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BMC Pulmonary Medicine Jan 2024Pulmonary fibrosis (PF) is a progressive fibrosing interstitial pneumonia that leads to respiratory failure and other complications, which is ultimately fatal....
BACKGROUND
Pulmonary fibrosis (PF) is a progressive fibrosing interstitial pneumonia that leads to respiratory failure and other complications, which is ultimately fatal. Mesenchymal stem cells (MSCs) transplant is a promising strategy to solve this problem, while the procurement of MSCs from the patient for autotransplant remains a challenge.
METHODS
Here, we presented olfactory mucosa mesenchymal stem cells (OM-MSCs) from mouse turbinate and determined the preventing efficacy of allotransplant for PF. We demonstrated the antiinflammation and immunomodulatory effects of OM-MSCs. Flow cytometric analysis was used to verify the effect of OM-MSCs on monocyte-derived macrophage populations in the lung.
RESULTS
Administration of OM-MSCs reduces inflammation, attenuates the matrix metallopeptidase 13 (MMP13) expression level and restores the bleomycin (BLM)-induced pulmonary fibrosis by assessing the architecture of lung, collagen type I; (COL1A1), actin alpha 2, smooth muscle, aorta (ACTA2/α-SMA) and hydroxyproline. This therapeutic effect of OM-MSCs was related to the increase in the ratio of nonclassical monocytes to proinflammatory monocytes in the lung.
CONCLUSIONS
This study suggests that transplant of OM-MSCs represents an effective and safe treatment for PF.
Topics: Humans; Mice; Animals; Pulmonary Fibrosis; Inflammation; Mesenchymal Stem Cells; Immunomodulation; Olfactory Mucosa
PubMed: 38178092
DOI: 10.1186/s12890-023-02834-5 -
Frontiers in Endocrinology 2023This study aims to access the efficacy of the binasal speculum in endoscopic endonasal surgery by evaluating clinical outcomes and examining its utility through...
OBJECTIVE
This study aims to access the efficacy of the binasal speculum in endoscopic endonasal surgery by evaluating clinical outcomes and examining its utility through process-based performance measures in both surgeons and assistants.
METHODS
A total of 59 patients with lesions in sellar region who underwent endoscopic endonasal surgery with the binasal speculum between September 2020 and March 2023 were included in this study. We assessed the extent of resection and documented postoperative nasal condition. Both surgeons and assistants completed post-use surveys to exam the utility of the binasal speculum and provide an overall grading.
RESULTS
Gross total resection (GTR) was successfully achieved in 94.9% (56/59) of patients, with subtotal resection (STR) observed in 5.1% (4/59) of patients. Intraoperative cerebrospinal fluid (CSF) leakage occurred in 23.7% (14/59) of cases, and nasoseptal flap (NSF) reconstruction was required in 55.9% (33/59) of cases. The nasal airway patency rapidly recovered within 14 days in a significant majority of patients (94.9%, 56/59). Moreover, olfactory function was regained within three months postoperatively by 91.5% (54/59) of patients. The overall post-use survey mean score was 26.4. Specifically, surgeons had a mean score of 26.5, while assistants had a slightly lower mean score of 26.2. The mean overall grading for the binasal speculum was 3. Both surgeons and assistants provided a mean overall grading of 3.
CONCLUSION
The binasal speculum provides nasal mucosa protection and reduces the risk of an endoscopic lens clouded by mucosa or blood. It plays a crucial role in accurate guidance and facilitates the swift delivery of surgical instruments, particularly in left-blinded nasal cavities. The binasal speculum reduces the learning curve, especially for endoscopic surgeons with limited experience, while enhancing collaboration and coordination between surgeons and assistants during surgery. Both surgeons and assistants rated the overall utility of the binasal speculum as "excellent."
