Analysis of chemical exchange in iridium N-heterocyclic carbene complexes using heteronuclear parahydrogen-enhanced NMR.

The signal amplification by reversible exchange process (SABRE) enhances NMR signals by unlocking hidden polarization in parahydrogen through interactions with to-be-hyperpolarized substrate molecules when both are transiently bound to an Ir-based organometallic catalyst. Recent efforts focus on optimizing polarization transfer from parahydrogen-derived hydride ligands to the substrate in SABRE. However, this requires quantitative information on ligand exchange rates, which common NMR techniques struggle to provide.

Yeast Solutions and Hyperpolarization Enable Real-Time Observation of Metabolized Substrates Even at Natural Abundance.

Metabolic changes in an organism often occur much earlier than macroscopic manifestations of disease, such as invasive tumors. Therefore, noninvasive tools to monitor metabolism are fundamental as they provide insights into in vivo biochemistry. NMR represents one of the gold standards for such insights by observing metabolites.

Modeling Ligand Exchange Kinetics in Iridium Complexes Catalyzing SABRE Nuclear Spin Hyperpolarization.

Large signal enhancements can be obtained for NMR analytes using the process of nuclear spin hyperpolarization. Organometallic complexes that bind parahydrogen can themselves become hyperpolarized. Moreover, if parahydrogen and a to-be-hyperpolarized analyte undergo chemical exchange with the organometallic complex it is possible to catalytically sensitize the detection of the analyte via hyperpolarization transfer through spin-spin coupling in this organometallic complex.

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

Background: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma.

Coupling Constants of <1 Hz Enable C Hyperpolarization of Pyruvate via Reversible Exchange of Parahydrogen.

Observing pyruvate metabolism has become a focal point of molecular magnetic resonance imaging. Signal amplification by reversible exchange (SABRE) has recently emerged as a versatile hyperpolarization technique. Tuning of the spin order transfer (SOT) in SABRE is challenging as the small H-C couplings, in the C-pyruvate case, result in SOT being not readily discernible.

Evolution of in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance.

Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance.

Exceptionally Mild and High-Yielding Synthesis of Vinyl Esters of Alpha-Ketocarboxylic Acids, Including Vinyl Pyruvate, for Parahydrogen-Enhanced Metabolic Spectroscopy and Imaging.

Metabolic changes often occur long before pathologies manifest and treatment becomes challenging. As key elements of energy metabolism, α-ketocarboxylic acids (α-KCA) are particularly interesting, e.g.

Nitrogen-15 dynamic nuclear polarization of nicotinamide derivatives in biocompatible solutions.

Dissolution dynamic nuclear polarization (dDNP) increases the sensitivity of magnetic resonance imaging by more than 10,000 times, enabling in vivo metabolic imaging to be performed noninvasively in real time. Here, we are developing a group of dDNP polarized tracers based on nicotinamide (NAM). We synthesized 1-N-NAM and 1-N nicotinic acid and hyperpolarized them with dDNP, reaching (13.

Spying on parahydrogen-induced polarization transfer using a half-tesla benchtop MRI and hyperpolarized imaging enabled by automation.

Nuclear spin hyperpolarization is a quantum effect that enhances the nuclear magnetic resonance signal by several orders of magnitude and has enabled real-time metabolic imaging in humans. However, the translation of hyperpolarization technology into routine use in laboratories and medical centers is hampered by the lack of portable, cost-effective polarizers that are not commercially available. Here, we present a portable, automated polarizer based on parahydrogen-induced hyperpolarization (PHIP) at an intermediate magnetic field of 0.

LIGHT-SABRE Hyperpolarizes 1-C-Pyruvate Continuously without Magnetic Field Cycling.

Nuclear spin hyperpolarization enables real-time observation of metabolism and intermolecular interactions . 1-C-pyruvate is the leading hyperpolarized tracer currently under evaluation in several clinical trials as a promising molecular imaging agent. Still, the quest for a simple, fast, and efficient hyperpolarization technique is ongoing.

Parahydrogen-induced polarization and spin order transfer in ethyl pyruvate at high magnetic fields.

Nuclear magnetic resonance has experienced great advances in developing and translating hyperpolarization methods into procedures for fundamental and clinical studies. Here, we propose the use of a wide-bore NMR for large-scale (volume- and concentration-wise) production of hyperpolarized media using parahydrogen-induced polarization. We discuss the benefits of radio frequency-induced parahydrogen spin order transfer, we show that 100% polarization is theoretically expected for homogeneous B and B magnetic fields for a three-spin system.

