Pharmacodynamics of the S1P receptor modulator cenerimod in a phase 2b randomised clinical trial in patients with moderate to severe SLE.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoreactive T and B lymphocytes. Sphingosine-1- phosphate (S1P) is involved in lymphocyte egress from peripheral lymphoid organs into the circulation. In phase 2a clinical trial, the potent, selective S1P receptor modulator cenerimod reduced circulating antibody-secreting cells and interferon (IFN)-associated biomarkers.

Cenerimod, a sphingosine-1-phosphate receptor modulator, versus placebo in patients with moderate-to-severe systemic lupus erythematosus (CARE): an international, double-blind, randomised, placebo-controlled, phase 2 trial.

Background: Sphingosine-1-phosphate (S1P) is a signalling molecule that has an inhibitory role in atherosclerosis, inflammation, cell proliferation, and immunity. Cenerimod is a selective S1P receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). We aimed to determine the efficacy, safety, and tolerability of four doses of cenerimod in adults with moderate-to-severe SLE receiving standard of care background therapy.

Symmetry-breaking dynamics of a photoionized carbon dioxide dimer.

Photoionization can initiate structural reorganization of molecular matter and drive formation of new chemical bonds. Here, we used time-resolved extreme ultraviolet (EUV) pump - EUV probe Coulomb explosion imaging of carbon dioxide dimer ion dynamics, that combined with ab initio molecular dynamics simulations, revealed unexpected asymmetric structural rearrangement. We show that ionization by the pump pulse induces rearrangement from the slipped-parallel (C) geometry of the neutral dimer towards a T-shaped (C) structure on the ~100 fs timescale, although the most stable slipped-parallel (C) structure of the ionic dimer.

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects.

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored.

Pharmacokinetics, pharmacodynamics and safety of the novel C-X-C chemokine receptor 3 antagonist ACT-777991: Results from the first-in-human study in healthy adults.

Aims: The C-X-C chemokine receptor 3 (CXCR3) axis is highly upregulated in the tissue of patients with type 1 diabetes. Antagonizing CXCR3 may reduce the migration of CXCR3-expressing cells to the pancreas. The pharmacokinetics (PKs), target engagement (TE) (inhibition of CXCR3 internalization) and safety of single- and multiple-ascending doses (SADs and MADs) of ACT-777991, a novel orally available potent CXCR3 antagonist, were assessed in a double-blind, randomized, placebo-controlled phase 1 study.

Simultaneous electrostatic trapping of merged cation & anion beams.

Simultaneous trapping of merged cation and anion beams in the hybrid electrostatic ion beam trap (HEIBT) opens new opportunities for the study of the interactions of isolated atomic molecular or cluster ions with oppositely charged ionic species. Application of the trapped merged beams requires a detailed understanding of the trapping dynamics and the effect of the Coulombic attractive and repulsive forces between the ions on their motion in the trap. The simultaneous trapping regime is explored experimentally for SF anion and SF cation beams and compared to realistic ion trajectory simulations.

Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes.

Treatment of patients with recent-onset type 1 diabetes with an anti-CD3 antibody leads to the transient stabilization of C-peptide levels in responder patients. Partial efficacy may be explained by the entry of islet-reactive T-cells spared by and/or regenerated after the anti-CD3 therapy. The CXCR3/CXCL10 axis has been proposed as a key player in the infiltration of autoreactive T cells into the pancreatic islets followed by the destruction of β cells.

Discovery of Clinical Candidate ACT-777991, a Potent CXCR3 Antagonist for Antigen-Driven and Inflammatory Pathologies.

The CXCR3 chemokine receptor is a G protein-coupled receptor mainly expressed on immune cells from the lymphoid lineage, including activated T cells. Binding of its inducible chemokine ligands CXCL9, CXCL10, and CXCL11 leads to downstream signaling events and the migration of activated T cells to sites of inflammation. Herein, we report the third part of our CXCR3 antagonist program in the field of autoimmunity, culminating in the discovery of the clinical compound ACT-777991 ().

Sequential mechanism in H formation dynamics on the ethanol dication.

Two- and three-body Coulomb explosion dynamics of isolated ethanol dications are studied single-photon double-ionization with ultrafast extreme-ultraviolet pulses. The measured 3-body momentum correlations obtained 3D coincidence imaging of the ionic products provide evidence for several concerted and sequential mechanisms: (1) a concerted 3-body breakup mechanism, with dominating channels such as CH + COH + H; (2) sequential dissociation in which the ejection of a low-kinetic-energy neutral OH precedes the Coulomb explosion of CH → CH + CH; and (3) a sequential 3-body breakup mechanism that dominates H formation from the ethanol dication a mechanism that is different from the well-studied H formation in the 2-body Coulomb explosion of the methanol dication. Furthermore, we report surprising branching ratios of the competing C-O bond dissociation channels, resulting in HO, HO and OH formation.

An "inverse" harpoon mechanism.

Electron-transfer reactions are ubiquitous in chemistry and biology. The electrons' quantum nature allows their transfer across long distances. For example, in the well-known harpoon mechanism, electron transfer results in Coulombic attraction between initially neutral reactants, leading to a marked increase in the reaction rate.

Sequential and concerted C-C and C-O bond dissociation in the Coulomb explosion of 2-propanol.

