and function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center.

The forkhead box transcription factor genes and are expressed in the condensing mesenchyme of the developing skeleton prior to the onset of chondrocyte differentiation. To determine the roles of these transcription factors in limb development we deleted both and in lateral plate mesoderm using the Prx1-cre mouse line. Resulting compound homozygous mice died shortly after birth with exencephaly, and malformations to this sternum and limb skeleton.

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury.

Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia-induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia-reperfusion (I/R) injury.

The Lymphatic Vasculature in Cardiac Development and Ischemic Heart Disease.

In recent years, the lymphatic system has received increasing attention due to the fast-growing number of findings about its diverse novel functional roles in health and disease. It is well documented that the lymphatic vasculature plays major roles in the maintenance of tissue-fluid balance, the immune response, and in lipid absorption. However, recent studies have identified an additional growing number of novel and sometimes unexpected functional roles of the lymphatic vasculature in normal and pathological conditions in different organs.

Metabolism: How removal of damaged cells impacts energy availability in the retina.

Once thought to be a quiescent process, elimination of damaged cells by professional phagocytes is now understood to modulate metabolite availability within tissues. A new study reveals that the retinal pigment epithelium serves as a local source of insulin after engulfment of damaged photoreceptors.

Quality and cost of healthcare services in patients with diabetes in Iran: Results of a nationwide short-term longitudinal survey.

Aims: To investigate the journey of patients with diabetes in the healthcare system using nationally-representative patient-reported data.

Methods: Participants were recruited using a machine-learning-based sampling method based on healthcare structures and medical outcome data and were followed up for three months. We assessed the resource utilization, direct/indirect costs, and quality of healthcare services.

Pathophysiological Roles of the cGAS-STING Inflammatory Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) inflammatory pathway is a component of the innate immune system that recognizes cytosolic nucleic acids. The pathway has been implicated in several processes including aging, autoinflammatory conditions, cancer, and metabolic diseases. The cGAS-STING pathway represents a promising therapeutic target in a variety of chronic inflammatory diseases.

Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts.

Background: Diabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor α (TNFα) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and β-oxidation. Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts.

Methods: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury or in a Langendorff-perfused system.

Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways.

Significance Statement: Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of angiopoietin-Tie2 vascular signaling promotes injury, whereas activation of Tie2 is protective.

Regions of Highly Recurrent Electrogram Morphology With Low Cycle Length Reflect Substrate for Atrial Fibrillation.

Traditional anatomically guided ablation and attempts to perform electrogram-guided atrial fibrillation (AF) ablation (CFAE, DF, and FIRM) have not been shown to be sufficient treatment for persistent AF. Using biatrial high-density electrophysiologic mapping in a canine rapid atrial pacing model of AF, we systematically investigated the relationship of electrogram morphology recurrence (EMR) (Rec% and CL) with established AF electrogram parameters and tissue characteristics. Rec% correlates with stability of rotational activity and with the spatial distribution of parasympathetic nerve fibers.

Mice Exhibit Similar Therapeutic Responses to Sildenafil, Ambrisentan, and Treprostinil as Pulmonary Arterial Hypertension (PAH) Patients, Supporting Mice as a Useful PAH Model.

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. mice with -mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50-80% mortality from the age of 3-6 months, indicating that the mice model is a long-sought-after murine PAH model.

[WITHDRAWN] Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.

The authors have requested that this preprint be removed from Research Square.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage.

Ferric derisomaltose therapy and heart failure: implications and molecular insights.

Iron is essential to the production of myocardial energy and proteins critical for cardiovascular function. Nearly 50% of patients with heart failure with reduced ejection fraction (HFrEF) meet current criteria for iron deficiency, and there has been considerable interest in intravenous repletion of iron stores as a therapeutic strategy to improve HFrEF outcomes. However, the data on intravenous iron therapy in HFrEF have been mixed.

Cardiomyocyte PAI-1 influences the cardiac transcriptome and limits the extent of cardiac fibrosis in response to left ventricular pressure overload.

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice.

Mechanical forces in lymphatic vessel development: Focus on transcriptional regulation.

The lymphatic system is crucial for the maintenance of interstitial fluid and protein homeostasis. It has important roles in collecting excess plasma and interstitial fluid leaked from blood vessels, lipid absorption and transportation in the digestive system, and immune surveillance and response. The development of lymphatic vessels begins during fetal life as lymphatic endothelial progenitor cells first differentiate into lymphatic endothelial cells (LECs) by expressing the master lymphatic vascular regulator, prospero-related homeobox 1 (PROX1).

Formation of the glomerular microvasculature is regulated by VEGFR-3.

Microvascular dysfunction is a key driver of kidney disease. Pathophysiological changes in the kidney vasculature are regulated by vascular endothelial growth factor receptors (VEGFRs), supporting them as potential therapeutic targets. The tyrosine kinase receptor VEGFR-3, encoded by and activated by the ligands VEGF-C and VEGF-D, is best known for its role in lymphangiogenesis.

Angiopoietin-1 Is Required for Vortex Vein and Choriocapillaris Development in Mice.

Background: The choroidal vasculature, including the choriocapillaris and vortex veins, is essential for providing nutrients to the metabolically demanding photoreceptors and retinal pigment epithelium. Choroidal vascular dysfunction leads to vision loss and is associated with age-related macular degeneration and the poorly understood pachychoroid diseases including central serous chorioretinopathy and polypoidal choroidal vasculopathy that are characterized by formation of dilated pachyvessels throughout the choroid.

Methods: Using neural crest-specific knockout mice, we show that Angiopoietin 1, a ligand of the endothelial receptor TEK (also known as Tie2) is essential for choriocapillaris development and vortex vein patterning.

Gestational exposure to silver nanoparticles enhances immune adaptation and protection against streptozotocin-induced diabetic nephropathy in mice offspring.

Silver nanoparticles (AgNPs) possess unique antimicrobial properties. As a result, they are being increasingly used in a wide range of applications. Several studies have shown detrimental effects of AgNPs exposure, including inflammation, accumulation, and cellular damage to different organs.

Serological Measurement of Poly-IgA Immune Complex Levels in IgA Nephropathy and IgA Vasculitis.

Both IgA nephropathy and IgA vasculitis, formerly known as Henoch-Schӧnlein purpura, are immune deposition diseases. IgA nephropathy is caused by the deposition of aberrantly formed poly-IgA complexes from blood circulation to the kidney glomerulus; IgA vasculitis is characterized by IgA-dominant immune deposits to small vessels of the skin and other organs, including the kidney. Therefore, measuring the disease-causing poly-IgA contents in the plasma is needed to study these conditions.

Stromal Transcription Factor 21 Regulates Development of the Renal Stroma Interaction with Wnt/-Catenin Signaling.

Background: Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that transcription factor 21 (Tcf21) is required for ureteric bud branching.