Topics: Humans; Retrospective Studies; Nose; Surgical Flaps; Plastic Surgery Procedures; Cerebrospinal Fluid Leak; Surgical Instruments
PubMed: 38174332
DOI: 10.3389/fendo.2023.1250755 -
Cellular & Molecular Immunology Feb 2024Numerous pathogens can infect the olfactory tract, yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune... (Review)
Review
Numerous pathogens can infect the olfactory tract, yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune barrier. Situated in the nasal passages, the olfactory mucosa is directly exposed to the environment to sense airborne odorants; however, this also means it can serve as a direct route of entry from the outside world into the brain. As a result, olfactotropic infections can have serious consequences, including dysfunction of the olfactory system, CNS invasion, dissemination to the lower respiratory tract, and transmission between individuals. Recent research has shown that a distinctive immune response is needed to protect this neuronal and mucosal tissue. A better understanding of innate, adaptive, and structural immune barriers in the olfactory mucosa is needed to develop effective therapeutics and vaccines against olfactotropic microbes such as SARS-CoV-2. Here, we summarize the ramifications of SARS-CoV-2 infection of the olfactory mucosa, review the subsequent immune response, and discuss important areas of future research for olfactory immunity to infectious disease.
Topics: Humans; SARS-CoV-2; COVID-19; Olfactory Mucosa; Brain; Immunity
PubMed: 38143247
DOI: 10.1038/s41423-023-01119-5 -
Biomolecules Dec 2023The olfactory neuroepithelium (OE) is one of the few neuronal tissues where environmental pathogens can gain direct access. Despite this vulnerable arrangement, little...
The olfactory neuroepithelium (OE) is one of the few neuronal tissues where environmental pathogens can gain direct access. Despite this vulnerable arrangement, little is known about the protective mechanisms in the OE to prevent viral infection and its antiviral responses. We systematically investigated acute responses in the olfactory mucosa upon exposure to vesicular stomatitis virus (VSV) via RNA-seq. VSVs were nasally inoculated into C57BL/6 mice. Olfactory mucosae were dissected for gene expression analysis at different time points after viral inoculation. Interferon functions were determined by comparing the viral load in interferon receptor knockout ( and ) with wildtype OE. Antiviral responses were observed as early as 24 h after viral exposure in the olfactory mucosa. The rapidly upregulated transcripts observed included specific type I as well as type III interferons () and interferon-stimulated genes. Genetic analyses demonstrated that both type I and type III IFN signaling are required for the suppression of viral replication in the olfactory mucosa. Exogenous IFN application effectively blocks viral replication in the OE. These findings reveal that the OE possesses an innate ability to suppress viral infection. Type I and type III IFNs have prominent roles in OE antiviral functions.
Topics: Animals; Mice; Interferon Lambda; Mice, Inbred C57BL; Interferons; Olfactory Mucosa; Virus Diseases; Virus Replication; Antiviral Agents
PubMed: 38136633
DOI: 10.3390/biom13121762 -
Nature Jan 2024Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of...
Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of approximately 2,000 or more OR alleles. OR gene choice is mediated by a multichromosomal enhancer hub that activates transcription at a single OR, followed by OR-translation-dependent feedback that stabilizes this choice. Here, using single-cell genomics, we show formation of many competing hubs with variable enhancer composition, only one of which retains euchromatic features and transcriptional competence. Furthermore, we provide evidence that OR transcription recruits enhancers and reinforces enhancer hub activity locally, whereas OR RNA inhibits transcription of competing ORs over distance, promoting transition to transcriptional singularity. Whereas OR transcription is sufficient to break the symmetry between equipotent enhancer hubs, OR translation stabilizes transcription at the prevailing hub, indicating that there may be sequential non-coding and coding mechanisms that are implemented by OR alleles for transcriptional prevalence. We propose that coding OR mRNAs possess non-coding functions that influence nuclear architecture, enhance their own transcription and inhibit transcription from their competitors, with generalizable implications for probabilistic cell fate decisions.
Topics: Alleles; Cell Lineage; Enhancer Elements, Genetic; Gene Expression Regulation; Olfactory Receptor Neurons; Receptors, Odorant; Regulatory Sequences, Nucleic Acid; RNA; Transcription, Genetic; Genomics; Single-Cell Analysis
PubMed: 38123679
DOI: 10.1038/s41586-023-06845-4 -
BMC Biology Dec 2023Olfactory sensory neurons detect odourants via multiple long cilia that protrude from their dendritic endings. The G protein-coupled receptor GPRC5C was identified as...
BACKGROUND
Olfactory sensory neurons detect odourants via multiple long cilia that protrude from their dendritic endings. The G protein-coupled receptor GPRC5C was identified as part of the olfactory ciliary membrane proteome, but its function and localization is unknown.
