MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on or analogues showed improved viability efficacy compared with the corresponding acids.

Cardioprotective effects of vaccination in hospitalized patients with COVID-19.

COVID-19 vaccination has been shown to prevent and reduce the severity of COVID-19 disease. The aim of this study was to explore the cardioprotective effect of COVID-19 vaccination in hospitalized COVID-19 patients. In this retrospective, single-center cohort study, we included hospitalized COVID-19 patients with confirmed vaccination status from July 2021 to February 2022.

Decarboxylative Ketonization of Aliphatic Carboxylic Acids in a Continuous Flow Reactor Catalysed by Manganese Oxide on Silica.

The sustainable synthesis of long carbon chain molecules from carbon dioxide, water and electricity relies on the development of waste-free, highly selective C-C bond forming reactions. An example for such a power-to-chemicals process is the industrial-scale fermentation for the production of hexanoic acid. Herein, we describe how this product is transformed into 6-undecanone via decarboxylative ketonization using a heterogeneous manganese oxide/silica catalyst.

Vaccination protects against acute respiratory distress syndrome (ARDS) in hospitalized patients with COVID-19.

This study aimed to analyze the effect of COVID-19 vaccination on the occurrence of ARDS in hospitalized COVID-19 patients. The study population of this retrospective, single-center cohort study consisted of hospitalized COVID-19 patients with known vaccination status and chest computed tomography imaging between July 2021 and February 2022. The impact of vaccination on ARDS in COVID-19 patients was assessed through logistic regression adjusting for demographic differences and confounding factors with statistical differences determined using confidence intervals and effect sizes.

An Activation-Specific Anti-Mac-1 Designed-Ankyrin-Repeat-Protein Attenuates Colitis in Mice.

(1) Background: Inflammatory bowel diseases are complex and multifactorial disorders of unknown etiology. The extravasation of activated leukocytes is a critical step in the pathogenesis of these diseases. Leukocyte integrin Mac-1 (αβ; CD11b/CD18) is crucial for the extravasation of myeloid cells, and a novel activation-specific anti-Mac-1 Designed Ankyrin Repeat protein (DARPin F7) is a promising therapeutic agent for inflammatory diseases.

Restoring speech intelligibility for hearing aid users with deep learning.

Almost half a billion people world-wide suffer from disabling hearing loss. While hearing aids can partially compensate for this, a large proportion of users struggle to understand speech in situations with background noise. Here, we present a deep learning-based algorithm that selectively suppresses noise while maintaining speech signals.

Time from blood draw to multiple electrode aggregometry and association with platelet reactivity.

Results from multiple electrode aggregometry (MEA) may vary according to pre-analytic factors. This study aimed to analyze the association of time from blood draw to MEA in patients undergoing percutaneous coronary intervention (PCI). In this observational single-center cohort study, platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; final concentration [Fc] 6.

Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead .

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable.

An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury.

The acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition. The number of ARDS cases has risen dramatically recently but specific treatment options are limited. ARDS is associated with an overshooting inflammatory response and neutrophils play a central role in its pathogenesis.

Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial.

Background: Matrix-associated autologous chondrocyte implantation (ACI) is a well-established treatment for cartilage defects. High-level evidence at midterm follow-up is limited, especially for ACI using spheroids (spherical aggregates of ex vivo expanded human autologous chondrocytes and self-synthesized extracellular matrix).

Purpose: To assess the safety and efficacy of 3-dimensional matrix-associated ACI using spheroids to treat medium to large cartilage defects on different locations in the knee joint (patella, trochlea, and femoral condyle) at 5-year follow-up.

Extracellular Vesicles Are Associated With Outcome in Veno-Arterial Extracorporeal Membrane Oxygenation and Myocardial Infarction.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is being increasingly applied in patients with circulatory failure, but mortality remains high. An inflammatory response syndrome initiated by activation of blood components in the extracorporeal circuit may be an important contributing factor. Patients with ST-elevation myocardial infarction (STEMI) may also experience a systemic inflammatory response syndrome and are at risk of developing cardiogenic shock and cardiac arrest, both indications for VA-ECMO.

Medical history of coronary artery disease and time to electrocardiogram in the emergency department: a real-life, single-center, retrospective analysis.

