07. Our results showed that tracheal R increased due to caliber reduction of the trachea after endotracheal intubation by 33.9 ± 52.5-fold (range, 8.6- to 255.5-fold). In order to maintain an inspiratory flow of 1 L/s, the value of P for the intubated trachea would increase from 0.07 cm H2O to a mean of 2.4 ± 3.7 cm H2O (range, 0.6 to 18 cm H2O). In two of our patients, the rT/rETT ratios were < 0.5 (0.33 and 0.44, respectively); this translated into a more significant increase in the calculated ΔPs, 18 and 4.2 cm H2O, respectively.
The common value of X due to endotracheal intubation is between 0.5 and 0.6, which in and of itself results in an increase in R across the intubated trachea up to 32-fold. The calculated increase in P as a result of this is between 2 and 3 cm H2O for adolescents or young adults. The addition of pressure support of at least 3 cm H2O during spontaneous ventilation via an endotracheal tube, which is common practice in pediatric critical care, should alleviate any respiratory distress emanating from the increased R. However, a value for X < 0.5, which was found in 10% of our patients (2 of 20 patients), results in a much higher calculated increase in the pressure gradient and, therefore, a higher level of pressure support is required to overcome this increase.
To assess the safety of minibronchoalveolar lavage done by respiratory therapists for the evaluation of suspected ventilator-associated pneumonia and to determine the diagnostic agreement between ...quantitative lower airway cultures obtained by the minibronchoalveolar lavage and protected specimen brush techniques.
A prospective direct comparison of two diagnostic techniques.
An academic tertiary care center in St. Louis, Missouri.
72 consecutive patients suspected of having ventilator-associated pneumonia on the basis of clinical evidence.
Sampling of lower airway secretions using the protected specimen brush and minibronchoalveolar lavage techniques.
Clinical complications and quantitative cultures of respiratory secretions.
72 patients suspected of having ventilator-associated pneumonia (first episode) were evaluated using minibronchoalveolar lavage. In 42 patients, lower airway secretions were also obtained using the protected specimen brush technique. No change in arterial blood oxygen saturation or heart rate occurred after minibronchoalveolar lavage (P > 0.2). Mean arterial pressure slightly increased with minibronchoalveolar lavage (baseline mean pressure, 90.1 mm Hg CI, 88.4 to 91.7 mm Hg; average within-person change, 2.6 mm Hg; P = 0.024). Good diagnostic agreement was shown for quantitative cultures obtained with the protected specimen brush and minibronchoalveolar lavage techniques (kappa statistic, 0.63; concordance, 83.3%); 10(3) colony forming units/mL was used as the threshold for a clinically significant culture result.
Minibronchoalveolar lavage is a safe and technically simple procedure for obtaining quantitative lower airway cultures in patients requiring mechanical ventilation. Quantitative culture results obtained by minibronchoalveolar lavage are similar to those obtained by the protected specimen brush technique.
Aims. The radio galaxy NGC 1275, recently identified as a very high energy (VHE, >100 GeV) γ-ray emitter by MAGIC, is one of the few non-blazar active galactic nuclei detected in the VHE regime. The ...purpose of this work is to better understand the origin of the γ-ray emission and locate it within the galaxy. Methods. We studied contemporaneous multifrequency observations of NGC 1275 and modeled the overall spectral energy distribution. We analyzed unpublished MAGIC observations carried out between October 2009 and February 2010, and the previously published observations taken between August 2010 and February 2011. We studied the multiband variability and correlations by analyzing data of Fermi-LAT in the 100 MeV–100 GeV energy band, as well as Chandra (X-ray), KVA (optical), and MOJAVE (radio) data taken during the same period. Results. Using customized Monte Carlo simulations corresponding to early MAGIC stereoscopic data, we detect NGC 1275 also in the earlier MAGIC campaign. The flux level and energy spectra are similar to the results of the second campaign. The monthly light curve above 100 GeV shows a hint of variability at the 3.6σ level. In the Fermi-LAT band, both flux and spectral shape variabilities are reported. The optical light curve is also variable and shows a clear correlation with the γ-ray flux above 100 MeV. In radio, three compact components are resolved in the innermost part of the jet. One of these components shows a similar trend as the Fermi-LAT and KVA light curves. The γ-ray spectra measured simultaneously with MAGIC and Fermi-LAT from 100 MeV to 650 GeV can be well fitted either by a log-parabola or by a power-law with a subexponential cutoff for the two observation campaigns. A single-zone synchrotron-self-Compton model, with an electron spectrum following a power-law with an exponential cutoff, can explain the broadband spectral energy distribution and the multifrequency behavior of the source. However, this model suggests an untypical low bulk-Lorentz factor or a velocity alignment closer to the line of sight than the parsec-scale radio jet.