Synthesis of C and H Labeled Vinyl Pyruvate and Hyperpolarization of Pyruvate.

The hyperpolarization of nuclear spins has enabled unique applications in chemistry, biophysics, and particularly metabolic imaging. Parahydrogen-induced polarization (PHIP) offers a fast and cost-efficient way of hyperpolarization. Nevertheless, PHIP lags behind dynamic nuclear polarization (DNP), which is already being evaluated in clinical studies.

(1 → 3)-β-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial.

Purpose: To investigate whether (1 → 3)-β-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI).

Methods: Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results.

Extensively Drug-Resistant Klebsiella pneumoniae Counteracts Fitness and Virulence Costs That Accompanied Ceftazidime-Avibactam Resistance Acquisition.

The ability of extensively drug-resistant (XDR) Klebsiella pneumoniae to rapidly acquire resistance to novel antibiotics is a global concern. Moreover, Klebsiella clonal lineages that successfully combine resistance and hypervirulence have increasingly occurred during the last years. However, the underlying mechanisms of counteracting fitness costs that accompany antibiotic resistance acquisition remain largely unexplored.

Frequency-Selective Manipulations of Spins allow Effective and Robust Transfer of Spin Order from Parahydrogen to Heteronuclei in Weakly-Coupled Spin Systems.

We present a selectively pulsed (SP) generation of sequences to transfer the spin order of parahydrogen (pH ) to heteronuclei in weakly coupled spin systems. We analyze and discuss the mechanism and efficiency of SP spin order transfer (SOT) and derive sequence parameters. These new sequences are most promising for the hyperpolarization of molecules at high magnetic fields.

Selective excitation of hydrogen doubles the yield and improves the robustness of parahydrogen-induced polarization of low-γ nuclei.

We describe a new method for pulsed spin order transfer of parahydrogen-induced polarization (PHIP) that enables high polarization in incompletely H-labeled molecules by exciting only the desired protons in a frequency-selective manner. This way, the effect of selected -couplings is suspended. Experimentally 1.

Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study).

Unlabelled: Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction.

Objectives: This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock.

Design: Multicenter, randomized, and placebo-controlled study.

Coherent Evolution of Signal Amplification by Reversible Exchange in Two Alternating Fields (alt-SABRE).

Parahydrogen (pH ) is a convenient and cost-efficient source of spin order to enhance the magnetic resonance signal. Previous work showed that transient interaction of pH with a metal organic complex in a signal amplification by reversible exchange (SABRE) experiment enabled more than 10 % polarization for some N molecules. Here, we analyzed a variant of SABRE, consisting of a magnetic field alternating between a low field of ∼1 μT, where polarization transfer is expected to take place, and a higher field >50 μT (alt-SABRE).

RhoA Signaling in Immune Cell Response and Cardiac Disease.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops.

Selective excitation doubles the transfer of parahydrogen-induced polarization to heteronuclei.

In this work, we present a new pulse sequence to transform the spin order added to a molecule after the pairwise addition of parahydrogen into 13C polarization. Using a selective 90° preparation instead of a non-selective 45° excitation, the new variant performed twice as well as previous implementations in both simulations and experiments, exemplified with hyperpolarized ethyl acetate. This concept is expected to extend to other nuclei and other spin order transfer schemes that use non-selective excitation.

Effect of Long-term Anti-VEGF Treatment on Viability and Function of RPE Cells.

Purpose/aim Of The Study: Vascular endothelial growth factor (VEGF)-antagonists are given over long time periods in the clinic, but the long-term effects on retinal pigment epithelium (RPE) cells are not fully investigated. This study aims to investigate these effects with two clinical relevant VEGF antagonists, bevacizumab and aflibercept, on the function of primary RPE cells.

Materials And Methods: All tests were conducted with primary porcine RPE.

RhoA: a dubious molecule in cardiac pathophysiology.

The Ras homolog gene family member A (RhoA) is the founding member of Rho GTPase superfamily originally studied in cancer cells where it was found to stimulate cell cycle progression and migration. RhoA acts as a master switch control of actin dynamics essential for maintaining cytoarchitecture of a cell. In the last two decades, however, RhoA has been coined and increasingly investigated as an essential molecule involved in signal transduction and regulation of gene transcription thereby affecting physiological functions such as cell division, survival, proliferation and migration.