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The Journal of Pediatrics Mar 2021Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary... (Review)
Review
Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary (sensory) cilia are essential structures and have wide ranging functions. Our understanding of the genetics, pathophysiology, and clinical manifestations of motile ciliopathies, including primary ciliary dyskinesia (PCD), has rapidly advanced since the disease was linked to ciliary ultrastructural defects nearly five decades ago. We will provide an overview of different types of cilia, their role in child health and disease, focusing on motile ciliopathies, and describe recent advances that have led to improved diagnostics and may yield therapeutic targets to restore ciliary structure and function.
Topics: Cilia; Ciliary Motility Disorders; Humans
PubMed: 33242470
DOI: 10.1016/j.jpeds.2020.11.040 -
American Journal of Respiratory and... Apr 2023Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has...
Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. To establish and interrogate the role of the gut microbiome in calibrating body temperature. We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.
Topics: Animals; Mice; Gastrointestinal Microbiome; Body Temperature; Microbiota; Sepsis; Anti-Bacterial Agents; RNA, Ribosomal, 16S
PubMed: 36378114
DOI: 10.1164/rccm.202201-0161OC -
Nature Biotechnology Jun 2023Expansion microscopy enables nanoimaging with conventional microscopes by physically and isotropically magnifying preserved biological specimens embedded in a...
Expansion microscopy enables nanoimaging with conventional microscopes by physically and isotropically magnifying preserved biological specimens embedded in a crosslinked water-swellable hydrogel. Current expansion microscopy protocols require prior treatment with reactive anchoring chemicals to link specific labels and biomolecule classes to the gel. We describe a strategy called Magnify, which uses a mechanically sturdy gel that retains nucleic acids, proteins and lipids without the need for a separate anchoring step. Magnify expands biological specimens up to 11 times and facilitates imaging of cells and tissues with effectively around 25-nm resolution using a diffraction-limited objective lens of about 280 nm on conventional optical microscopes or with around 15 nm effective resolution if combined with super-resolution optical fluctuation imaging. We demonstrate Magnify on a broad range of biological specimens, providing insight into nanoscopic subcellular structures, including synaptic proteins from mouse brain, podocyte foot processes in formalin-fixed paraffin-embedded human kidney and defects in cilia and basal bodies in drug-treated human lung organoids.
Topics: Mice; Animals; Humans; Microscopy; Kidney
PubMed: 36593399
DOI: 10.1038/s41587-022-01546-1 -
Nature Communications Jun 2023Fever is a common symptom of influenza and coronavirus disease 2019 (COVID-19), yet its physiological role in host resistance to viral infection remains less clear....
Fever is a common symptom of influenza and coronavirus disease 2019 (COVID-19), yet its physiological role in host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increases host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. The gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group. These findings implicate a mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.
Topics: Cricetinae; Animals; Mice; Humans; Influenza A virus; COVID-19; Gastrointestinal Microbiome; SARS-CoV-2; Influenza, Human; Body Temperature; Fever; Bile Acids and Salts; Mesocricetus
PubMed: 37391427
DOI: 10.1038/s41467-023-39569-0 -
Current Opinion in Cell Biology Aug 2022Multiciliated cells (MCC) are evolutionary conserved, highly specialized cell types that contain dozens to hundreds of motile cilia that they use to propel fluid... (Review)
Review
Multiciliated cells (MCC) are evolutionary conserved, highly specialized cell types that contain dozens to hundreds of motile cilia that they use to propel fluid directionally. To template these cilia, each MCC produces between 30 and 500 basal bodies via a process termed centriole amplification. Much progress has been made in recent years in understanding the pathways involved in MCC fate determination, differentiation, and ciliogenesis. Recent studies using mammalian cell culture systems, mice, Xenopus, and other model organisms have started to uncover the mechanisms involved in centriole and cilia biogenesis. Yet, how MCC progenitor cells regulate the precise number of centrioles and cilia during their differentiation remains largely unknown. In this review, we will examine recent findings that address this fundamental question.
Topics: Animals; Cell Differentiation; Centrioles; Cilia; Mammals; Mice; Xenopus laevis
PubMed: 35716530
DOI: 10.1016/j.ceb.2022.102105 -
Molecular Reproduction and Development Feb 2021Cilia/flagella are cell organelles that protrude from the surface of many eukaryotic cells and perform various functions. They are assembled and maintained by a...
Cilia/flagella are cell organelles that protrude from the surface of many eukaryotic cells and perform various functions. They are assembled and maintained by a conserved mechanism called intraflagellar transport (IFT), a bi-directional transportation process originally discovered in . Twenty-two core IFT components have been identified so far, and these complexes, together with the BBSome components, further form IFT particles that lie in close proximity to the basal body. They move from the base to the tip of the flagellum, and then back to the base. Like cilia defects, disruption of IFT/BBSome also gives rise to various genetic and developmental disorders, also called ciliapathies. Global disruption of IFT components causes embryonic lethality, which makes it impossible to study the role of IFT in reproduction. We summarize recent findings and the strategy to study the role of IFT in reproduction using mouse models. Finally, we show some examples of human IFT mutations and discuss the potential roles of IFT components in non-ciliated cells.
Topics: Animals; Female; Flagella; Humans; Male; Protein Transport; Reproduction
PubMed: 33507597
DOI: 10.1002/mrd.23451 -
Current Opinion in Genetics &... Jun 2019Multiciliated cells (MCCs) are specialized in fluid propulsion through directional beating of myriads of superficial motile cilia, which rest on modified centrioles... (Review)
Review
Multiciliated cells (MCCs) are specialized in fluid propulsion through directional beating of myriads of superficial motile cilia, which rest on modified centrioles named basal bodies. MCCs are found throughout metazoans, and serve functions as diverse as feeding and locomotion in marine organisms, as well as mucus clearance, cerebrospinal fluid circulation, and egg transportation in mammals. Impaired MCC differentiation or activity causes diseases characterized by severe chronic airway infections and reduced fertility. Through studies in Xenopus and mouse mainly, MCC biology has made significant progress on several fronts in recent years. The gene regulatory network that controls MCC specification and differentiation has been deciphered to a large extent. The enigmatic deuterosomes, which serve as centriole amplification platforms in vertebrate MCCs, have started to be studied at the molecular level. Principles of ciliary beating coordination within and between MCCs have been identified.
Topics: Animals; Cell Differentiation; Centrioles; Cilia; Ependyma; Epidermis; Mice; Microscopy, Electron, Scanning; Trimethoprim, Sulfamethoxazole Drug Combination; Xenopus laevis
PubMed: 31102978
DOI: 10.1016/j.gde.2019.04.006