The number of substances nominally listed in the prohibited list of the World Anti‐Doping Agency increases each year. Moreover, many of these substances do not have a single analytical target and ...must be monitored through different metabolites, artifacts, degradation products, or biomarkers. A new analytical method was developed and validated for the simultaneous analysis of peptides and organic molecules using a single sample preparation and LC‐Q‐HRMS detection. The simultaneous analysis of 450 target molecules was performed after cleanup on a mixed‐mode solid‐phase extraction cartridge, combined with untreated urine. The cleanup solvent and reconstitution solvent were the most important parameters for achieving a comprehensive sample preparation approach. A fast chromatographic run based on a multistep gradient was optimized under different flows; the detection of all substances without isomeric coelution was achieved in 11 minutes, and the chromatographic resolution was considered a critical parameter, even in high‐resolution mass spectrometry detection. The mass spectrometer was set to operate by switching between positive and negative ionization mode for FULL‐MS, all‐ion fragmentation, and FULL‐MS/MS2. The suitable parameters for the curved linear trap (c‐trap) conditions were determined and found to be the most important factors for the development of the method. Only FULL‐MS/MS2 enables the detection of steroids and peptides at concentrations lower than the minimum required performance levels set by World Anti‐Doping Agency (1 ng mL−1). The combination of the maximum injection time of the ions into the c‐trap, multiplexing experiments, and loop count under optimized conditions enabled the method to be applied to over 10 000 samples in only 2 months during the 2016 Rio Summer Olympic and Paralympic Games. The procedure details all aspects, from sample preparation to mass spectrometry detection. FULL‐MS data acquisition is performed in positive and negative ion mode simultaneously and can be applied to untargeted approaches.
•Amyotrophic lateral sclerosis (ALS) patients had elevated tongue echo intensity (EI).•Tongue EI was correlated with ALS functional rating scale-revised bulbar sub-score.•Tongue EI holds promise as a ...novel biomarker of bulbar dysfunction in ALS.
To learn if quantitative ultrasound (QUS) distinguishes the tongues of healthy participants and amyotrophic lateral sclerosis (ALS) patients by echo intensity (EI) and to evaluate if EI correlates with measures of bulbar function.
Ultrasound was performed along the midline of the anterior tongue surface in 16 ALS patients and 16 age-matched controls using a linear hockey stick 16–7 MHz transducer. A region of interest was manually drawn and then EI was determined for the upper 1/3 of the muscle. For patients, the ALS functional rating scale – revised (ALSFRS-R) was used to calculate bulbar sub-scores and the Iowa Oral Performance Instrument (IOPI) was used to measure tongue strength.
EI was significantly higher in ALS patients than in healthy participants (49.8 versus 37.8 arbitrary units, p < 0.01). In the patient group, EI was negatively correlated with ALSFRS-R bulbar sub-score (RS = −0.65, p < 0.01). An inverse correlation between EI and tongue strength did not reach significance (RS = −0.34, p = 0.28).
This study suggests that EI can differentiate healthy from diseased tongue muscle, and correlates with a standard functional measure in ALS patients.
Tongue EI may represent a novel biomarker for bulbar dysfunction in ALS.
Abstract
GRB 221009A is a long gamma-ray burst among the most energetic and nearest (
z
= 0.151) detected so far. The energy fluence of the burst was so large to cause ionization of the upper layers ...of Earth’s atmosphere and also observable signals in satellite-borne particle detectors. Electron signals, with the same GRB time development, can arise from the interaction of energetic photons with the particle detector and support structures. This effect was previously reported for the HEPP-L on board the China Seismo-Electromagnetic Satellite. We searched for the same effect on the particle detectors on board five POES and MetOp satellites. Electron signals in coincidence with the gamma-ray emission of the burst were found in three satellites, which were well illuminated by the GRB. The properties of the found electron signals are reported and discussed.
Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM is a novel diagnostic biomarker ...over-expressed in the serum of IBD patients. This paper reports on the first electrochemical OSM immunosensor, developed using a multistep fabrication process aimed at covalently immobilizing OSM antibodies on a mixed self-assembled monolayer coated gold working electrode. Cyclic voltammetry, atomic force microscopy (AFM), IR spectroscopy and optical characterizations were used to validate the sensor functionalization protocol. Electrochemical impedance spectroscopy (EIS) measurements were performed to assess the reliability of the immunosensor preparation and to verify the antibody-antigen complexes formation. The label-free immunosensor showed high sensitivity identifying OSM at clinically relevant concentrations (37–1000 pg mL−1) with low detection limit of 2.86 pg mL−1. Both sensitivity and selectivity of the proposed immunosensor were also demonstrated in human serum in the presence of interfering biomarkers, making it an innovative potential platform for the OSM biomarker detection in IBD patients’ serum.
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•First electrochemical immunosensor developed to detect OSM biomarker in serum.•A covalently immobilization of OSM antibodies was performed on gold electrodes.•The immunosensor exhibited a low detection limit by EIS measurements.•Detection in serum in the presence of interfering species was performed.•The immunosensor represents a potential tool for early diagnosis of IBD.
