Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake

Preferred protonation site of a series of sulfa drugs in the gas phase revealed by IR spectroscopy

Sulfa drugs are an important class of pharmaceuticals in the treatment of bacterial infections. The amido/imido tautomerism of these molecules in their neutral form has been widely discussed in the literature. Here, we study the protonation preferences of sulfa drugs upon electrospray ionization (ESI) using IR action spectroscopy of the ionized gas-phase molecules in a mass spectrometer. Our set of molecules includes sulfanilamide (SA), the progenitor of the family of sulfa drugs, and the actual, sulfonamide nitrogen substituted, sulfa drugs sulfamethoxazole (SMX), sulfisoxazole (SIX), sulfamethizole (SMZ), sulfathiazole (STZ), sulfapyridine (SP) and sulfaguanidine (SG). IR multiple photon dissociation (IRMPD) spectra were recorded for the protonated sulfa drugs using a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS) and an optical parametric oscillator/amplifier (OPO/OPA) as well as the FELIX free electron laser (FEL) as IR sources. The OPO provides tunable IR radiation in the NH stretch region (3100–3700 cm$$^{-1}$$), while the FEL covers the fingerprint region (520–1750 cm$$^{-1}$$). Comparison of experimental IR spectra with spectra predicted using density functional theory allowed us to determine the gas-phase protonation site. For SA, the sulfonamide NH$$_2$$ group was identified as the protonation site, which contrasts the situation in solution, where the anilinic NH$$_2$$ group is protonated. For the derivative sulfa drugs, the favored protonation site is the nitrogen atom included in the heterocycle, except for SG, where protonation occurs at the sulfonamide nitrogen atom. The theoretical investigations show that the identified protonation isomers correspond to the lowest-energy gas-phase structures

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia?

Background: Nitrous oxide (NO, laughing gas) is increasingly used as a recreational drug and is presumed relatively safe and innocent. It is often being used in combination with other substances, such as cannabis. Case summary: A young adult attended the emergency room because of chest pain after recreational use of very high-dose nitrous oxide in combination with cannabis. Electrocardiography demonstrated ST-elevation in the anterior leads. Coronary angiography showed thrombus in the proximal and thrombotic occlusion of the distal left anterior descending coronary artery for which primary percutaneous coronary intervention was attempted. Thrombus aspiration was unsuccessful and the patient was further treated with a glycoprotein IIb/IIIa in addition to dual platelet therapy. Blood results showed low vitamin B12 and folic acid status with concomitant hyperhomocysteinaemia, a known cause of hypercoagulation. Transthoracic echocardiogram showed a moderately reduced left ventricular ejection fraction (LVEF). Three months later, an improvement in LVEF and no recurrent angina or symptoms of heart failure were noticed. Discussion: We report a case of acute myocardial infarction secondary to very high-dose nitrous oxide abuse in combination with cannabis and possible hypoxia. We propose that severe hyperhomocysteinaemia secondary to nitrous oxide-induced vitamin B12 deficiency together with the vasoconstrictive effects of cannabis might pose a seriously increased risk for intracoronary, among others, thrombus formation. In conclusion, we contest the safety and innocence of recreational nitrous oxide (ab)use, notably in the context of other factors increasing the risk of coagulation

Extending Honeytrap with Lua scripting: Honeytrap LUA implementation

This report describes the process, motivation and design choices made during the Bachelor End Project in collaboration with DutchSec. The project consists of implementing Lua-scripting into Honeytrap, which is programmed in Go. The following chapters will discuss which design choices were made, how the research was performed and how the final functionalities were implemented. A detailed system verification is done with proof of added value and besides that the system testing methods are described. Furthermore a conclusion is given that discusses what the project has achieved, what the use-cases are and whether it does what the client wants it to do.Computer Scienc

Infrared Multiple Photon Dissociation (IRMPD) Spectroscopy of the Proton-Bound Dimer of 1-Methylcytosine in the Gas Phase

