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  1. Article: One person can make a difference: identification of people with a rare genetic lung disease.

    Horani, Amjad / Brody, Steven L

    ERJ open research

    2023  Volume 9, Issue 2

    Abstract: To improve access to care for rare conditions in resource-restricted regions, a concerted effort to establish centres of excellence and training of local physicians is ... ...

    Abstract To improve access to care for rare conditions in resource-restricted regions, a concerted effort to establish centres of excellence and training of local physicians is needed
    Language English
    Publishing date 2023-04-17
    Publishing country England
    Document type Editorial
    ZDB-ID 2827830-6
    ISSN 2312-0541
    ISSN 2312-0541
    DOI 10.1183/23120541.00122-2023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn.

    Hyland, Rachael M / Brody, Steven L

    Cells

    2021  Volume 11, Issue 1

    Abstract: Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods ...

    Abstract Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods they have essential roles in airway clearance in the respiratory tract and regulating cerebral spinal fluid flow in the brain. Dysregulation of motile cilia is best understood through the lens of the genetic disorder primary ciliary dyskinesia (PCD). PCD encompasses all genetic motile ciliopathies resulting from over 60 known genetic mutations and has a unique but often underrecognized neonatal presentation. Neonatal respiratory distress is now known to occur in the majority of patients with PCD, laterality defects are common, and very rarely brain ventricle enlargement occurs. The developmental function of motile cilia and the effect and pathophysiology of motile ciliopathies are incompletely understood in humans. In this review, we will examine the current understanding of the role of motile cilia in human development and clinical considerations when assessing the newborn for suspected motile ciliopathies.
    MeSH term(s) Cilia/pathology ; Ciliopathies/diagnosis ; Ciliopathies/pathology ; Embryonic Development ; Humans ; Infant, Newborn ; Models, Biological
    Language English
    Publishing date 2021-12-31
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11010125
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Variations in infection control practices suggest a need for guidelines in primary ciliary dyskinesia patient care.

    Caliskan, Ayse B / Horani, Amjad / Manion, Michele / Brody, Steven L

    Pediatric pulmonology

    2022  Volume 57, Issue 4, Page(s) 1072–1075

    Abstract: Primary ciliary dyskinesis (PCD) is an autosomal recessive disorder associated with impaired mucociliary clearance caused by defects in ciliary structure and function. The major clinical feature of PCD is recurring or persistent respiratory tract ... ...

    Abstract Primary ciliary dyskinesis (PCD) is an autosomal recessive disorder associated with impaired mucociliary clearance caused by defects in ciliary structure and function. The major clinical feature of PCD is recurring or persistent respiratory tract infection. Respiratory tract colonization with drug-resistant organisms impacts the frequency of infections and lung function decline. Protective gear has been employed by caregivers in an attempt to control respiratory tract bacterial spread between patients with cystic fibrosis, but use in PCD is not known. We conducted a web-based survey to investigate infection control and prevention practices of PCD centers in North America, and how practices have been influenced by the COVID-19 pandemic. The response rate was 87.0%. Before the COVID-19 pandemic, glove, gown, and mask use were variable, and only 3.7% of centers used masks during encounters with PCD outpatients. After COVID-19 mandates are lifted, 48.1% of centers plan to continue to use masks during outpatient care, while the practice regarding the use of gloves and gowns was not influenced by the current pandemic. There is no uniform practice for infection control in PCD care indicating the need for practice guidelines. Mitigation of respiratory virus transmission learned during the COVID-19 pandemic may impact future infection control approaches used for patients with PCD and other lung diseases.
    MeSH term(s) COVID-19/prevention & control ; Ciliary Motility Disorders/complications ; Cystic Fibrosis/complications ; Humans ; Infection Control ; Kartagener Syndrome/complications ; Kartagener Syndrome/therapy ; Pandemics/prevention & control ; Patient Care
    Language English
    Publishing date 2022-01-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632784-9
    ISSN 1099-0496 ; 8755-6863
    ISSN (online) 1099-0496
    ISSN 8755-6863
    DOI 10.1002/ppul.25836
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Frequenting Sequencing: How Genetics Teaches Us Cilia Biology.

    Horani, Amjad / Brody, Steven L

    American journal of respiratory cell and molecular biology

    2019  Volume 61, Issue 4, Page(s) 403–404

    MeSH term(s) Cilia ; Dyneins ; Humans ; Kartagener Syndrome ; Mutation
    Chemical Substances Dyneins (EC 3.6.4.2)
    Language English
    Publishing date 2019-03-21
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2019-0103ED
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: HY-DIN' in the Cilia: Discovery of Central Pair-related Mutations in Primary Ciliary Dyskinesia.

