Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study.

Objective: The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc.

Investigation of Muscarinic Acetylcholine Receptor M Activation in Atomistic Detail: A Chemist's Viewpoint.

We analyzed the precise ligand:receptor interactions required for activation of the muscarinic acetylcholine receptor M, a prototypical G protein-coupled receptor and potential diabetes target. Starting from literature-known compounds and docking solutions, ligands were tailored for the modulation of this receptor's activation. Several aspects of the structure-activity relationship of agonists were investigated in atomistic detail, in order to delineate how the receptor can be activated via the orthosteric site.

ASH living guidelines on use of anticoagulation for thromboprophylaxis in patients with COVID-19: executive summary.

COVID-19-related critical and acute illness are associated with an increased risk of venous thromboembolism (VTE). These evidence-based recommendations of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other healthcare professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness, acute illness, and those being discharged from the hospital, who do not have suspected or confirmed VTE. ASH formed a multidisciplinary panel, including three patient representatives, and applied a conflicts of interest management policy to minimize potential bias.

Depth-resolved characterization of Meissner screening breakdown in surface treated niobium.

We report direct measurements of the magnetic field screening at the limits of the Meissner phase for two superconducting niobium (Nb) samples. The samples are processed with two different surface treatments that have been developed for superconducting radio-frequency (SRF) cavity applications-a "baseline" treatment and an oxygen-doping ("O-doping") treatment. The measurements show: (1) that the screening length is significantly longer in the "O-doping" sample compared to the "baseline" sample; (2) that the screening length near the limits of the Meissner phase increases with applied field; (3) the evolution of the screening profile as the material transitions from the Meissner phase to the mixed phase; and (4) a demonstration of the absence of any screening profile for the highest applied field, indicative of the full flux entering the sample.

Fcγ-receptor-IIIA bioactivity of circulating and synovial immune complexes in rheumatoid arthritis.

Objective: Previous technical limitations prevented the proof of Fcγ-receptor (FcγR)-activation by soluble immune complexes (sICs) in patients. FcγRIIIa (CD16) is a risk factor in rheumatoid arthritis (RA). We aimed at determining the presence of CD16-activating sICs in RA and control diseases.

Discovery and characterization of small-molecule TGR5 ligands with agonistic activity.

The Takeda G protein-coupled receptor 5 (TGR5) is activated endogenously by primary and secondary bile acids. This receptor is considered a candidate target for addressing inflammatory and metabolic disorders. We have targeted TGR5 with structure-based methods for ligand finding using the recently solved experimental structures, as well as structures obtained from molecular dynamics simulations.

G protein-specific mechanisms in the serotonin 5-HT receptor regulate psychosis-related effects and memory deficits.

G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HTR), a prominent target for the treatment of schizophrenia.

Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT receptor.

The intricate involvement of the serotonin 5-HT receptor (5-HTR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative.

Rhesus Cytomegalovirus-encoded Fcγ-binding glycoproteins facilitate viral evasion from IgG-mediated humoral immunity.

Human cytomegalovirus (HCMV) encodes four viral Fc-gamma receptors (vFcγRs) that counteract antibody-mediated activation , but their role in infection and pathogenesis is unknown. To examine the function of vFcγRs in animal hosts closely related to humans, we identified and characterized vFcγRs encoded by rhesus CMV (RhCMV). We demonstrate that Rh05, Rh152/151 and Rh173 represent the complete set of RhCMV vFcγRs, each displaying functional similarities to their respective HCMV orthologs with respect to antagonizing host FcγR activation .

Cryo-EM structure of cell-free synthesized human histamine 2 receptor/G complex in nanodisc environment.

Here we describe the cryo-electron microscopy structure of the human histamine 2 receptor (HR) in an active conformation with bound histamine and in complex with G heterotrimeric protein at an overall resolution of 3.4 Å. The complex was generated by cotranslational insertion of the receptor into preformed nanodisc membranes using cell-free synthesis in E.

A virtual library of small molecules mimicking dipeptides.

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small-molecule dipeptide mimic library to target proteins binding small peptides.

Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU: 2023.

Rationale: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care hospitals have implemented systems aimed at detecting and responding to such patients.

Objectives: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients.

Executive Summary: Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU.

Rationale: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care facilities have implemented systems aimed at detecting and responding to such patients.

Objectives: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients.

Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity.

The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and the resulting effects is important.

Development of Fluorescent AF64394 Analogues Enables Real-Time Binding Studies for the Orphan Class A GPCR GPR3.

The orphan G protein-coupled receptor (oGPCR) GPR3 represents a potential drug target for the treatment of Alzheimer's disease and metabolic disorders. However, the limited toolbox of pharmacological assays hampers the development of advanced ligands. Here, we developed a signaling pathway-independent readout of compound-GPR3 interaction.

EP4 Receptor Conformation Sensor Suited for Ligand Screening and Imaging of Extracellular Prostaglandins.

Prostaglandins are important lipid mediators with a wide range of functions in the human body. They act mainly via plasma membrane localized prostaglandin receptors, which belong to the G-protein coupled receptor class. Due to their localized formation and short lifetime, it is important to be able to measure the distribution and abundance of prostaglandins in time and/or space.

On the construction of LIECE models for the serotonin receptor 5-HT[Formula: see text]R.

Computer-aided approaches to ligand design need to balance accuracy with speed. This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding ([Formula: see text]G[Formula: see text]). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy.

Structure-based discovery of novel cruzain inhibitors with distinct trypanocidal activity profiles.

Over 110 years after the first formal description of Chagas disease, the trypanocidal drugs thus far available have limited efficacy and several side effects. This encourages the search for novel treatments that inhibit T. cruzi targets.

A new high parallel-field spectrometer at TRIUMF's β-NMR facility.

A new high field spectrometer has been built to extend the capabilities of the β-detected nuclear magnetic resonance (β-NMR) facility at TRIUMF. This new beamline extension allows β-NMR spectroscopy to be performed with fields up to 200 mT parallel to a sample's surface (perpendicular to the ion beam), allowing depth-resolved studies of local electromagnetic fields with spin polarized probes at a much higher applied magnetic field than previously available in this configuration. The primary motivation and application is to allow studies of superconducting radio frequency (SRF) materials close to the critical fields of Nb metal, which is extensively used to fabricate SRF cavities.

NMR-Based Metabolite Profiling and the Application of STOCSY toward the Quality and Authentication Assessment of European EVOOs.

Extra virgin olive oil (EVOO) possesses a high-value rank in the food industry, thus making it a common target for adulteration. Hence, several methods have been essentially made available over the years. However, the issue of authentication remains unresolved with national and food safety organizations globally struggling to regulate and control its market.