Little is known about the origin of the high-energy and sustained emission from solar long-duration gamma-ray flares (LDGRFs) identified with the Compton Gamma Ray Observatory, the Solar Maximum ...Mission, and now Fermi. Though the Fermi Large Area Telescope (LAT) has identified dozens of flares with LDGRF signatures, the nature of this phenomenon has been a challenge to explain due to both extreme energies and long durations. The highest-energy emission has generally been attributed to pion production from the interaction of 300 MeV protons with the ambient matter. The extended duration suggests that particle acceleration occurs over large volumes extending high in the corona, either from stochastic acceleration within large coronal loops or from back precipitation from coronal mass ejection-driven shocks. It is possible to test these models by making a direct comparison between the properties of the accelerated ion population producing the γ-ray emission derived from the Fermi/LAT observations and the characteristics of solar energetic particles (SEPs) measured by the Payload for Matter-Antimatter Exploration and Light Nuclei Astrophysics spacecraft in the energy range corresponding to the pion-related emission detected with Fermi. For 14 of these events, we compare the two populations-SEPs in space and the interacting particles at the Sun-and discuss the implications in terms of potential sources. Our analysis shows that the two proton numbers are poorly correlated, with their ratio spanning more than 5 orders of magnitude, suggesting that the back precipitation of shock-acceleration particles is unlikely to be the source of the LDGRF emission.
Signal intensity increases possibly suggestive of gadolinium retention have recently been reported on unenhanced T1-weighted images of the pediatric brain following multiple exposures to ...gadolinium-based MR contrast agents. Our aim was to determine whether T1 signal changes suggestive of gadolinium deposition occur in the brains of pediatric nonneurologic patients after multiple exposures to gadobenate dimeglumine.
Thirty-four nonneurologic patients (group 1; 17 males/17 females; mean age, 7.18 years) who received between 5 and 15 injections (mean, 7.8 injections) of 0.05 mmol/kg of gadobenate during a mean of 2.24 years were compared with 24 control patients (group 2; 16 males/8 females; mean age, 8.78 years) who had never received gadolinium-based contrast agents. Exposure to gadobenate was for diagnosis and therapy monitoring. Five blinded readers independently determined the signal intensity at ROIs in the dentate nucleus, globus pallidus, pons, and thalamus on unenhanced T1-weighted spin-echo images from both groups. Unpaired
tests were used to compare signal-intensity values and dentate nucleus-pons and globus pallidus-thalamus signal-intensity ratios between groups 1 and 2.
Mean signal-intensity values in the dentate nucleus, globus pallidus, pons, and thalamus of gadobenate-exposed patients ranged from 366.4 to 389.2, 360.5 to 392.9, 370.5 to 374.9, and 356.9 to 371.0, respectively. Corresponding values in gadolinium-based contrast agent-naïve subjects were not significantly different (
> .05). Similarly, no significant differences were noted by any reader for comparisons of the dentate nucleus-pons signal-intensity ratios. One reader noted a difference in the mean globus pallidus-thalamus signal-intensity ratios (1.06 ± 0.006 versus 1.02 ± 0.009,
= .002), but this reflected nonsignificantly higher T1 signal in the thalamus of control subjects. The number of exposures and the interval between the first and last exposures did not influence signal-intensity values.
Signal-intensity increases potentially indicative of gadolinium deposition are not seen in pediatric nonneurologic patients after multiple exposures to low-dose gadobenate.
The High-energy Particle Detector (HEPD) on board the China Seismo-Electromagnetic Satellite (CSES-01)-launched on 2018 February 2-is a light and compact payload suitable for measuring electrons ...(3-100 MeV), protons (30-250 MeV), and light nuclei (up to a few hundreds of MeV). The Sun-synchronous orbit and large acceptance allow HEPD to measure cosmic-ray particles near the 65° latitude limit for a fair amount of time per day. In this work, three semiannual galactic hydrogen energy spectra between ∼40 and 250 MeV are presented, including a comparison with theoretical spectra from HelMod, a 2D Monte Carlo model developed to simulate the solar modulation of cosmic rays throughout the heliosphere. To our knowledge, these are the first hydrogen energy spectra below 250 MeV measured at 1 au between 2018 and 2020.
The China Seismo-Electromagnetic Satellite (CSES) aims to monitor electromagnetic, particle, and plasma perturbations in the iono-magnetosphere and inner Van Allen radiation belts originated by ...electromagnetic sources external and internal to the geomagnetic cavity, cosmic rays, and solar events. In particular, the objective of the space mission is to investigate lithosphere-atmosphere-ionosphere coupling mechanisms (including the effects of lightning, earthquakes, volcanoes, and artificial electromagnetic emissions) that induce perturbations of the top side of the ionosphere and lower boundary of the radiation belts. To this purpose, the mission has been conceived to take advantage of a multi-instrument payload comprising nine detectors for the measurement of electromagnetic field components, plasma parameters, and energetic particles, as well as X-ray flux. The Italian team participating in the CSES mission has built one of these devices, the High-Energy Particle Detector (HEPD), for high-precision observations of electrons, protons, and light nuclei. During its trip along the orbit, and thanks to the large set of detectors operated on board, CSES completely monitors the Earth, acting as an excellent instrument for space weather. The satellite was launched on 2018 February 2, with an expected life span of 5 yr. This article describes the CSES mission with a particular focus on the HEPD apparatus and its in-flight performance.
Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression, and packaging of mitochondrial DNA (mtDNA). Recently, a pathogenic homozygous variant in TFAM (P178L) has ...been associated with a severe mtDNA depletion syndrome leading to neonatal liver failure and early death. We have performed a biochemical characterization of the TFAM variant P178L in order to understand the molecular basis for the pathogenicity of this mutation. We observe no effects on DNA binding, and compaction of DNA is only mildly affected by the P178L amino acid change. Instead, the mutation severely impairs mtDNA transcription initiation at the mitochondrial heavy and light strand promoters. Molecular modeling suggests that the P178L mutation affects promoter sequence recognition and the interaction between TFAM and the tether helix of POLRMT, thus explaining transcription initiation deficiency.
•TFAM variant P178L is associated with a severe mtDNA depletion syndrome.•In patient fibroblasts, 7S DNA level is increased relative to mtDNA level.•The mutation severely impairs mtDNA transcription initiation.•Molecular modeling predicts that the mutation affects POLRMT recruitment to the promoter.
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