Correlating Predicted Reactivities with Experimental Inhibition Data of Covalent ChlaDUB1 Inhibitors.

Covalent inhibition with electrophiles of suitable reactivity allows for prolonged inactivation of a targeted enzyme, in comparison to noncovalent inhibitors. To fine-tune covalently reacting groups, various computational workflows have been developed for reactivity prediction. Their results are typically evaluated based on assays that use cysteine, glutathione, or other model nucleophiles, but the relevance of the predictions for the situation in a particular enzyme environment remains under-investigated.

Photo-BQCA: Positive Allosteric Modulators Enabling Optical Control of the M Receptor.

The field of G protein-coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, i.e., photoswitchable ligands.

Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors.

The delta opioid receptor (δOR or DOR) is a G protein-coupled receptor (GPCR) showing a promising profile as a drug target for nociception and analgesia. Herein, we design and synthesize new fluorescent antagonist probes with high δOR selectivity that are ideally suited for single-molecule microscopy (SMM) applications in unmodified, untagged receptors. Using our new probes, we investigated wild-type δOR localization and mobility at low physiological receptor densities for the first time.

Structure-Based Design and Synthesis of Covalent Inhibitors for Deubiquitinase and Acetyltransferase ChlaDUB1 of .

Upon infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen , a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell apoptosis. secretes deubiquitinase ChlaDUB1 into the host cell, leading among other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell apoptosis.

Erroneous statement.

In the recent paper by Lee et al. reporting reproductive toxicity testing of BVN008, a newly developed tetanus, diphtheria, and acellular pertussis vaccine, the statement is made "BVN008 is a booster vaccine identical to the current Tdap vaccines, Boostrix (GSK) and Adacel (Sanofi)." However, as the authors report, the acellular pertussis portion of BVN008 was provided by BIKEN (Japan).

Oxidative Stress Reaction to Hypobaric-Hyperoxic Civilian Flight Conditions.

Background: In military flight operations, during flights, fighter pilots constantly work under hyperoxic breathing conditions with supplemental oxygen in varying hypobaric environments. These conditions are suspected to cause oxidative stress to neuronal organ tissues. For civilian flight operations, the Federal Aviation Administration (FAA) also recommends supplemental oxygen for flying under hypobaric conditions equivalent to higher than 3048 m altitude, and has made it mandatory for conditions equivalent to more than 3657 m altitude.

Self-Reported Well-Being of Family Caregivers of Children with Medical Complexity.

Objective: Provide an in-depth and psychometrically rigorous profile of the emotional well-being and sleep-related health of family caregivers of children with medical complexity (CMC).

Methods: Cross-sectional survey study of family caregivers of CMC receiving care from a pediatric complex care center between May 2021 and March 2022. Patient Reported Outcomes Measurement Information System Short-Forms (PROMIS-SF) assessed global mental health, emotional distress (anxiety, depression, anger), psychological strengths (self-efficacy, emotional regulation, meaning and purpose), and sleep-related health (fatigue, sleep-related impairment).

Arylazobenzimidazoles: versatile visible-light photoswitches with tuneable -isomer stability.

Benzimidazole heterocycles are of great importance in medicinal chemistry due to their applicability to a wide range of pharmacological targets, therefore representing a prototypical "privileged structure". In photopharmacology, azoheteroarene photoswitches have emerged as valuable tools for a variety of applications due to the high tuneability of their photophysical properties. Benzimidazole-based photoswitches could therefore enable the optically-controlled investigation of many pharmacological targets and find application in materials science.

Development and Initial Characterization of the First F-CXCR2-Targeting Radiotracer for PET Imaging of Neutrophils.

The interleukin-8 receptor beta (CXCR2) is a highly promising target for molecular imaging of inflammation and inflammatory diseases. This is due to its almost exclusive expression on neutrophils. Modified fluorinated ligands were designed based on a squaramide template, with different modification sites and synthetic strategies explored.

Exposure to Non-Steady-State Oxygen Is Reflected in Changes to Arterial Blood Gas Values, Prefrontal Cortical Activity, and Systemic Cytokine Levels.

Onboard oxygen-generating systems (OBOGSs) provide increased inspired oxygen (FO) to mitigate the risk of neurologic injury in high altitude aviators. OBOGSs can deliver highly variable oxygen concentrations oscillating around a predetermined FO set point, even when the aircraft cabin altitude is relatively stable. Steady-state exposure to 100% FO evokes neurovascular vasoconstriction, diminished cerebral perfusion, and altered electroencephalographic activity.