    Dutcher, Susan K / Brody, Steven L

    American journal of respiratory cell and molecular biology

    2019  Volume 62, Issue 3, Page(s) 281–282

    MeSH term(s) Axoneme ; Cilia ; Ciliary Motility Disorders ; Humans ; Microfilament Proteins ; Mutation
    Chemical Substances HYDIN protein, human ; Microfilament Proteins
    Language English
    Publishing date 2019-09-30
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2019-0316ED
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Neuraminidase Activity Modulates Cellular Coinfection during Influenza A Virus Multicycle Growth.

    Guo, Zijian / He, Yuanyuan / Xu, Jian / Benegal, Ananya N / Brody, Steven L / Vahey, Michael D

    mBio

    2023  Volume 14, Issue 3, Page(s) e0359122

    Abstract: Infection of individual cells by multiple virions plays critical roles in the replication and spread of many viruses, but mechanisms that control cellular coinfection during multicycle viral growth remain unclear. Here, we investigate virus-intrinsic ... ...

    Abstract Infection of individual cells by multiple virions plays critical roles in the replication and spread of many viruses, but mechanisms that control cellular coinfection during multicycle viral growth remain unclear. Here, we investigate virus-intrinsic factors that control cellular coinfection by influenza A virus (IAV). Using quantitative fluorescence to track the spread of virions from single infected cells, we identify the IAV surface protein neuraminidase (NA) as a key determinant of cellular coinfection. We map this effect to NA's ability to deplete viral receptors from both infected and neighboring uninfected cells. In cases in which viral infectious potential is low, genetic or pharmacological inhibition of NA increases the local spread of infection by increasing the viral load received by neighboring cells. These results identify virus-intrinsic factors that contribute to cellular multiplicity of infection and suggest that optimal levels of NA activity depend on the infectious potential of the virus in question.
    MeSH term(s) Animals ; Dogs ; Humans ; Influenza A virus/physiology ; Neuraminidase/genetics ; Coinfection ; Influenza, Human ; Madin Darby Canine Kidney Cells
    Chemical Substances Neuraminidase (EC 3.2.1.18)
    Language English
    Publishing date 2023-04-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.03591-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Simvastatin as a topical anti-inflammatory: Effect on airway epithelial cell homeostasis.

    Farrell, Nyssa Fox / Pan, Jiehong / Huang, Tao / Piccirillo, Jay F / Goldstein, Bradley J / Brody, Steven L

    International forum of allergy & rhinology

    2023  Volume 13, Issue 9, Page(s) 1817–1820

    MeSH term(s) Humans ; Simvastatin/pharmacology ; Simvastatin/therapeutic use ; Epithelial Cells ; Anti-Inflammatory Agents/therapeutic use ; Respiratory System ; Chronic Disease ; Rhinitis/drug therapy
    Chemical Substances Simvastatin (AGG2FN16EV) ; Anti-Inflammatory Agents
    Language English
    Publishing date 2023-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625826-2
    ISSN 2042-6984 ; 2042-6976
    ISSN (online) 2042-6984
    ISSN 2042-6976
    DOI 10.1002/alr.23137
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models.

    Puray-Chavez, Maritza / LaPak, Kyle M / Jasuja, Ria / Pan, Jiehong / Xu, Jian / Eschbach, Jenna E / Mohammed, Shawn / Lawson, Dana Q / Wang, Qibo / Brody, Steven L / Major, Michael B / Goldfarb, Dennis / Kutluay, Sebla B

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. From a screen of human airway derived cell lines that express varying levels of ACE2/TMPRSS2, we found a subset that express comparably high ... ...

    Abstract Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. From a screen of human airway derived cell lines that express varying levels of ACE2/TMPRSS2, we found a subset that express comparably high endogenous levels of ACE2 but surprisingly did not support SARS-CoV-2 replication. Here we report that this resistance is mediated by a basally active cGAS-STING pathway culminating in interferon (IFN)-mediated restriction of SARS-CoV-2 replication at a post-entry step. Pharmacological inhibition of JAK1/2, depletion of the IFN-α receptor and cGAS-STING pathway effectors substantially increased SARS-CoV-2 replication in these cell models. While depletion of cGAS or STING was sufficient to reduce the preexisting levels of IFN-stimulated genes (ISGs), SARS-CoV-2 infection in STING knockout cells independently induced ISG expression. Remarkably, SARS-CoV-2-induced ISG expression in STING knockout cell as well as in primary human airway cultures was limited to uninfected bystander cells, demonstrating efficient antagonism of the type I/III IFN-pathway, but not viral sensing or IFN production, in productively infected cells. Of note, SARS-CoV-2-infected primary human airway cells also displayed markedly lower levels of STING expression, raising the possibility that SARS-CoV-2 can target STING expression or preferentially infect cells that express low levels of STING. Finally, ectopic ACE2 overexpression overcame the IFN-mediated blocks, suggesting the ability of SARS-CoV-2 to overcome these possibly saturable blocks to infection. Our study highlights that in addition to viral receptors, basal activation of the cGAS-STING pathway and innate immune defenses may contribute to defining SARS-CoV-2 cellular tropism.
    Language English
    Publishing date 2024-01-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.07.574522
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma.

