Rounded Turn SLIM Design for High-Resolution Ion Mobility Mass Spectrometry Analysis of Small Molecules.

Various rounded turn designs in Structures for Lossless Ion Manipulation (SLIM) were explored via ion trajectory simulations. The optimized design was integrated into a SLIM ion mobility (IM) system coupled with a time-of-flight (TOF) mass spectrometer (MS) for further experimental investigation. The SLIM-TOF IM-MS system was assessed for IM resolution and ion transmission efficiency across a wide / range using various RF frequencies and buffer gas combinations.

A framework for developing Generic Implant Safety Procedures (GISPs) for scanning patients with medical implants and devices in MRI.

UK guidelines for MR safety recommend that MRI departments refer to the implant manufacturer for advice regarding the MRI safety of scanning patients with an implantable medical device prior to scanning [1]. This process of assuring safety can be time consuming, leading to delays and potential cancellations of a patient's MRI. Furthermore, at times the implant cannot be identified, or the implant manufacturers cannot provide up to date MRI safety information.

Analysis of the neuromuscular deficits caused by STAM1 deficiency.

The endosomal sorting complexes required for transport (ESCRT) pathway is composed of a series of protein complexes that are essential for sorting cargo through the endosome. In neurons, the ESCRT pathway is a key mediator of many cellular pathways that regulate neuronal morphogenesis as well as synaptic growth and function. The ESCRT-0 complex, consisting of HGS (hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (signal-transducing adaptor molecule), acts as a gate keeper to this pathway, ultimately determining the fate of the endosomal cargo.

An Untargeted Lipidomics Workflow Incorporating High-Resolution Demultiplexing (HRdm) Drift Tube Ion Mobility-Mass Spectrometry.

Global discovery lipidomics can provide comprehensive chemical information toward understanding the intricacies of metabolic lipid disorders such as dyslipidemia; however, the isomeric complexity of lipid species remains an analytical challenge. Orthogonal separation strategies, such as ion mobility (IM), can be inserted into liquid chromatography-mass spectrometry (LC-MS) untargeted lipidomic workflows for additional isomer separation and high-confidence annotation, and the emergence of high-resolution ion mobility (HRIM) strategies provides marked improvements to the resolving power ( > 200) that can differentiate small structural differences characteristic of isomers. One such HRIM strategy, high-resolution demultiplexing (HRdm), utilizes multiplexed drift tube ion mobility spectrometry (DTIMS) with post-acquisition algorithmic deconvolution to access high IM resolutions while retaining the measurement precision inherent to the drift tube technique; however, HRdm has yet to be utilized in untargeted studies.

ENDOTHELIAL-DEPENDENT VASCULAR REACTIVITY AFTER CARDIOPULMONARY BYPASS IS ASSOCIATED WITH UNIQUE METABOLOMIC SIGNATURES.

Cardiopulmonary bypass (CPB), an extracorporeal method necessary for the surgical correction of complex congenital heart defects, incites significant inflammation that affects vascular function. These changes are associated with alterations in cellular metabolism that promote energy production to deal with this stress. Utilizing laser Doppler perfusion monitoring coupled with iontophoresis in patients undergoing corrective heart surgery, we hypothesized that temporal, untargeted metabolomics could be performed to assess the link between metabolism and vascular function.

Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper-Amino Acid Complexation and Ion Mobility-Mass Spectrometry.

Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation.

Ion Mobility-Mass Spectrometry Strategies to Elucidate the Anhydrous Structure of Noncovalent Guest/Host Complexes.

Structural mass spectrometry (MS) techniques are fast and sensitive analytical methods to identify noncovalent guest/host complexation phenomena for desirable solution-phase properties. Current MS-based studies on guest/host complexes of drug and drug-like molecules are sparse, and there is limited guidance on how to interpret MS information in the context of host nanoencapsulation and inclusion. Here, we use structural MS strategies, combining energy-resolved MS (ERMS), ion mobility-MS (IM-MS), and computational modeling, to characterize 14 chemically distinct drug and drug-like compounds for their propensity to form guest/host complexes with the widely used excipient, beta-cyclodextrin (βCD).

Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.

Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion.

Taurine modulates host cell responses to VacA toxin.

Colonization of the human stomach with strains producing active forms of the secreted toxin VacA is associated with an increased risk of peptic ulcer disease and gastric cancer, compared with colonization with strains producing hypoactive forms of VacA. Previous studies have shown that active s1m1 forms of VacA cause cell vacuolation and mitochondrial dysfunction. In this study, we sought to define the cellular metabolic consequences of VacA intoxication.

High-resolution ion mobility based on traveling wave structures for lossless ion manipulation resolves hidden lipid features.

High-resolution ion mobility (resolving power > 200) coupled with mass spectrometry (MS) is a powerful analytical tool for resolving isobars and isomers in complex samples. High-resolution ion mobility is capable of discerning additional structurally distinct features, which are not observed with conventional resolving power ion mobility (IM, resolving power ~ 50) techniques such as traveling wave IM and drift tube ion mobility (DTIM). DTIM in particular is considered to be the "gold standard" IM technique since collision cross section (CCS) values are directly obtained through a first-principles relationship, whereas traveling wave IM techniques require an additional calibration strategy to determine accurate CCS values.

Programable Albumin-Hitchhiking Nanobodies Enhance the Delivery of STING Agonists to Potentiate Cancer Immunotherapy.

Stimulator of interferon genes (STING) is a promising target for potentiating antitumor immunity, but multiple pharmacological barriers limit the clinical utility, efficacy, and/or safety of STING agonists. Here we describe a modular platform for systemic administration of STING agonists based on nanobodies engineered for hitchhiking of agonist cargo on serum albumin. Using site-selective bioconjugation chemistries to produce molecularly defined products, we found that covalent conjugation of a STING agonist to anti-albumin nanobodies improved pharmacokinetics and increased cargo accumulation in tumor tissue, stimulating innate immune programs that increased the infiltration of activated natural killer cells and T cells, which potently inhibited tumor growth in multiple mouse tumor models.

A human milk oligosaccharide prevents intestinal inflammation in adulthood via modulating gut microbial metabolism.

Observational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2'-fucosyllactose (2'-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption.

AutonoMS: Automated Ion Mobility Metabolomic Fingerprinting.

Automation is dramatically changing the nature of laboratory life science. Robotic lab hardware that can perform manual operations with greater speed, endurance, and reproducibility opens an avenue for faster scientific discovery with less time spent on laborious repetitive tasks. A major bottleneck remains in integrating cutting-edge laboratory equipment into automated workflows, notably specialized analytical equipment, which is designed for human usage.

Evaluation of Surface-Induced Dissociation Ion Mobility-Mass Spectrometry for Lipid Structural Characterization.

The complexity of the lipidome has necessitated the development of novel analytical approaches for the identification and structural analysis of morphologically diverse classes of lipids. At this time, a variety of dissociation techniques have been utilized to probe lipid decomposition pathways in search of structurally diagnostic fragment ions. Here, we investigate the application of surface-induced dissociation (SID), a fragmentation technique that imparts energy to the target molecule via collision with a coated surface, for the fragmentation of seven lipids across four major lipid subclasses.

Deficiency of the lipid flippase ATP10A causes diet-induced dyslipidemia in female mice.

Genetic association studies have linked ATP10A and closely related type IV P-type ATPases (P4-ATPases) to insulin resistance and vascular complications, such as atherosclerosis. ATP10A translocates phosphatidylcholine and glucosylceramide across cell membranes, and these lipids or their metabolites play important roles in signal transduction pathways regulating metabolism. However, the influence of ATP10A on lipid metabolism in mice has not been explored.

Solvent Composition Can Have a Measurable Influence on the Ion Mobility-Derived Collision Cross Section of Small Molecules.

Ion mobility (IM) is an important analytical technique for increasing identification coverage of metabolites in untargeted studies, especially when integrated into traditional liquid chromatography-mass spectrometry workflows. While there has been extensive work surrounding best practices to obtain and standardize collision cross section (CCS) measurements necessary for comparing across different IM techniques and laboratories, there has been little investigation into experimental factors beyond the mobility separation region that could potentially influence CCS measurements. The first-principles derived CCS of 15 chemical standards were evaluated across 27 aqueous:organic solvent compositions using a high-precision drift tube instrument.