Flavonoid-Phenolic Acid Hybrids Are Potent Inhibitors of Ferroptosis via Attenuation of Mitochondrial Impairment.

Cinnamic acid, ferulic acid, and the flavonoids quercetin and taxifolin (dihydroquercetin) are naturally occurring compounds found in plants. They are often referred to as polyphenols and are known, among others, for their pharmacological effects supporting health through the inhibition of aging processes and oxidative stress. To improve their bioavailability, pharmacological activities, and safety, the creation of novel flavonoid-phenolic acid hybrids is an area of active research.

"Photo-Adrenalines": Photoswitchable β -Adrenergic Receptor Agonists as Molecular Probes for the Study of Spatiotemporal Adrenergic Signaling.

β -adrenergic receptor (β -AR) agonists are used for the treatment of asthma and chronic obstructive pulmonary disease, but also play a role in other complex disorders including cancer, diabetes and heart diseases. As the cellular and molecular mechanisms in various cells and tissues of the β -AR remain vastly elusive, we developed tools for this investigation with high temporal and spatial resolution. Several photoswitchable β -AR agonists with nanomolar activity were synthesized.

Three-Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo.

To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two-photon photopharmacology and optogenetics. However, three-photon brain stimulation in vivo remains to be demonstrated.

Bridging the Binding Sites 2.0: Photoswitchable Dualsteric Ligands for the Cannabinoid 2 Receptor.

The cannabinoid receptor 2 (CBR) has high, unexploited therapeutic potential in several central nervous system disorders due to its involvement in neuroinflammatory processes and pathologies like neurodegeneration. Dualsteric/bitopic ligands are currently developed to achieve receptor subtype selectivity and biased signaling. To obtain a molecular tool compound with photoswitchable potential dualsteric properties, we applied two different approaches to link a positive allosteric modulator with an orthosteric agonist via a photochromic unit.

Visible-Light Photoswitchable Benzimidazole Azo-Arenes as β-Arrestin2-Biased Selective Cannabinoid 2 Receptor Agonists.

The cannabinoid 2 receptor (CB R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB R "efficacy-switch".

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model.

We present the synthesis and characterization of merged human butyrylcholinesterase (BChE) inhibitor/cannabinoid receptor 2 (CBR) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration.

Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter.

Purpose: A new PET radiotracer F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed.

The impact of free-radical stabilization techniques on in vivo subsurface mechanical properties in highly cross-linked polyethylene acetabular liners.

Highly cross-linked polyethylene (HXLPE) for total hip arthroplasty was developed to improve wear resistance in vivo and associated complications in comparison to ultrahigh molecular weight polyethylene. This material typically goes through various free-radical stabilization techniques by remelting, single-annealing, or sequentially annealing the polyethylene to improve in vivo oxidation and wear properties. The purpose of this study is to determine if there is evidence of subsurface microhardness changes in retrieved HXLPE liner at the rim and articular subsurface after extended in vivo time that could be associated with oxidation and its effects on mechanical properties and implant integrity.

Amber Light Control of Peptide Secondary Structure by a Perfluoroaromatic Azobenzene Photoswitch.

The incorporation of photoswitches into the molecular structure of peptides and proteins enables their dynamic photocontrol in complex biological systems. Here, a perfluorinated azobenzene derivative triggered by amber light was site-specifically conjugated to cysteines in a helical peptide by perfluoroarylation chemistry. In response to the photoisomerization (trans→cis) of the conjugated azobenzene with amber light, the secondary structure of the peptide was modulated from a disorganized into an amphiphilic helical structure.

Novel benzimidazole-based pseudo-irreversible butyrylcholinesterase inhibitors with neuroprotective activity in an Alzheimer's disease mouse model.

As levels of acetylcholinesterase (AChE) decrease while levels of butyrylcholinesterase (BChE) increase in later stages of Alzheimer's disease (AD), BChE stands out as a promising target for treatment of AD. Therefore, several benzimidazole-carbamates were designed based on docking studies to inhibit BChE selectively over AChE, while retaining a reasonable solubility. Synthesized molecules exhibit IC values from 2.

Development of an Indole-Amide-Based Photoswitchable Cannabinoid Receptor Subtype 1 (CBR) "Cis-On" Agonist.

Activation of the human cannabinoid receptor type 1 (CBR) with high spatiotemporal control is useful to study processes involved in different pathologies related to nociception, metabolic alterations, and neurological disorders. To synthesize new agonist ligands for CBR, we have designed different classes of photoswitchable molecules based on an indole core. The modifications made to the central core have allowed us to understand the molecular characteristics necessary to design an agonist with optimal pharmacological properties.