    Kudrna, Katrina / Staab, Elizabeth B / Eilers, Evan / Thomes, Paul / Maurya, Shailendra / Brody, Steven L / Wyatt, Todd A / Bailey, Kristina L / Dickinson, John D

    bioRxiv : the preprint server for biology

    2024  

    Abstract: In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet ... ...

    Abstract In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet cells (eGC) deep within the thickened epithelial layer disconnected from the lumenal surface. mTOR is a highly conserved pathway that regulates cell size and proliferation. We hypothesized that the balance between mTOR and autophagy signaling regulates key features of the asthma epithelial layer. Airway histological sections from subjects with asthma had increased frequency of eGC and increased levels of mTOR phosphorylation target-Ribosomal S6. Using human airway epithelial cells (hAECs) with IL-13 stimulation and timed withdrawal to stimulate resolution, we found that multiple key downstream phosphorylation targets downstream from the mTOR complex were increased during early IL-13-mediated mucous metaplasia, and then significantly declined during resolution. The IL-13-mediated changes in mTOR signaling were paralleled by morphologic changes with airway epithelial hypertrophy, hyperplasia, and frequency of eGC. We then examined the relationship between mTOR and autophagy using mice deficient in autophagy protein Atg16L1. Despite having increased cytoplasmic mucins, mouse AECs from Atg16L1 deficient mice had no significant difference in mTOR downstream signaling. mTOR inhibition with rapamycin led to a loss of IL-13-mediated epithelial hypertrophy, hyperplasia, ectopic GC distribution, and reduction in cytoplasmic MUC5AC levels. mTOR inhibition was also associated with a reduction in aberrant IL-13-mediated hAEC proliferation and migration. Our findings demonstrate that mTOR signaling is associated with mucous metaplasia and is crucial to the disorganized airway epithelial structure and function characteristic of muco-obstructive airway diseases such as asthma.
    Graphical abstract key concepts: The airway epithelium in asthma is disorganized and characterized by cellular proliferation, aberrant migration, and goblet cell mucous metaplasia.mTOR signaling is a dynamic process during IL-13-mediated mucous metaplasia, increasing with IL-13 stimulation and declining during resolution.mTOR signaling is strongly increased in the asthmatic airway epithelium.mTOR signaling is associated with the development of key features of the metaplastic airway epithelium including cell proliferation and ectopic distribution of goblet cells and aberrant cellular migration.Inhibition of mTOR leads to decreased epithelial hypertrophy, reduced ectopic goblet cells, and cellular migration.
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.12.579905
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Ultrastructure expansion microscopy (U-ExM) of mouse and human kidneys for analysis of subcellular structures.

    Langner, Ewa / Puapatanakul, Pongpratch / Pudlowski, Rachel / Alsabbagh, Dema Yaseen / Miner, Jeffrey H / Horani, Amjad / Dutcher, Susan K / Brody, Steven L / Wang, Jennifer T / Suleiman, Hani Y / Mahjoub, Moe R

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for ... ...

    Abstract Ultrastructure expansion microscopy (U-ExM) involves the physical magnification of specimens embedded in hydrogels, which allows for super-resolution imaging of subcellular structures using a conventional diffraction-limited microscope. Methods for expansion microscopy exist for several organisms, organs, and cell types, and used to analyze cellular organelles and substructures in nanoscale resolution. Here, we describe a simple step-by-step U-ExM protocol for the expansion, immunostaining, imaging, and analysis of cytoskeletal and organellar structures in kidney tissue. We detail the critical modified steps to optimize isotropic kidney tissue expansion, and preservation of the renal cell structures of interest. We demonstrate the utility of the approach using several markers of renal cell types, centrioles, cilia, the extracellular matrix, and other cytoskeletal elements. Finally, we show that the approach works well on mouse and human kidney samples that were preserved using different fixation and storage conditions. Overall, this protocol provides a simple and cost-effective approach to analyze both pre-clinical and clinical renal samples in high detail, using conventional lab supplies and standard widefield or confocal microscopy.
    Language English
    Publishing date 2024-02-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.16.580708
    Database MEDical Literature Analysis and Retrieval System OnLINE

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