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  1. Article ; Online: Register transitions in an in vivo canine model as a function of intrinsic laryngeal muscle stimulation, fundamental frequency, and sound pressure level.

    Schlegel, Patrick / Berry, David A / Moffatt, Clare / Zhang, Zhaoyan / Chhetri, Dinesh K

    The Journal of the Acoustical Society of America

    2024  Volume 155, Issue 3, Page(s) 2139–2150

    Abstract: Phonatory instabilities and involuntary register transitions can occur during singing. However, little is known regarding the mechanisms which govern such transitions. To investigate this phenomenon, we systematically varied laryngeal muscle activation ... ...

    Abstract Phonatory instabilities and involuntary register transitions can occur during singing. However, little is known regarding the mechanisms which govern such transitions. To investigate this phenomenon, we systematically varied laryngeal muscle activation and airflow in an in vivo canine larynx model during phonation. We calculated voice range profiles showing average nerve activations for all combinations of fundamental frequency (F0) and sound pressure level (SPL). Further, we determined closed-quotient (CQ) and minimum-posterior-area (MPA) based on high-speed video recordings. While different combinations of muscle activation favored different combinations of F0 and SPL, in the investigated larynx there was a consistent region of instability at about 400 Hz which essentially precluded phonation. An explanation for this region may be a larynx specific coupling between sound source and subglottal tract or an effect based purely on larynx morphology. Register transitions crossed this region, with different combinations of cricothyroid and thyroarytenoid muscle (TA) activation stabilizing higher or lower neighboring frequencies. Observed patterns in CQ and MPA dependent on TA activation reproduced patterns found in singers in previous work. Lack of control of TA stimulation may result in phonation instabilities, and enhanced control of TA stimulation may help to avoid involuntary register transitions, especially in the singing voice.
    MeSH term(s) Animals ; Dogs ; Laryngeal Muscles/physiology ; Vocalization, Animal ; Phonation/physiology ; Sound ; Video Recording
    Language English
    Publishing date 2024-03-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219231-7
    ISSN 1520-8524 ; 0001-4966
    ISSN (online) 1520-8524
    ISSN 0001-4966
    DOI 10.1121/10.0025135
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Mettl3 epitranscriptomic writer amplifies p53 stress responses.

    Raj, Nitin / Wang, Mengxiong / Seoane, Jose A / Zhao, Richard L / Kaiser, Alyssa M / Moonie, Nancie A / Demeter, Janos / Boutelle, Anthony M / Kerr, Craig H / Mulligan, Abigail S / Moffatt, Clare / Zeng, Shelya X / Lu, Hua / Barna, Maria / Curtis, Christina / Chang, Howard Y / Jackson, Peter K / Attardi, Laura D

    Molecular cell

    2022  Volume 82, Issue 13, Page(s) 2370–2384.e10

    Abstract: The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using ... ...

    Abstract The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m
    MeSH term(s) Animals ; Carcinogenesis ; Methyltransferases/metabolism ; Mice ; RNA ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Transcription Factors ; Tumor Suppressor Protein p53 ; RNA (63231-63-0) ; Methyltransferases (EC 2.1.1.-) ; Mettl3 protein, mouse (EC 2.1.1.-)
    Language English
    Publishing date 2022-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2022.04.010
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  3. Article: The Mettl3 epitranscriptomic writer amplifies p53 stress responses

    Raj, Nitin / Wang, Mengxiong / Seoane, Jose A. / Zhao, Richard L. / Kaiser, Alyssa M. / Moonie, Nancie A. / Demeter, Janos / Boutelle, Anthony M. / Kerr, Craig H. / Mulligan, Abigail S. / Moffatt, Clare / Zeng, Shelya X. / Lu, Hua / Barna, Maria / Curtis, Christina / Chang, Howard Y. / Jackson, Peter K. / Attardi, Laura D.

    Molecular cell. 2022 July 07, v. 82, no. 13

    2022  

    Abstract: The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using ... ...

    Abstract The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m⁶A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in in vivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.
    Keywords DNA damage ; gene expression ; genome ; humans ; mass spectrometry ; neoplasms ; transcription factors
    Language English
    Dates of publication 2022-0707
    Size p. 2370-2384.e10.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2022.04.010
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  4. Article ; Online: Analysis of focused ultrasound-induced blood-brain barrier permeability in a mouse model of Alzheimer's disease using two-photon microscopy.