RESULTS
High-resolution confocal and electron microscopy revealed that GPRC5C is located at the base of sensory cilia in olfactory neurons, but not in primary cilia of immature neurons or stem cells. Additionally, GPRC5C localization in sensory cilia parallels cilia formation and follows the formation of the basal body. In closer examination, GPRC5C was found in the ciliary transition zone. GPRC5C deficiency altered the structure of sensory cilia and increased ciliary layer thickness. However, primary cilia were unaffected. Olfactory sensory neurons from Gprc5c-deficient mice exhibited altered localization of olfactory signalling cascade proteins, and of ciliary phosphatidylinositol-4,5-bisphosphat. Sensory neurons also exhibited increased neuronal activity as well as altered mitochondrial morphology, and knockout mice had an improved ability to detect food pellets based on smell.
CONCLUSIONS
Our study shows that GPRC5C regulates olfactory cilia composition and length, thereby controlling odour perception.
Topics: Animals; Mice; Cilia; Mice, Knockout; Odorants; Olfactory Receptor Neurons; Receptors, G-Protein-Coupled; Smell
PubMed: 38110903
DOI: 10.1186/s12915-023-01790-0 -
ELife Dec 2023Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the...
Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this 'privileged' repertoire. Our experiments identify early transcription as a potential 'epigenetic' contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.
Topics: Animals; Mice; Receptors, Odorant; Olfactory Receptor Neurons; Epigenomics; Alleles; Epigenesis, Genetic
PubMed: 38108811
DOI: 10.7554/eLife.87445 -
Journal of Neuroinflammation Dec 2023The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's...
BACKGROUND
The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD.
METHODS
To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air-liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing.
RESULTS
Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation.
CONCLUSIONS
The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.
Topics: Humans; SARS-CoV-2; COVID-19; Anosmia; Neuroinflammatory Diseases; Alzheimer Disease; Olfactory Mucosa
PubMed: 38098019
DOI: 10.1186/s12974-023-02979-4 -
Nature Communications Dec 2023In numerous insects, the olfactory receptor family forms a unique class of heteromeric cation channels. Recent progress in resolving the odorant receptor structures...
In numerous insects, the olfactory receptor family forms a unique class of heteromeric cation channels. Recent progress in resolving the odorant receptor structures offers unprecedented opportunities for deciphering their molecular mechanisms of ligand recognition. Unexpectedly, these structures in apo or ligand-bound states did not reveal the pathway taken by the ligands between the extracellular space and the deep internal cavities. By combining molecular modeling with electrophysiological recordings, we identified amino acids involved in the dynamic entry pathway and the binding of VUAA1 to Drosophila melanogaster's odorant receptor co-receptor (Orco). Our results provide evidence for the exact location of the agonist binding site and a detailed and original mechanism of ligand translocation controlled by a network of conserved residues. These findings would explain the particularly high selectivity of Orcos for their ligands.
Topics: Animals; Receptors, Odorant; Drosophila melanogaster; Ligands; Olfactory Receptor Neurons; Drosophila; Translocation, Genetic
PubMed: 38081900
DOI: 10.1038/s41467-023-44058-5 -
Current Biology : CB Dec 2023Olfactory coding, from insects to humans, is canonically considered to involve considerable across-fiber coding already at the peripheral level, thereby allowing...
Olfactory coding, from insects to humans, is canonically considered to involve considerable across-fiber coding already at the peripheral level, thereby allowing recognition of vast numbers of odor compounds. We show that the migratory locust has evolved an alternative strategy built on highly specific odorant receptors feeding into a complex primary processing center in the brain. By collecting odors from food and different life stages of the locust, we identified 205 ecologically relevant odorants, which we used to deorphanize 48 locust olfactory receptors via ectopic expression in Drosophila. Contrary to the often broadly tuned olfactory receptors of other insects, almost all locust receptors were found to be narrowly tuned to one or very few ligands. Knocking out a single receptor using CRISPR abolished physiological and behavioral responses to the corresponding ligand. We conclude that the locust olfactory system, with most olfactory receptors being narrowly tuned, differs from the so-far described olfactory systems.
Topics: Animals; Humans; Odorants; Grasshoppers; Smell; Olfactory Receptor Neurons; Receptors, Odorant; Insecta
PubMed: 38070506
DOI: 10.1016/j.cub.2023.11.017