Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein.

Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer when misexpressed. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 cytotoxicity is not shared with DUXA or DUXB, but surprisingly is shared with platypus sDUX, which binds DNA as a homodimer and activates numerous ZGA genes and long terminal repeat (LTR) elements. DUXA, although transcriptionally inactive, has DNA binding overlap with DUX4, and DUXA-VP64 activates DUX4 targets and is cytotoxic.

Influenza virus decreases albumin uptake and megalin expression in alveolar epithelial cells.

Introduction: Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.

Clinical Utility of Pepsin and Bile Acid in Tracheal Secretions for Accurate Diagnosis of Aspiration in ICU Patients.

Background: Aspiration of stomach content or saliva in critical conditions-e.g., shock, intoxication, or resuscitation-can lead to acute lung injury.

Restoration of Foxp3 Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology.

Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets.

Intracellular signaling pathways of muscarinic acetylcholine receptor-mediated detrusor muscle contractions.

Acetylcholine plays an essential role in the regulation of detrusor muscle contractions, and antimuscarinics are widely used in the management of overactive bladder syndrome. However, several adverse effects limit their application and patients' compliance. Thus, this study aimed to further analyze the signal transduction of M and M receptors in the murine urinary bladder to eventually find more specific therapeutic targets.

Lineage Tracing of Bone Cells in the Regenerating Fin and During Repair of Bone Lesions.

Small teleost fishes such as zebrafish and medaka show remarkable regeneration capabilities upon tissue injury or amputation. To elucidate cellular mechanisms of teleost tissue repair and regeneration processes, the Cre/LoxP recombination system for cell lineage tracing is a widely used technique. In this chapter, we describe protocols used for inducible Cre/LoxP recombination-mediated lineage tracing of osteoblast progenitors during medaka fin regeneration as well as during the repair of osteoporosis-like bone lesions in the medaka vertebral column.

Case Report: Durable therapy response to Osimertinib in rare EGFR Exon 18 mutated NSCLC.

Up to 20% of all non-small cell lung cancer patients harbor tumor specific driver mutations that are effectively treated with tyrosine kinase inhibitors. However, for the rare EGFR deletion-insertion mutation of exon 18, there is very little evidence regarding the effectiveness of tyrosine kinase inhibitors. A particular challenge for clinicians in applying tyrosine kinase inhibitors is not only diagnosing a mutation but also interpreting rare mutations with unclear therapeutic significance.

Aging impairs the neurovascular interface in the heart.

Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes.

Amending the injured heart by in vivo reprogramming.

Ischemic heart injury causes death of cardiomyocyte (CM), formation of a fibrotic scar, and often adverse cardiac remodeling, resulting in chronic heart failure. Therapeutic interventions have lowered myocardial damage and improved heart function, but pharmacological treatment of heart failure has only shown limited progress in recent years. Over the past two decades, different approaches have been pursued to regenerate the heart, by transplantation of newly generated CMs derived from pluripotent stem cells, generation of new CMs by reprogramming of cardiac fibroblasts, or by activating proliferation of preexisting CMs.

Analysis of rare fusions in NSCLC: Genomic architecture and clinical implications.

Objectives: Molecular diagnosis for targeted therapies has been improved significantly in non-small-cell lung cancer (NSCLC) patients in recent years. Here we report on the prevalence of rare fusions in NSCLC and dissect their genomic architecture and potential clinical implications.

Materials And Methods: Overall, n = 5554 NSCLC patients underwent next-generation sequencing (NGS) for combined detection of oncogenic mutations and fusions either at primary diagnosis (n = 5246) or after therapy resistance (n = 308).

Comparative analysis of full-length 16s ribosomal RNA genome sequencing in human fecal samples using primer sets with different degrees of degeneracy.

Next-generation sequencing has revolutionized the field of microbiology research and greatly expanded our knowledge of complex bacterial communities. Nanopore sequencing provides distinct advantages, combining cost-effectiveness, ease of use, high throughput, and high taxonomic resolution through its ability to process long amplicons, such as the entire 16s rRNA genome. We examine the performance of the conventional 27F primer (27F-I) included in the 16S Barcoding Kit distributed by Oxford Nanopore Technologies (ONT) and that of a more degenerate 27F primer (27F-II) in the context of highly complex bacterial communities in 73 human fecal samples.