    Burgess, Alison / Nhan, Tam / Moffatt, Clare / Klibanov, A L / Hynynen, Kullervo

    Journal of controlled release : official journal of the Controlled Release Society

    2014  Volume 192, Page(s) 243–248

    Abstract: Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver ... ...

    Abstract Transcranial focused ultrasound (FUS) can cause temporary, localized increases in blood-brain barrier (BBB) permeability for effective drug delivery to the brain. In pre-clinical models of Alzheimer's disease, FUS has successfully been used to deliver therapeutic agents and endogenous therapeutic molecules to the brain leading to plaque reduction and improved behavior. However, prior to moving to clinic, questions regarding how the compromised vasculature in Alzheimer's disease responds to FUS need to be addressed. Here, we used two-photon microscopy to study changes in FUS-mediated BBB permeability in transgenic (TgCRND8) mice and their non-transgenic littermates. A custom-built ultrasound transducer was attached to the skull, covering a cranial window. Methoxy-X04 was used to visualize amyloid deposits in vivo. Fluorescent intravascular dyes were used to identify leakage from the vasculature after the application of FUS. Dye leakage occurred in both transgenic and non-transgenic mice at similar acoustic pressures but exhibited different leakage kinetics. Calculation of the permeability constant demonstrated that the vasculature in the transgenic mice was much less permeable after FUS than the non-transgenic littermates. Further analysis demonstrated that the change in vessel diameter following FUS was lessened in amyloid coated vessels. These data suggest that changes in vessel diameter may be directly related to permeability and the presence of amyloid plaque may reduce the permeability of a vessel after FUS. This study indicates that the FUS parameters used for the delivery of therapeutic agents to the brain may need to be adjusted for application in Alzheimer's disease.
    MeSH term(s) Alkenes ; Alzheimer Disease/drug therapy ; Alzheimer Disease/pathology ; Animals ; Benzene Derivatives ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Brain/blood supply ; Brain/metabolism ; Brain/pathology ; Cerebral Amyloid Angiopathy/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Drug Delivery Systems/instrumentation ; Female ; Male ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence, Multiphoton ; Permeability ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Stilbenes ; Ultrasonics/instrumentation
    Chemical Substances 1,4-bis(4'-hydroxystyryl)-2-methoxybenzene ; Alkenes ; Benzene Derivatives ; Stilbenes
    Language English
    Publishing date 2014-10-28
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2014.07.051
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  5. Article ; Online: International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell's Diverticulum.

    Moffatt, Clare / Bath, Jonathan / Rogers, Richard T / Colglazier, Jill J / Braet, Drew J / Coleman, Dawn M / Scali, Salvatore T / Back, Martin R / Magee, Gregory A / Plotkin, Anastasia / Dueppers, Philip / Zimmermann, Alexander / Afifi, Rana O / Khan, Sophia / Zarkowsky, Devin / Dyba, Gregory / Soult, Michael C / Mani, Kevin / Wanhainen, Anders /
    Setacci, Carlo / Lenti, Massimo / Kabbani, Loay S / Weaver, Mitchell R / Bissacco, Daniele / Trimarchi, Santi / Stoecker, Jordan B / Wang, Grace J / Szeberin, Zoltan / Pomozi, Eniko / Gelabert, Hugh A / Tish, Shahed / Hoel, Andrew W / Cortolillo, Nicholas S / Spangler, Emily L / Passman, Marc A / De Caridi, Giovanni / Benedetto, Filippo / Zhou, Wei / Abuhakmeh, Yousef / Newton, Daniel H / Liu, Christopher M / Tinelli, Giovanni / Tshomba, Yamume / Katoh, Airi / Siada, Sammy S / Khashram, Manar / Gormley, Sinead / Mullins, John R / Schmittling, Zachary C / Maldonado, Thomas S / Politano, Amani D / Rynio, Pawel / Kazimierczak, Arkadiusz / Gombert, Alexander / Jalaie, Houman / Spath, Paolo / Gallitto, Enrico / Czerny, Martin / Berger, Tim / Davies, Mark G / Stilo, Francesco / Montelione, Nunzio / Mezzetto, Luca / Veraldi, Gian Franco / D'Oria, Mario / Lepidi, Sandro / Lawrence, Peter / Woo, Karen

    Annals of vascular surgery

    2023  Volume 95, Page(s) 23–31

    Abstract: Background: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD ... ...