The vibrational spectrum of a hemiprotonated pair of the nucleobase cytosine has been recorded in the 300−1810 cm⁻¹ domain using action spectroscopy on electrosprayed positive ions with a free-electron laser. The singly charged, gaseous cation has the same structure as that reported from crystallography, inferred from a strong absorption seen at 1761 cm⁻¹, identified as the carbonyl stretch of the protonated ring mixed with in-plane bending of the bridging H⁺ based on a 29 cm⁻¹ shift to lower frequency when all five of the exchangeable hydrogens are replaced by deuterium. IRMPD expels the neutral from the proton-bound dimer, leaving behind a protonated monomer. Whereas the bridging H⁺ in the dimer ion lies between the nitrogens of the two rings, IRMPD of the protonated monomer ion resulting from the dimer shows its H⁺ preferably situated on the carbonyl oxygen, indicating that the proton moves from one basic atom to another when the dimer ion dissociates

Robert C. Dunbar (1943–2017)

Rob Dunbar, who passed away on 31 October 2017 at the age of 74, was one of the most respected and beloved ion chemists. The fundamental understanding gained from his work on ion spectroscopy, dissociation rates, and infrared emission processes arc his lasting legacy, which will continue to influence our field in the coming years. Those lucky enough to have known Rob personally remember his devotion to the pursuit of ever-deepening understanding of ion chemistry, his modesty, generosity, and his ability to balance his scientific work with his love for the arts and literature

Structure Elucidation of the Diagnostic Product Ion at m/z 97 Derived from Androst-4-en-3-One-Based Steroids by ESI-CID and IRMPD Spectroscopy

Structure elucidation of steroids by mass spectrometry has been of great importance to various analytical arenas and numerous studies were conducted to provide evidence for the composition and origin of (tandem) mass spectrometry-derived product ions used to characterize and identify steroidal substances. The common product ion at m/z 97 generated from androst-4-ene-3-one analogs has been subject of various studies, including stable isotope-labeling and (high resolution/high accuracy) tandem mass spectrometry, but its gas-phase structure has never been confirmed. Using high resolution/high accuracy mass spectrometry and low resolution tandem mass spectrometry, density functional theory (DFT) calculation, and infrared multiple photon dissociation (IRMPD) spectroscopy employing a free electron laser, the structure of m/z 97 derived from testosterone was assigned to protonated 3-methyl-2-cyclopenten-1-one. This ion was identified in a set of six cyclic C6HgO+ isomers as computed at the B3LYP/6-311++G(2d,2p) level of theory (protonated 3-methyl-2-cyclopenten-1-one, 2-methyl-2-cyclopenten-1-one and 2-cyclohexen-1-one). Product ions of m/z 97 obtained from MS2 and MS3 experiments of protonated 3-methyl-2-cyclopenten-1-one, 2-methyl-2-cyclopenten-1-one, 2-cyclohexen-1-one, and testosterone corrobo-rated the suggested gas-phase ion structure, which was eventually substantiated by IRMPD spectroscopy yielding a spectrum that convincingly matched the predicted counterpart. Finally, the dissociation pathway of the protonated molecule of testosterone to m/z 97 was revisited and an alternative pathway was suggested that considers the exclusion of C-10 along with the inclusion of C-5, which was experimentally demonstrated with stable isotope labeling

The Sequence of Coronene Hydrogenation Revealed by Gas-phase IR Spectroscopy

The solar magnetic field (SMF) has historically been considered as dipole in order to build models of the radially expanding corona, that is, the solar wind in the solar minimum. The simplified approach suggests the existence of only one quasi-stationary current sheet (QCS) of solar origin in the heliosphere, namely, the heliospheric current sheet (HCS). However, the SMF becomes more complicated over the solar cycle, comprising higher-order components. The overlapping of the dipole and multipole components of the SMF suggests a formation of more than one QCS in the corona, which may expand further to the heliosphere. We study the impact of the.,Qquadrupole and octupole harmonics of the SMF on the formation and spatial characteristics of QCSs, building a stationary axisymmetric MHD model of QCSs in the heliosphere. It is shown that if the dipole component dominates, a single QCS appears in the solar wind at low heliolatitudes as the classic HCS. In other.,Qcases, the number of QCSs varies from one to three, depending on the relative input of the quadrupole and octupole components. QCSs possess a conic form and may occur at a wide variety of heliolatitudes. The existence of QCSs opens wide opportunities for explanations of puzzling observations of cosmic rays and energetic particles in the heliosphere and, at the same time, raises a risk of misinterpretation of in situ crossings of QCSs because of mixing up the HCS and higherheliolatitude QCSs, which can be significantly disturbed in the dynamical solar wind.</p