Impact of Linker Composition on VHL PROTAC Cell Permeability.

The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area.

Highlights from the 11th Bronchitis International Symposium: "Heterogeneity of Lung Disease in a Changing Environment," Groningen, The Netherlands, 2024.

This meeting report provides an overview of the highlights of the Bronchitis XI international symposium, held in June 2024 in Groningen, The Netherlands. The theme of this year's symposium was "heterogeneity of lung disease in a changing environment," and the symposium contained five different sessions focused on (i) heterogeneity of chronic lung disease, (ii) environmental changes with impact on lung disease, (iii) the aging lung, (iv) bronchitis, and (v) innovative therapy. The highlights from each of these sessions will be discussed separately, providing an overview of latest studies, new data, and enthralling discussions.

Learning from a crisis: a qualitative study on how nurses reshaped their work environment during the COVID-19 pandemic.

Background: The global nursing shortages exacerbated by the COVID-19 pandemic necessitated a drastic reorganization in nursing practices. Work routines, the composition of teams and subsequently mundane nursing practices were all altered to sustain the accessibility and quality of care. These dramatic changes demanded a reshaping of the nurses' work environment.

Systematic RADaR analysis of responses to the open-ended question in the Culture of Care Barometer survey of a Dutch hospital.

Objectives: Systematically measuring the work environment of healthcare employees is key to continuously improving the quality of care and addressing staff shortages. In this study, we systematically analyse the responses to the one open-ended question posed in the Dutch version of the Culture of Care Barometer (CoCB-NL) to examine (1) if the responses offered new insights into healthcare employees' perceptions of their work environment and (2) if the original CoCB had any themes missing.

Design: Retrospective text analysis using Rigorous and Accelerated Data Reduction technique.

Measuring the work environment among healthcare professionals: Validation of the Dutch version of the Culture of Care Barometer.

Objectives: A positive work environment (WE) is paramount for healthcare employees to provide good quality care. To stimulate a positive work environment, employees' perceptions of the work environment need to be assessed. This study aimed to assess the reliability and validity of the Dutch version of the Culture of Care Barometer (CoCB-NL) survey in hospitals.

Atypical cofilin signaling drives dendritic cell migration through the extracellular matrix via nuclear deformation.

To mount an adaptive immune response, dendritic cells must migrate to lymph nodes to present antigens to T cells. Critical to 3D migration is the nucleus, which is the size-limiting barrier for migration through the extracellular matrix. Here, we show that inflammatory activation of dendritic cells leads to the nucleus becoming spherically deformed and enables dendritic cells to overcome the typical 2- to 3-μm diameter limit for 3D migration through gaps in the extracellular matrix.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign.

A quantitative collagen uptake assay.

Collagen remodelling is a vital process for embryonic development and homoeostatic maintenance of the adult body. Collagen remodelling is a complex process in fibroblasts, macrophages and other cells, whereby new collagen is secreted and polymerized into fibrils and old collagen is removed by proteolysis and endocytosis. Whereas the production of collagen is well-studied, the removal of collagen is less understood.

Giant worm-shaped ESCRT scaffolds surround actin-independent integrin clusters.

Endosomal Sorting Complex Required for Transport (ESCRT) proteins can be transiently recruited to the plasma membrane for membrane repair and formation of extracellular vesicles. Here, we discovered micrometer-sized worm-shaped ESCRT structures that stably persist for multiple hours at the plasma membrane of macrophages, dendritic cells, and fibroblasts. These structures surround clusters of integrins and known cargoes of extracellular vesicles.

BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α Antagonist.

After acute myocardial infarction, early reperfusion is the most effective strategy for reducing cardiac damage and improving clinical outcome. However, restoring blood flow to the ischemic myocardium can paradoxically induce injury by itself (reperfusion injury), with microvascular dysfunction being one contributing factor. α adrenergic receptors have been hypothesized to be involved in this process.

5-Ethynyluridine: A Bio-orthogonal Uridine Variant for mRNA-Based Therapies and Vaccines.

The identification of pseudo- and N -methylpseudo-uridine (Ψ and mΨ, respectively) as immunosilent uridine analogues has propelled the development of mRNA-based vaccines and therapeutics. Here, we have characterised another uridine analogue, 5-ethynyluridine (EU), which has an ethynyl moiety. We show that this uridine analogue does not cause immune activation in human macrophages, as it does not induce interleukin-6 secretion or expression of the inflammatory and antiviral genes MX1, PKR, and TAP2.

Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages.

Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-β). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders.

BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit.

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood.

Mitochondrial interaction of fibrosis-protective 5-methoxy tryptophan enhances collagen uptake by macrophages.