F-actin nanostructures rearrangements and regulation are essential for SARS-CoV-2 particle production in host pulmonary cells.

Our study focused on deciphering the role of F-actin and related regulatory factors during SARS-CoV-2 particle production and transmission in human pulmonary cells. Quantitative high-resolution microscopies revealed that the late phases of SARS-CoV-2 infection induce a strong rearrangement of F-actin nanostructures dependent on the viral M, E, and N structural proteins. Intracellular vesicles containing viral components are labeled with Rab7 and Lamp1 and are surrounded by F-actin ring-shaped structures, suggesting their role in viral trafficking toward the cell membrane for virus release.

Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.

Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM.

The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung.

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc on the aging of the lung and pulmonary circulation.

ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth.

Long noncoding RNAs (lncRNAs) influence the transcription of gene networks in many cell types, but their role in tumor-associated macrophages (TAMs) is still largely unknown. We found that the lncRNA ADPGK-AS1 was substantially upregulated in artificially induced M2-like human macrophages, macrophages exposed to lung cancer cells in vitro, and TAMs from human lung cancer tissue. ADPGK-AS1 is partly located within mitochondria and binds to the mitochondrial ribosomal protein MRPL35.

A succinate/SUCNR1-brush cell defense program in the tracheal epithelium.

Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a signaling cascade involving the succinate receptor 1 (SUCNR1), phospholipase Cβ2, and the cation channel transient receptor potential channel subfamily M member 5 (TRPM5). Stimulated brush cells then trigger a long-range Ca wave spreading radially over the tracheal epithelium through a sequential signaling process.

kcnj13 regulates pigment cell shapes in zebrafish and has diverged by cis-regulatory evolution between Danio species.

Teleost fish of the genus Danio are excellent models to study the genetic and cellular bases of pigment pattern variation in vertebrates. The two sister species Danio rerio and Danio aesculapii show divergent patterns of horizontal stripes and vertical bars that are partly caused by the divergence of the potassium channel gene kcnj13. Here, we show that kcnj13 is required only in melanophores for interactions with xanthophores and iridophores, which cause location-specific pigment cell shapes and thereby influence colour pattern and contrast in D.

Circular RNA circPLOD2 regulates pericyte function by targeting the transcription factor KLF4.

Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the formation and maintenance of blood vessels. Here, we characterize hypoxia-regulated circular RNAs (circRNAs) in human pericytes and show that the circular RNA of procollagen-lysine,2-oxoglutarate 5-dioxygenase-2 (circPLOD2) is induced by hypoxia and regulates pericyte functions.

Prognostic Impact of the Immune-Cell Infiltrate in N1-Positive Non-Small-Cell Lung Cancer.

Introduction: The tumoral immune milieu plays a crucial role for the development of non-small-cell lung cancer (NSCLC) and may influence individual prognosis. We analyzed the predictive role of immune cell infiltrates after curative lung cancer surgery.

Materials And Methods: The tumoral immune-cell infiltrate from 174 patients with pN1 NSCLC and adjuvant chemotherapy was characterized using immunofluorescence staining.

Systematic Analysis of Smooth Muscle and Cartilage Ring Formation during Mouse Tracheal Tubulogenesis.

The trachea tube is the exclusive route to allow gas exchange between the external environment and the lungs. Recent studies have shown the critical role of mesenchymal cells in tracheal tubulogenesis. Improved methods for studying the dynamics of the tracheal mesenchyme development are needed to investigate the cellular and molecular mechanisms during tracheal tubulogenesis.

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.

Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.

Aims: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility.

Skin-infiltrating T cells display distinct inflammatory signatures in lichen planus, bullous pemphigoid and pemphigus vulgaris.

Introduction: We here thought to dissect the inflammatory signature in lesions of three skin disorders, which show a common adaptive immune response against autoantigens of the skin but are characterized by diverging clinical phenotypes. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are type-2-dependent, IgG autoantibody-driven blistering disorders of mucous membranes and skin, which target desmoglein (Dsg)3 and bullous pemphigoid (BP)180, respectively. In contrast, lichen planus (LP) is a common chronic inflammatory disease of the skin and mucous membranes with a pronounced dermal T cell infiltrate.