Identification and characterization of an enhancer element regulating expression of Cdkn1c (p57 gene).

The mammalian p57 protein is a member of the CIP/KIP family of cyclin-dependent kinase inhibitors and plays an essential role in the development of multiple tissues during embryogenesis as well as in the maintenance of tissue stem cells in adults. Although several transcription factors have been implicated in regulating the p57 gene, cis-elements such as enhancers that regulate its expression have remained ill-defined. Here we identify a candidate enhancer for the mouse p57 gene (Cdkn1c) within an intron of the Kcnq1 locus by 4C-seq analysis in mouse embryonic stem cells (mESCs).

Dual-color live imaging unveils stepwise organization of multiple basal body arrays by cytoskeletons.

For mucociliary clearance of pathogens, tracheal multiciliated epithelial cells (MCCs) organize coordinated beating of cilia, which originate from basal bodies (BBs) with basal feet (BFs) on one side. To clarify the self-organizing mechanism of coordinated intracellular BB-arrays composed of a well-ordered BB-alignment and unidirectional BB-orientation, determined by the direction of BB to BF, we generated double transgenic mice with GFP-centrin2-labeled BBs and mRuby3-Cep128-labeled BFs for long-term, high-resolution, dual-color live-cell imaging in primary-cultured tracheal MCCs. At early timepoints of MCC differentiation, BB-orientation and BB-local alignment antecedently coordinated in an apical microtubule-dependent manner.

Ablation of p57+ Quiescent Cancer Stem Cells Suppresses Recurrence after Chemotherapy of Intestinal Tumors.

Unlabelled: Quiescent cancer stem cells (CSC) are resistant to conventional anticancer treatments and have been shown to contribute to disease relapse after therapy in some cancer types. The identification and characterization of quiescent CSCs could facilitate the development of strategies to target this cell population and block recurrence. Here, we established a syngeneic orthotopic transplantation model in mice based on intestinal cancer organoids to profile quiescent CSCs.

Modifiers of the Risk of Diabetes for Long-Term Outcomes After Coronary Revascularization: CREDO-Kyoto PCI/CABG Registry.

Background: Diabetes is a well-known risk factor for adverse outcomes after coronary revascularization.

Objectives: This study sought to determine high-risk subgroups in whom the excess risks of diabetes relative to nondiabetes are particularly prominent and thus may benefit from more aggressive interventions.

Methods: The study population consisted of 39,427 patients (diabetes: n = 15,561; nondiabetes: n = 23,866) who underwent first percutaneous coronary intervention (n = 33,144) or coronary artery bypass graft (n = 6,283) in the pooled CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Graft) registry.

Association of peripheral venous pressure with adverse post-discharge outcomes in patients with acute heart failure: a prospective cohort study.

Aims: Congestion is the major cause of hospitalization for heart failure (HF). Traditional bedside assessment of congestion is limited by insufficient accuracy. Peripheral venous pressure (PVP) has recently been shown to accurately predict central venous congestion.

A case of gastrointestinal stromal tumor metastasized to the left ventricular myocardium.

Background: Gastrointestinal stromal tumors (GISTs), which are the most common soft tissue tumors of the gastrointestinal tract, originate from Cajal interneurons. The main metastatic sites of GISTs are the liver and intra-abdominal cavity, and metastasis to the heart is rare.

Case Presentation: The patient was a 78-year-old man who was diagnosed with a rectal GIST 20 years previously.

Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57 cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury.

Ezrin knockdown reduces procaterol-stimulated ciliary beating without morphological changes in mouse airway cilia.

Mucociliary clearance, which is conducted by beating cilia cooperating with the surface mucous layer, is a major host defense mechanism of the airway epithelium. Ezrin, a crosslinker between membrane proteins and the actin cytoskeleton, is located in microvilli and around the basal bodies in airway ciliary cells. It is also likely that ezrin plays an important role in apical localization of β2 adrenergic receptor (β2AR) in airway ciliary cells.

Peripheral Venous Pressure Measurements to Evaluate Congestion in Heart Failure.

Background: Accurate bedside assessment of congestion in the management of patients with heart failure remains challenging. As a continuous conduit of circulating fluid, systemic congestion represented by high right atrial pressure (RAP) may be reflected by peripheral venous pressure (PVP). We evaluated the reliability of PVP measurements for assessing congestion beyond conventional clinical assessments.

Daple deficiency causes hearing loss in adult mice by inducing defects in cochlear stereocilia and apical microtubules.

The V-shaped arrangement of hair bundles on cochlear hair cells is critical for auditory sensing. However, regulation of hair bundle arrangements has not been fully understood. Recently, defects in hair bundle arrangement were reported in postnatal Dishevelled-associating protein (ccdc88c, alias Daple)-deficient mice.

Coronary Revascularization in the Past Two Decades in Japan (From the CREDO-Kyoto PCI/CABG Registries Cohort-1, -2, and -3).