An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism.

The mechanisms by which the early-life microbiota protects against environmental factors that promote childhood obesity remain largely unknown. Using a mouse model in which young mice are simultaneously exposed to antibiotics and a high-fat (HF) diet, we show that Lactobacillus species, predominant members of the small intestine (SI) microbiota, regulate intestinal epithelial cells (IECs) to limit diet-induced obesity during early life. A Lactobacillus-derived metabolite, phenyllactic acid (PLA), protects against metabolic dysfunction caused by early-life exposure to antibiotics and a HF diet by increasing the abundance of peroxisome proliferator-activated receptor γ (PPAR-γ) in SI IECs.

Metabolism of parathyroid organoids.

Introduction: We successfully developed a broad spectrum of patient-derived endocrine organoids (PDO) from benign and malignant neoplasms of thyroid, parathyroid, and adrenal glands. In this study, we employed functionally intact parathyroid PDOs from benign parathyroid tissues to study primary hyperparathyroidism (PHPT), a common endocrine metabolic disease. As proof of concept, we examined the utility of parathyroid PDOs for bioenergetic and metabolic screening and assessed whether parathyroid PDO metabolism recapitulated matched PHPT tissues.

Deficiency of the lipid flippase ATP10A causes diet-induced dyslipidemia in female mice.

Genetic association studies have linked ATP10A and closely related type IV P-type ATPases (P4-ATPases) to insulin resistance and vascular complications, such as atherosclerosis. ATP10A translocates phosphatidylcholine and glucosylceramide across cell membranes, and these lipids or their metabolites play important roles in signal transduction pathways regulating metabolism. However, the influence of ATP10A on lipid metabolism in mice has not been explored.

Temporal changes in glucose metabolism reflect polarization in resident and monocyte-derived macrophages after myocardial infarction.

Introduction: Metabolic reprogramming from glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation may mediate macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. We hypothesized that changes in cardiac macrophage glucose metabolism would reflect polarization status after myocardial infarction (MI), ranging from the early inflammatory phase to the later wound healing phase.

Methods: MI was induced by permanent ligation of the left coronary artery in adult male C57BL/6J mice for 1 (D1), 3 (D3), or 7 (D7) days.

Noncovalent Host-Guest Complexes of Artemisinin with α-, β-, and γ- Cyclodextrin Examined by Structural Mass Spectrometry Strategies.

Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides with amphiphilic properties, which can improve the stability, solubility, and bioavailability of therapeutic compounds. There has been growing interest in the advancement of efficient and reliable analytical methods that assist with elucidating CD host-guest drug complexation. In this study, we investigate the noncovalent ion complexes formed between naturally occurring dextrins (αCD, βCD, γCD, and maltohexaose) with the poorly water-soluble antimalarial drug, artemisinin, using a combination of ion mobility-mass spectrometry (IM-MS), tandem MS/MS, and theoretical modeling approaches.

Lipid kinase PIK3C3 maintains healthy brown and white adipose tissues to prevent metabolic diseases.

Adequate mass and function of adipose tissues (ATs) play essential roles in preventing metabolic perturbations. The pathological reduction of ATs in lipodystrophy leads to an array of metabolic diseases. Understanding the underlying mechanisms may benefit the development of effective therapies.

Performance evaluation of in-source ion activation hardware for collision-induced unfolding of proteins and protein complexes on a drift tube ion mobility-mass spectrometer.

Native ion mobility-mass spectrometry (IM-MS) has emerged as an information-rich technique for gas phase protein structure characterization; however, IM resolution is currently insufficient for the detection of subtle structural differences in large biomolecules. This challenge has spurred the development of collision-induced unfolding (CIU) which utilizes incremental gas phase activation to unfold a protein in order to expand the number of measurable descriptors available for native protein ions. Although CIU is now routinely used in native mass spectrometry studies, the interlaboratory reproducibility of CIU has not been established.