We report new constraints on the size of large extra dimensions from data collected by the MINOS experiment between 2005 and 2012. Our analysis employs a model in which sterile neutrinos arise as ...Kaluza-Klein states in large extra dimensions and thus modify the neutrino oscillation probabilities due to mixing between active and sterile neutrino states. Using Fermilab’s Neutrinos at the Main Injector beam exposure of 10.56×1020 protons on target, we combine muon neutrino charged current and neutral current data sets from the Near and Far Detectors and observe no evidence for deviations from standard three-flavor neutrino oscillations. The ratios of reconstructed energy spectra in the two detectors constrain the size of large extra dimensions to be smaller than 0.45 μm at 90% C.L. in the limit of a vanishing lightest active neutrino mass. Stronger limits are obtained for nonvanishing masses.
Regulatory exosite I of thrombin is present on prothrombin in a precursor state (proexosite I) that specifically binds the Tyr63-sulfated peptide, hirudin54–65(Hir54–65(SO3−)) and the nonsulfated ...analog. The role of proexosite I in the mechanism of factor Va acceleration of prothrombin activation was investigated in kinetic studies of the effects of peptide binding. The initial rate of human prothrombin activation by factor Xa was inhibited by the peptides in the presence of factor Va but not in the absence of the cofactor. Factor Xa and factor Va did not bind the peptide with significant affinity compared with prothrombin. Maximum inhibition reduced the factor Va-accelerated rate to a level indistinguishable from the rate in the absence of the cofactor. The effect of Hir54–65(SO3−) on the kinetics of prothrombin activation obeyed a model in which binding of the peptide to proexosite I prevented productive prothrombin interactions with the factor Xa-factor Va complex. Comparison of human and bovine prothrombin as substrates demonstrated a similar correlation between peptide binding and inhibition of factor Va acceleration. Inhibition of prothrombin activation by hirudin peptides was opposed by assembly on phospholipid vesicles of the membrane-bound factor Xa-factor-Va-prothrombin complex. Factor Va interactions of human and bovine prothrombin activation are concluded to share a common mechanism in which proexosite I participates in productive interactions of prothrombin as the substrate of the factor Xa-factor Va complex, possibly by directly mediating productive prothrombin-factor Va binding.
We report on the detection of very-high energy (VHE, E > 100 GeV) γ-ray emission from NGC 1275, the central radio galaxy of the Perseus cluster of galaxies. The source has been detected by the MAGIC ...telescopes with a statistical significance of 6.6σ above 100 GeV in 46 h of stereo observations carried out between August 2010 and February 2011. The measured differential energy spectrum between 70 GeV and 500 GeV can be described by a power law with a steep spectral index of Γ = −4.1 ± 0.7stat ± 0.3syst, and the average flux above 100 GeV is Fγ = (1.3 ± 0.2stat ± 0.3syst) × 10-11 cm-2 s-1. These results, combined with the power-law spectrum measured in the first two years of observations by the Fermi-LAT above 100 MeV, with a spectral index of Γ ≃ − 2.1, strongly suggest the presence of a break or cut-off around tens of GeV in the NGC 1275 spectrum. The light curve of the source above 100 GeV does not show hints of variability on a month time scale. Finally, we report on the nondetection in the present data of the radio galaxy IC 310, previously discovered by the Fermi-LAT and MAGIC. The derived flux upper limit FU.L.γ (>300 GeV) = 1.2 × 10-12 cm-2 s-1 is a factor ~ 3 lower than the mean flux measured by MAGIC between October 2009 and February 2010, thus confirming the year time-scale variability of the source at VHE.
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