Molecular basis of proton sensing by G protein-coupled receptors.

Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues.

Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study.

Background And Objective: Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.

Principal Component Analysis (PCA) of Molecular Descriptors for Improving Permeation through the Blood-Brain Barrier of Quercetin Analogues.

Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood-brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking.

Coevolution-Driven Method for Efficiently Simulating Conformational Changes in Proteins Reveals Molecular Details of Ligand Effects in the β2AR Receptor.

With the advent of AI-powered structure prediction, the scientific community is inching closer to solving protein folding. An unresolved enigma, however, is to accurately, reliably, and deterministically predict alternative conformational states that are crucial for the function of, e.g.

Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning.

Sugar porters (SPs) represent the largest group of secondary-active transporters. Some members, such as the glucose transporters (GLUTs), are well known for their role in maintaining blood glucose homeostasis in mammals, with their expression upregulated in many types of cancers. Because only a few sugar porter structures have been determined, mechanistic models have been constructed by piecing together structural states of distantly related proteins.

Determinants of sugar-induced influx in the mammalian fructose transporter GLUT5.

In mammals, glucose transporters (GLUT) control organism-wide blood-glucose homeostasis. In human, this is accomplished by 14 different GLUT isoforms, that transport glucose and other monosaccharides with varying substrate preferences and kinetics. Nevertheless, there is little difference between the sugar-coordinating residues in the GLUT proteins and even the malarial transporter HT1, which is uniquely able to transport a wide range of different sugars.

Protocols for perioperative management of direct oral anticoagulants in hospitals: opportunities for improvement.

Objectives: To investigate and describe the protocolized perioperative management in patient using Direct oral anticoagulants (DOACs) in Dutch hospitals.

Methods: Between August and December 2020, a nationwide survey in 70 hospitals in the Netherlands was conducted. We asked hospital pharmacists to submit their protocols for perioperative management of DOAC (apixaban, dabigatran, edoxaban and rivaroxaban) users.

Protocolized management of bleeding in hospitals in The Netherlands in patients treated with direct oral anticoagulants.

Objective: To investigate and describe the protocolized treatment of DOAC-related bleeds in all Dutch hospitals.

Methods: From August to December 2020 a nationwide survey among all 70 hospitals in the Netherlands was conducted on their protocols for management of bleeding in patients treated with direct oral anticoagulants (DOACs, i.e.

Extracorporeal hemoadsorption with the CytoSorb device as a potential therapeutic option in severe intoxications: Review of the rationale and current clinical experiences.

What Is Known And Objective: Many severe intoxications occur with substances with no specific antidote, which is why methods of extracorporeal elimination represent a particularly useful and even critical component in their management. The purpose of this review is to summarize the accumulating evidence and clinical results from the application of CytoSorb hemoadsorption therapy in patients with severe intoxications.

Comment: The technology represents a promising technique with an increasing number of publications in a variety of severe intoxication scenarios suggesting that early intervention might provide rapid substance removal with subsequent overall clinical improvement.

On Existence and Admissibility of Singular Solutions for Systems of Conservation Laws.

A weak notion of solution for systems of conservation laws in one dimension is put forward. In the framework introduced here, it can be shown that the Cauchy problem for any system of conservation laws has a solution. The solution concept is an extension of the notion of singular -shocks which have been used to provide solutions for Riemann problems in various systems, for example in cases where strict hyperbolicity or the genuine-nonlinearity condition are not satisfied, or in cases where initial conditions have large variation.

Thromboembolic Events While Taking Direct Oral Anticoagulants: An Analysis of Post-market WHO Database Reports from 2012 to 2020.

Background And Objective: Several cases of venous thromboembolism in patients treated with direct oral anticoagulants (DOACs) have been reported in the literature, but a quantative analysis of postmarketing reports is lacking. The objective of this study was to determine the post-marketing odds ratio (OR) and reporting odds ratio (ROR) of venous thromboembolism in patients receiving DOACs compared among each other and to vitamin K antagonists (VKAs).

Methods: The OR and ROR were used to determine the ratio of reports for deep vein thrombosis and pulmonary embolism between 1 January, 2012 and 15 November, 2020 using the World Health Organization VigiLyze database.

Impact of minor bleeds on confidence in anticoagulation therapy, adherence to treatment and quality of life in patients using a non-vitamin K antagonist oral anticoagulant for atrial fibrillation.

Objective: In a previous study on the reasons for discontinuation of novel oral anticoagulation therapy (NOAC) in patients with atrial fibrillation, we showed that minor bleeding was the second most important reason for NOAC discontinuation. This finding suggest that the impact of minor bleeds on the patient's perspective on NOACs cannot be ignored, especially those minor bleeds for which the patient searched medical care. We therefore performed a study in which we explored the impact of minor bleed (clinically relevant non-major bleeds) on patient confidence in therapy, adherence to treatment and quality of life in AF patients using NOAC's.

Costs of minor bleeds in atrial fibrillation patients using a non-vitamin K antagonist oral anticoagulant.

Background: A very common side effect of non-vitamin K antagonist oral anticoagulant (NOAC) is (minor) bleeding. Data about impact and costs of minor bleeds in NOAC therapy is still limited or not present in current literature. In this patient orientated study, we aim to provide an estimate of the costs of minor bleeds in patients with atrial fibrillation (AF) treated with a NOAC.

On the image inpainting problem from the viewpoint of a nonlocal Cahn-Hilliard type equation.

Motivated by the fact that the fractional Laplacean generates a wider choice of the interpolation curves than the Laplacean or bi-Laplacean, we propose a new non-local partial differential equation inspired by the Cahn-Hilliard model for recovering damaged parts of an image. We also note that our model is linear and that the computational costs are lower than those for the standard Cahn-Hilliard equation, while the inpainting results remain of high quality. We develop a numerical scheme for solving the resulting equations and provide an example of inpainting showing the potential of our method.

Minor bleeding in patients with atrial fibrillation using a non-vitamin-K antagonist oral anticoagulant.

Aims: We sought to investigate the magnitude of minor bleeding and identify risk factors for minor bleeds during non-vitamin-K antagonist oral anticoagulant (NOAC) therapy.

Methods: This was an observational cohort study of patients with atrial fibrillation (AF) referred to a regional NOAC outpatient clinic between February 2013 and October 2017. The study population consisted of 875 consecutive patients with AF who visited the NOAC outpatient unit to initiate treatment with apixaban ( = 303), dabigatran ( = 267) or rivaroxaban ( = 305) for long-term ischemic stroke prophylaxis.

Reasons for discontinuation of novel oral anticoagulant therapy in patients with atrial fibrillation.

We sought to investigate the reasons for, and rates of, novel oral anticoagulant (DOAC) therapy discontinuation. This was an observational cohort study of patients with atrial fibrillation (AF) referred to a regional DOAC outpatient clinic between February 2013 and October 2017. The study population consisted of 875 consecutive patients with AF who visited the DOAC outpatient unit to initiate treatment with apixaban ( = 303), dabigatran ( = 267) or rivaroxaban ( = 305) for long-term ischemic stroke prophylaxis.