We study the competing mechanisms involved in the Coulomb explosion of 2-propanol CH CHOH dication, formed by an ultrafast extreme ultraviolet pulse. Over 20 product channels are identified and characterized using 3D coincidence imaging of the ionic fragments. The momentum correlations in the three-body fragmentation channels provide evidence for a dominant sequential mechanism, starting with the cleavage of a C-C bond, ejecting CH and CHCHOH cations, followed by a secondary fragmentation of the hydroxyethyl cation that can be delayed for up to a microsecond after ionization.

Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients.

GM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gene and substrate reduction therapies, both of which act directly on sphingolipidosis are entering clinical trials for treatment of these disorders.

CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis.

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI.

A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations as Target Engagement Biomarker.

The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist.

Correction: Dissociative detachment of the fluoroformate anion.

Correction for 'Dissociative detachment of the fluoroformate anion' by Eugene Shirman et al., Phys. Chem.

Dissociative detachment of the fluoroformate anion.

Dissociative photodetachment of the FCO2- fluoroformate complex by intense laser pulses is studied using 3D coincidence fragment imaging. The main channels are found to be CO2 + F and FCO + O. Cleavage of the C-F bond is attributed to dissociation on the B[combining tilde]2A1 excited state of the neutral FCO2 radical with significant internal excitation of the molecular fragment, while reductive dissociation of the CO2 moiety is assigned to higher lying states.

Time-resolved dissociative ionization and double photoionization of CO.

CO single-photon double photoionization, Coulomb explosion, and dissociative ionization are studied with ultrafast extreme-ultraviolet pump and time-delayed near-infrared probe pulses. Kinetic energy release and momentum correlations for the two-body CO + O and three-body O + C + O fragmentation products are determined by 3D coincidence fragment imaging. The transient enhancement of the ratio of two-body vs three-body Coulomb explosion events and the time dependence of low and high kinetic energy release dissociation events are discussed in terms of dissociative ionization and Coulomb explosion dynamics.

Preclinical to clinical translation of cenerimod, a novel S1P receptor modulator, in systemic lupus erythematosus.

Objectives:: SLE is an autoimmune disease characterised by aberrant lymphocyte activation and autoantibody production. This study provides an in-depth preclinical and clinical characterisation of the treatment effect of cenerimod, a sphingosine-1-phosphate receptor type 1 (S1P) modulator, in SLE.

Methods:: Cenerimod effect on lymphocyte numbers, organ pathology, inflammation, and survival was evaluated in the MRL/lpr lupus mouse model.

Absence of Triplets in Single-Photon Double Ionization of Methanol.

Despite the abundance of data concerning single-photon double ionization of methanol, the spin state of the emitted electron pair has never been determined. Here we present the first evidence that identifies the emitted electron pair spin as overwhelmingly singlet when the dication forms in low-energy configurations. The experimental data show that while the yield of the CHO + H Coulomb explosion channel is abundant, the metastable methanol dication is largely absent.

Immunoaffinity Targeted Mass Spectrometry Analysis of Human Plasma Samples Reveals an Imbalance of Active and Inactive CXCL10 in Primary Sjögren's Syndrome Disease Patients.

One of the most important advantages of mass spectrometry is the ability to quantify proteins and their modifications in parallel to obtain a holistic picture of the protein of interest. Here, we present a hybrid immunoaffinity targeted mass spectrometry (MS) method that combines efficient pan-antibody enrichment of a specific protein from plasma with the selectivity of high-resolution targeted MS analysis to quantitate specific proteoforms of interest. We used this approach to quantify plasma levels of the chemokine CXCL10 that has been associated with many immunological disorders such as systemic lupus erythematosus and primary Sjögren's Syndrome (pSS).

Time-resolving the ultrafast H roaming chemistry and H formation using extreme-ultraviolet pulses.

The time scales and formation mechanisms of tri-hydrogen cation products in organic molecule ionization processes are poorly understood, despite their cardinal role in the chemistry of the interstellar medium and in other chemical systems. Using an ultrafast extreme-ultraviolet pump and time-resolved near-IR probe, combined with high-level ab initio molecular dynamics calculations, here we report unambiguously that H formation in double-ionization of methanol occurs on a sub 100 fs time scale, settling previous conflicting findings of strong-field Coulomb explosion experiments. Our combined experimental-computational studies suggest that ultrafast competition, between proton-transfer and long-range electron-transfer processes, determines whether the roaming neutral H dynamics on the dication result in [Formula: see text] or [Formula: see text] fragments respectively.

Hybrid electrostatic ion beam trap (HEIBT): Design and simulation of ion-ion, ion-neutral, and ion-laser interactions.

Using dichroic electrostatic mirrors, which can reflect a fast ion beam while transmitting a counterion beam, allows extending the field of electrostatic ion trapping. We present the design and simulations of a hybrid electrostatic ion beam trap that allows simultaneous trapping of velocity matched cation and anion beams. The possible merged beam ion-ion, ion-neutral, and ion-laser experiments are discussed.

Impact of high-altitude therapy on type-2 immune responses in asthma patients.

Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma.

Methods: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study.

N-NO & NN-O bond cleavage dynamics in two- and three-body Coulomb explosion of the NO dication.

Triatomic Coulomb explosion dynamics are initiated by single-photon double ionization of NO with an ultrafast EUV pulse and are probed by delayed near-IR pulses. The triatomic benchmark system exhibits competing two- and three-body dissociation dynamics that are reflected in the time resolved branching ratios and in the co-linear three-body momentum correlation spectra. Both the N-NO and the NN-O bond dissociation channels result in vibrationally excited molecular products.