The treatment of coronary artery disease has substantially changed over the past two decades. However, it is unknown whether and how much these changes have contributed to the improvement of long-term outcomes after coronary revascularization. We assessed trends in the demographics, practice patterns and long-term outcomes in 24,951 patients who underwent their first percutaneous coronary intervention (PCI) (n = 20,106), or isolated coronary artery bypass grafting (CABG) (n = 4,845) using the data in a series of the CREDO-Kyoto PCI/CABG Registries (Cohort-1 [2000 to 2002]: n = 7,435, Cohort-2 [2005 to 2007]: n = 8,435, and Cohort-3 [2011 to 2013]: n = 9,081).

Planar cell polarity induces local microtubule bundling for coordinated ciliary beating.

Multiciliated cells (MCCs) in tracheas generate mucociliary clearance through coordinated ciliary beating. Apical microtubules (MTs) play a crucial role in this process by organizing the planar cell polarity (PCP)-dependent orientation of ciliary basal bodies (BBs), for which the underlying molecular basis remains elusive. Herein, we found that the deficiency of Daple, a dishevelled-associating protein, in tracheal MCCs impaired the planar polarized apical MTs without affecting the core PCP proteins, causing significant defects in the BB orientation at the cell level but not the tissue level.

Comparison of Outcomes of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting Among Patients With Three-Vessel Coronary Artery Disease in the New-Generation Drug-Eluting Stents Era (From CREDO-Kyoto PCI/CABG Registry Cohort-3).

There is a scarcity of data comparing long-term clinical outcomes between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three-vessel coronary artery disease (3VD) in the new-generation drug-eluting stents era. CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who had undergone first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. We identified 2525 patients with 3VD (PCI: n = 1747 [69%], and CABG: n = 778 [31%]).

A microtubule-LUZP1 association around tight junction promotes epithelial cell apical constriction.

Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di-phosphorylated myosin light chain (ppMLC)-driven contraction of actomyosin-based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions (AJs). Here, we revealed a ppMLC-triggered system at TJ-associated CRs for vertebrate apical constriction involving microtubules, LUZP1, and myosin phosphatase.

Loss of Fbxw7 Impairs Development of and Induces Heterogeneous Tumor Formation in the Mouse Mammary Gland.

Fbxw7 is an F-box protein that contributes to regulation of cell proliferation and cell fate determination as well as to tumor suppression in various tissues. In this study, we generated mice with mammary gland-specific ablation of Fbxw7 ( mice) and found that most neonates born to mutant dams die soon after birth as a result of defective maternal lactation. The mammary gland of mutant dams was markedly atrophic and manifested both excessive cell proliferation and apoptosis in association with the accumulation of Notch1 and p63.

Vasopressin escape and memory impairment in a model of chronic syndrome of inappropriate secretion of antidiuretic hormone in mice.

Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia.

Early Surgery vs. Surgery After Watchful Waiting for Asymptomatic Severe Aortic Stenosis.

Background: There is no large-scale study comparing postoperative mortality after aortic valve replacement (AVR) for asymptomatic severe aortic stenosis (AS) between initial treatment with AVR vs. eventual AVR after conservative management.

Methods and results: We analyzed data from a multicenter registry enrolling 3,815 consecutive patients with severe AS.

Impact of concomitant tricuspid regurgitation on long-term outcomes in severe aortic stenosis.

Aims: Tricuspid regurgitation (TR) has been reported to be associated with worse survival in various heart diseases, but there are few data in aortic stenosis (AS).

Methods And Results: In the Contemporary Outcomes after Surgery and Medical Treatment in Patients with Severe Aortic Stenosis (CURRENT AS) Registry enrolling 3815 consecutive patients with severe AS, there were 628 patients with moderate or severe TR (TR group) and 3187 patients with no or mild TR (no TR group). The study patients were subdivided into the initial aortic valve replacement (AVR) stratum (n = 1197) and the conservative stratum (n = 2618) according to treatment strategy.

Degradation of the endoplasmic reticulum-anchored transcription factor MyRF by the ubiquitin ligase SCF in a manner dependent on the kinase GSK-3.

The ubiquitin-proteasome system regulates the abundance of many cellular proteins by mediating their targeted degradation. We previously developed a method-differential proteomics-based identification of ubiquitylation substrates (DiPIUS)-for the comprehensive identification of substrates for a given F-box protein subunit of SCF-type ubiquitin ligases. We have now applied DiPIUS to the F-box protein Fbxw7 in three cell lines (mHepa, Neuro2A, and C2C12) and thereby identified myelin regulatory factor (MyRF), an endoplasmic reticulum-anchored transcription factor that is essential for myelination of nerves in the central nervous system, as a candidate substrate of Fbxw7 specifically in mHepa cells.

Five-Year Clinical Outcome of Asymptomatic vs. Symptomatic Severe Aortic Stenosis After Aortic Valve Replacement.

Background: There is discordance regarding the effect of symptom status before aortic valve replacement (AVR) on long-term outcome after AVR in severe aortic stenosis (AS).

Methods and results: The CURRENT AS registry is a multicenter retrospective registry enrolling 3,815 consecutive patients with severe AS. Among 1,196 patients managed with the initial AVR strategy, long-term clinical outcomes were compared between the symptomatic patients (n=905), and asymptomatic patients (n=291).