Background: Timely acquisition of 12-lead Electrocardiogram (ECG) in the emergency department (ED) is crucial and recommended by current guidelines.

Objectives: To evaluate the association of medical history of coronary artery disease (hCAD) on door-to-ECG time in the ED.

Methods: In this single center, retrospective cohort study, patients admitted to ED for cardiac evaluation were grouped according to hCAD and no hCAD.

Physiological roles of Casparian strips and suberin in the transport of water and solutes.

The formation of Casparian strips (CS) and the deposition of suberin at the endodermis of plant roots are thought to limit the apoplastic transport of water and ions. We investigated the specific role of each of these apoplastic barriers in the control of hydro-mineral transport by roots and the consequences on shoot growth. A collection of Arabidopsis thaliana mutants defective in suberin deposition and/or CS development was characterized under standard conditions using a hydroponic system and the Phenopsis platform.

Cardiomyocyte-specific miR-100 overexpression preserves heart function under pressure overload in mice and diminishes fatty acid uptake as well as ROS production by direct suppression of Nox4 and CD36.

MicroRNAs are key regulators of the cardiac response to injury. MiR-100 has recently been suggested to be involved in different forms of heart failure, but functional studies are lacking. In the present study, we examined the impact of transgenic miR-100 overexpression on cardiac structure and function during physiological aging and pathological pressure-overload-induced heart failure in mice after transverse aortic constriction surgery.

Early platelet dysfunction in patients receiving extracorporeal membrane oxygenation is associated with mortality.

Extracorporeal membrane oxygenation (ECMO) is used for patients with cardiopulmonary failure and is associated with severe bleeding and poor outcome. Platelet dysfunction may be a contributing factor. The aim of this prospective observational study was to characterize platelet dysfunction and its relation to outcome in ECMO patients.

PY receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells.

PY blockade improves patient outcomes after myocardial infarction. As well as antithrombotic effects, anti-inflammatory effects may contribute to this beneficial clinical outcome. Here we aimed to identify potential anti-inflammatory effects of PY receptor blockers on monocytes and macrophages.

Monocyte Dysfunction Detected by the Designed Ankyrin Repeat Protein F7 Predicts Mortality in Patients Receiving Veno-Arterial Extracorporeal Membrane Oxygenation.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used for critically ill patients requiring hemodynamic support but has been shown to induce an inflammatory response syndrome potentially leading to severe complications and poor outcome. Monocytes are comprised of different subsets and play a central role in the innate immune system. The small binding proteins, Designed Ankyrin Repeat Protein "F7" and single chain variable fragment "MAN-1," specifically detect the activated conformation of the leukocyte integrin Mac-1 enabling the highly sensitive detection of monocyte activation status.

Research and Development of Self-Contained Water Injection Systems.

Reducing fuel consumption and thus CO emissions is one of the most urgent tasks of current research in the field of internal combustion engines. Water Injection has proven its benefits to increase power or optimize fuel consumption of passenger cars. This technology enables knock mitigation to either increase the engine power output or raise the compression ratio and efficiency while enabling λ = 1 operation in the complete engine map to meet future emission targets.

A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction.

The monocyte β-integrin Mac-1 is crucial for leukocyte-endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the α I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry.

Annexin V positive microvesicles are elevated and correlate with flow rate in patients receiving veno-arterial extracorporeal membrane oxygenation.

Objectives: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used in critically ill patients requiring haemodynamic support. Microvesicles (MV) are released by activated blood cells acting as mediators of intercellular communication. We aimed to determine MV count and composition over time in patients with VA-ECMO and explore what drives MV formation.

Endothelial BMP4 Promotes Leukocyte Rolling and Adhesion and Is Elevated in Patients After Survived Out-of-Hospital Cardiac Arrest.

Leukocyte recruitment is a fundamental step in the inflammatory response during ischemia/reperfusion injury (IRI). Rolling and adhesion of leukocytes to activated endothelium promote tissue inflammation after IRI and require presentation of adhesion molecules E-selectin and ICAM-1 on the endothelial surface. Bone morphogenetic protein (BMP) 4 is a prominent member of the BMP family expressed and secreted by endothelial cells.