    Abstract Background: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch.
    Methods: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions.
    Results: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change.
    Conclusions: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality.
    MeSH term(s) Adolescent ; Humans ; Aorta, Thoracic/diagnostic imaging ; Aorta, Thoracic/surgery ; Aorta, Thoracic/abnormalities ; Deglutition Disorders/etiology ; Deglutition Disorders/surgery ; Diverticulum/diagnostic imaging ; Diverticulum/surgery ; Diverticulum/complications ; Heart Defects, Congenital/complications ; Subclavian Artery/diagnostic imaging ; Subclavian Artery/surgery ; Subclavian Artery/abnormalities ; Treatment Outcome ; Vascular Diseases/complications ; Adult ; Middle Aged
    Language English
    Publishing date 2023-05-24
    Publishing country Netherlands
    Document type Journal Article ; Multicenter Study
    ZDB-ID 1027366-9
    ISSN 1615-5947 ; 0890-5096
    ISSN (online) 1615-5947
    ISSN 0890-5096
    DOI 10.1016/j.avsg.2023.05.005
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  6. Article ; Online: Contemporary outcomes after treatment of aberrant subclavian artery and Kommerell's diverticulum.

    Bath, Jonathan / D'Oria, Mario / Rogers, Richard T / Colglazier, Jill J / Braet, Drew J / Coleman, Dawn M / Scali, Salvatore T / Back, Martin R / Magee, Gregory A / Plotkin, Anastasia / Dueppers, Philip / Zimmermann, Alexander / Afifi, Rana O / Khan, Sophia / Zarkowsky, Devin / Dyba, Gregory / Soult, Michael C / Mani, Kevin / Wanhainen, Anders /
    Setacci, Carlo / Lenti, Massimo / Kabbani, Loay S / Weaver, Mitchelle R / Bissacco, Daniele / Trimarchi, Santi / Stoecker, Jordan B / Wang, Grace J / Szeberin, Zoltan / Pomozi, Eniko / Moffatt, Clare / Gelabert, Hugh A / Tish, Shahed / Hoel, Andrew W / Cortolillo, Nicholas S / Spangler, Emily L / Passman, Marc A / De Caridi, Giovanni / Benedetto, Filippo / Zhou, Wei / Abuhakmeh, Yousef / Newton, Daniel H / Liu, Christopher M / Tinelli, Giovanni / Tshomba, Yamume / Katoh, Airi / Siada, Sammy S / Khashram, Manar / Gormley, Sinead / Mullins, John R / Schmittling, Zachary C / Maldonado, Thomas S / Politano, Amani D / Rynio, Pawel / Kazimierczak, Arkadiusz / Gombert, Alexander / Jalaie, Houman / Spath, Paolo / Gallitto, Enrico / Czerny, Martin / Berger, Tim / Davies, Mark G / Stilo, Francesco / Montelione, Nunzio / Mezzetto, Luca / Veraldi, Gian Franco / Lepidi, Sandro / Lawrence, Peter / Woo, Karen

    Journal of vascular surgery

    2023  Volume 77, Issue 5, Page(s) 1339–1348.e6

    Abstract: Objective: Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after ... ...

    Abstract Objective: Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset.
    Methods: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak.
    Results: Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P < .0001), female (64% vs 36%; P < .0001), and symptomatic (85% vs 59%; P < .0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P = .13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P = .02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio [OR], 19.8; 95% confidence interval [CI], 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms.
    Conclusions: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate.
    MeSH term(s) Humans ; Female ; Middle Aged ; Male ; Endoleak/etiology ; Aneurysm/diagnostic imaging ; Aneurysm/surgery ; Aneurysm/complications ; Subclavian Artery/diagnostic imaging ; Subclavian Artery/surgery ; Subclavian Artery/abnormalities ; Endovascular Procedures/adverse effects ; Stroke/etiology ; Diverticulum/diagnostic imaging ; Diverticulum/surgery ; Aorta, Thoracic/surgery ; Treatment Outcome ; Blood Vessel Prosthesis Implantation/adverse effects
    Language English
    Publishing date 2023-01-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 605700-7
    ISSN 1097-6809 ; 0741-5214
    ISSN (online) 1097-6809
    ISSN 0741-5214
    DOI 10.1016/j.jvs.2023.01.014
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