5-methoxy tryptophan (5-MTP) is an anti-fibrotic metabolite made by fibroblasts and epithelial cells, present in a micromolar concentrations in human blood, and is associated with the progression of fibrotic kidney disease, but the mechanism is unclear. Here, we show by microscopy and functional assays that 5-MTP influences mitochondria in human peripheral blood monocyte-derived macrophages. As a result, the mitochondrial membranes are more rigid, more branched, and are protected against oxidation.

A sensitive and less cytotoxic assay for identification of proliferating T cells based on bioorthogonally-functionalized uridine analogue.

Quantitative detection of T cell proliferation is an important readout in immunology research, as it is one of the hallmarks of T cell activation. Fluorescence-based methods for T cell proliferation mostly rely on the usage of probes that non-specifically conjugate to free primary amine groups in cells. Each cell division then results in a two-fold dilution of the probes which is detectable with flow cytometry.

Key drivers structuring rotifer communities in ponds: insights into an agricultural landscape.

Understanding the influence of environmental and spatial factors on the structure of aquatic communities remains a major challenge in community ecology. This study aims to identify main drivers of rotifer abundance and diversity in ponds embedded in an intensive agricultural landscape in Northeast Germany. We studied 42 ponds of glacial origin (kettle holes) covering a wide range of environmental parameters.

What makes (hydroxy)chloroquine ineffective against COVID-19: insights from cell biology.

Since chloroquine (CQ) and hydroxychloroquine (HCQ) can inhibit the invasion and proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured cells, the repurposing of these antimalarial drugs was considered a promising strategy for treatment and prevention of coronavirus disease (COVID-19). However, despite promising preliminary findings, many clinical trials showed neither significant therapeutic nor prophylactic benefits of CQ and HCQ against COVID-19. Here, we aim to answer the question of why these drugs are not effective against the disease by examining the cellular working mechanisms of CQ and HCQ in prevention of SARS-CoV-2 infections.

Defining a positive work environment for hospital healthcare professionals: A Delphi study.

Introduction: The work environment of healthcare professionals is important for good patient care and is receiving increasing attention in scientific research. A clear and unambiguous understanding of a positive work environment, as perceived by healthcare professionals, is crucial for gaining systematic objective insights into the work environment. The aim of this study was to gain consensus on the concept of a positive work environment in the hospital.

Rotavirus outbreak among adults in a university hospital in Germany.

Background: Rotaviruses are the main cause of acute viral gastroenteritis in children under five years of age. Adults seem to be less frequently affected by rotaviruses most likely due to partial immunity resulting from prior infections.

Objectives: To describe a hospital-associated outbreak of rotavirus infections among adults.

Psychometric evaluation of instruments measuring the work environment of healthcare professionals in hospitals: a systematic literature review.

Purpose: Research shows that the professional healthcare working environment influences the quality of care, safety climate, productivity, and motivation, happiness, and health of staff. The purpose of this systematic literature review was to assess instruments that provide valid, reliable and succinct measures of health care professionals' work environment (WE) in hospitals.

Data Sources: Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, CINAHL EBSCOhost and Google Scholar were systematically searched from inception through December 2018.

Elucidating the Thermodynamic Driving Forces of Polyanion-Templated Virus-like Particle Assembly.

A virus in its most simple form is comprised of a protein capsid that surrounds and protects the viral genome. The self-assembly of such structures, however, is a highly complex, multiprotein, multiinteraction process and has been a topic of study for a number of years. This self-assembly process is driven by the (mainly electrostatic) interaction between the capsid proteins (CPs) and the genome as well as by the protein-protein interactions, which primarily rely on hydrophobic interactions.

The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation.

Antigen presentation to T cells in major histocompatibility complex class II (MHC class II) requires the conversion of early endo/phagosomes into lysosomes by a process called maturation. Maturation is driven by the phosphoinositide kinase PIKfyve. Blocking PIKfyve activity by small molecule inhibitors caused a delay in the conversion of phagosomes into lysosomes and in phagosomal acidification, whereas production of reactive oxygen species (ROS) increased.

Experimental and Theoretical Determination of the pH inside the Confinement of a Virus-Like Particle.

In biology, a variety of highly ordered nanometer-size protein cages is found. Such structures find increasing application in, for example, vaccination, drug delivery, and catalysis. Understanding the physiochemical properties, particularly inside the confinement of a protein cage, helps to predict the behavior and properties of new materials based on such particles.

Nanoreactors via Encapsulation of Catalytic Gold Nanoparticles within Cowpea Chlorotic Mottle Virus Protein Cages.

Viral protein cage-based nanoreactors can be generated by encapsulation of catalytic metal nanoparticles within the capsid structure. In this method, coat proteins of the cowpea chlorotic mottle virus (CCMV) are used to sequester gold nanoparticles (Au NPs) in buffered solutions at neutral pH to form CCMV-Au hybrid nanoparticles. This chapter describes detailed methods for the encapsulation of Au NPs into CCMV protein cages.