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The EMBO Journal Aug 2023The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of...
The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.
Topics: Animals; Mice; Angiomotins; Zebrafish; Microfilament Proteins; Peptide Hydrolases; Intercellular Signaling Peptides and Proteins
PubMed: 37350545
DOI: 10.15252/embj.2022112900 -
Nature Apr 2024The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that...
The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.
Topics: Animals; Female; Humans; Male; Mice; Rabbits; Bacteria; Brain; Dependovirus; Eye; Glioblastoma; Herpesvirus 2, Human; Intravitreal Injections; Lymphatic System; Lymphatic Vessels; Macaca mulatta; Meninges; Optic Nerve; Swine; Zebrafish; Vascular Endothelial Growth Factor C
PubMed: 38418880
DOI: 10.1038/s41586-024-07130-8 -
The Journal of Thoracic and... Feb 2024Cross-sectional imaging allows identification of rare patients with a vascular ring and circumflex aorta. The key diagnostic feature is crossing of the transverse aortic... (Review)
Review
OBJECTIVE
Cross-sectional imaging allows identification of rare patients with a vascular ring and circumflex aorta. The key diagnostic feature is crossing of the transverse aortic arch from right to left posterior to the trachea and superior to the carina in a patient with a right aortic arch. We evaluated our patients who received an aortic uncrossing procedure.
METHODS
We reviewed all patients who underwent aortic uncrossing from 2002 to 2022. All patients received preoperative computed tomography imaging and bronchoscopy.
RESULTS
Eleven patients ranging in age from 1.5 to 10 years (median 4 years) underwent aortic uncrossing. Two patients had prior left ligamentum division, and 3 patients had prior left aortic arch division. All had significant clinical symptoms. Eight patients had deep hypothermic circulatory arrest (mean 34 minutes), and 3 patients had antegrade cerebral perfusion (median, 28 minutes). Patch material was not used for aortic augmentation, and no patient underwent a posterior tracheopexy or rotational esophagoplasty. Postoperative length of stay ranged from 4 to 31 days (median, 5 days). One patient required a temporary tracheostomy for bilateral recurrent laryngeal nerve paresis, which recovered. One patient required an aortic extension graft to alleviate esophageal compression from an unusual ectatic esophageal course. All patients had relief of airway symptoms and dysphagia.
CONCLUSIONS
In properly selected patients with a right aortic arch and circumflex aorta, aortic uncrossing is a safe and effective therapy to treat airway and esophageal compression. The procedure can be conducted with deep hypothermic circulatory arrest or antegrade cerebral perfusion. Careful attention to the location of the esophagus and recurrent laryngeal nerves is required.
Topics: Humans; Infant; Child, Preschool; Child; Aorta; Aorta, Thoracic; Bronchoscopy; Vascular Surgical Procedures; Perfusion
PubMed: 37406764
DOI: 10.1016/j.jtcvs.2023.06.013 -
Journal of Nanobiotechnology May 2024Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via... (Review)
Review
Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via the artful combination of supramolecular chemistry and nanotechnology. Benefiting from the tunable stimuli-responsiveness and compatible hierarchical organization, host-guest interactions have developed into the most popular mainstay for constructing supramolecular nanoplatforms. Characterized by the strong and diverse complexation property, cucurbit[8]uril (CB[8]) shows great potential as important building blocks for supramolecular theranostic systems. In this review, we summarize the recent progress of CB[8]-based supramolecular theranostics regarding the design, manufacture and theranostic mechanism. Meanwhile, the current limitations and corresponding reasonable solutions as well as the potential future development are also discussed.
Topics: Theranostic Nanomedicine; Bridged-Ring Compounds; Imidazoles; Humans; Animals; Nanoparticles; Heterocyclic Compounds, 2-Ring; Macrocyclic Compounds; Imidazolidines
PubMed: 38725031
DOI: 10.1186/s12951-024-02349-z -
Pediatric Cardiology Aug 2023We present the clinical course and echocardiographic and genetic findings of two fetuses with an unusual vascular ring, created by a left aortic arch with a right...
We present the clinical course and echocardiographic and genetic findings of two fetuses with an unusual vascular ring, created by a left aortic arch with a right arterial duct and an aberrant right subclavian artery. One fetus was diagnosed with 22q11.2 microdeletion and the other became symptomatic in infancy. It is important to consider the position of the arterial ductal ligament in patients who present with tracheoesophageal compressive symptoms in the presence of a left aortic arch. These cases also highlight that a vascular ring formed from a left arch may have similar associations to a vascular ring formed by a right aortic arch.
PubMed: 37566242
DOI: 10.1007/s00246-023-03261-3