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EMBO Reports Mar 2024The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B...
The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein's N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome.
Topics: Animals; DNA Methylation; Heterochromatin; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Mutation; Mammals; Primary Immunodeficiency Diseases; Face
PubMed: 38291337
DOI: 10.1038/s44319-024-00061-5 -
Journal of Asthma and Allergy 2018Standardization of the methacholine inhalation challenge, the most common direct bronchoprovocation test, is important. One aspect of standardization is the appropriate... (Review)
Review
Standardization of the methacholine inhalation challenge, the most common direct bronchoprovocation test, is important. One aspect of standardization is the appropriate washout period for pharmacologic agents which affect the response. This review summarizes the available data on pharmacologic inhibition of the methacholine response. Specific (anti-muscarinic) agents demonstrate marked bronchoprotection (up to 7 days for the long-acting drugs) which lasts longer than the duration of bronchodilation. The functional antagonist (beta 2 agonist class of medications) shows marked, but less, bronchoprotection which is relatively short lived and is similar to the duration of bronchodilator efficacy. Tolerance develops quickly, especially to the long-acting agents. Single doses of controller medications, such as inhaled corticosteroids (ICS) and leukotriene receptor antagonists, have no effect on the methacholine test, while regular use, at least for ICS, has a modest protective effect whose duration is uncertain and likely variable. Theophylline has a small effect and H1 blockers (all generations) have a negligible effect.
PubMed: 29785128
DOI: 10.2147/JAA.S160607 -
Three-axis classification of mouse lung mesenchymal cells reveals two populations of myofibroblasts.Development (Cambridge, England) Mar 2022The mesenchyme consists of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling, but are poorly defined...
The mesenchyme consists of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling, but are poorly defined morphologically and molecularly. Leveraging single-cell RNA-sequencing, 3D imaging and lineage tracing, we classify the mouse lung mesenchyme into three proximal-distal axes that are associated with the endothelium, epithelium and interstitium, respectively. From proximal to distal: the vascular axis includes vascular smooth muscle cells and pericytes that transition as arterioles and venules ramify into capillaries; the epithelial axis includes airway smooth muscle cells and two populations of myofibroblasts - ductal myofibroblasts, surrounding alveolar ducts and marked by CDH4, HHIP and LGR6, which persist post-alveologenesis, and alveolar myofibroblasts, surrounding alveoli and marked by high expression of PDGFRA, which undergo developmental apoptosis; and the interstitial axis, residing between the epithelial and vascular trees and sharing the marker MEOX2, includes fibroblasts in the bronchovascular bundle and the alveolar interstitium, which are marked by IL33/DNER/PI16 and Wnt2, respectively. Single-cell imaging reveals a distinct morphology of mesenchymal cell populations. This classification provides a conceptual and experimental framework applicable to other organs.
Topics: Animals; Lung; Mesenchymal Stem Cells; Mesoderm; Mice; Myofibroblasts; Pulmonary Alveoli
PubMed: 35302583
DOI: 10.1242/dev.200081 -
International Journal of Molecular... Jun 2022MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by...
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the effects of different types of continuous hypoxia (moderate or marked) on miRNAs are still poorly studied. Lately, some hypoxia-inducible miRNAs (HRMs, hypoxia-regulated miRNAs) have been identified. These HRMs are often activated in different types of cancers, suggesting their role in tumorigenesis. The aim of this study was to evaluate changes in miRNAs expression both in moderate continuous hypoxia and marked continuous hypoxia to better understand the possible relationship between hypoxia, miRNAs, and colorectal cancer. We used RT-PCR to detect the miRNAs expression in colorectal cancer cell lines in conditions of moderate and marked continuous hypoxia. The expression of miRNAs was analyzed using a two-way ANOVA test to compare the differential expression of miRNAs among groups. The levels of almost all analyzed miRNAs (miR-21, miR-23b, miR-26a, miR-27b, and miR-145) were greater in moderate hypoxia versus marked hypoxia, except for miR-23b and miR-21. This study identified a series of miRNAs involved in the response to different types of continuous hypoxia (moderate and marked), highlighting that they play a role in the development of cancer. To date, there are no other studies that demonstrate how these two types of continuous hypoxia could be able to activate different molecular pathways that lead to a different expression of specific miRNAs involved in tumorigenesis.
Topics: Carcinogenesis; Cell Transformation, Neoplastic; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; MicroRNAs
PubMed: 35682972
DOI: 10.3390/ijms23116294 -
Frontiers in Physiology 2022The recognition of tooth-marked tongues has important value for clinical diagnosis of traditional Chinese medicine. Tooth-marked tongue is often related to spleen...
The recognition of tooth-marked tongues has important value for clinical diagnosis of traditional Chinese medicine. Tooth-marked tongue is often related to spleen deficiency, cold dampness, sputum, effusion, and blood stasis. The clinical manifestations of patients with tooth-marked tongue include loss of appetite, borborygmus, gastric distention, and loose stool. Traditional clinical tooth-marked tongue recognition is conducted subjectively based on the doctor's visual observation, and its performance is affected by the doctor's subjectivity, experience, and environmental lighting changes. In addition, the tooth marks typically have various shapes and colors on the tongue, which make it very challenging for doctors to identify tooth marks. The existing methods based on deep learning have made great progress for tooth-marked tongue recognition, but there are still shortcomings such as requiring a large amount of manual labeling of tooth marks, inability to detect and locate the tooth marks, and not conducive to clinical diagnosis and interpretation. In this study, we propose an end-to-end deep neural network for tooth-marked tongue recognition based on weakly supervised learning. Note that the deep neural network only requires image-level annotations of tooth-marked or non-tooth marked tongues. In this method, a deep neural network is trained to classify tooth-marked tongues with the image-level annotations. Then, a weakly supervised tooth-mark detection network (WSTDN) as an architecture variant of the pre-trained deep neural network is proposed for the tooth-marked region detection. Finally, the WSTDN is re-trained and fine-tuned using only the image-level annotations to simultaneously realize the classification of the tooth-marked tongue and the positioning of the tooth-marked region. Experimental results of clinical tongue images demonstrate the superiority of the proposed method compared with previously reported deep learning methods for tooth-marked tongue recognition. The proposed tooth-marked tongue recognition model may provide important syndrome diagnosis and efficacy evaluation methods, and contribute to the understanding of ethnopharmacological mechanisms.
PubMed: 35492602
DOI: 10.3389/fphys.2022.847267 -
Frontiers in Neurology 2022Inclusion body myositis (IBM) is a progressive muscle disease affecting patients over the age of 40, with distinctive clinical and histopathological features. The... (Review)
Review
Inclusion body myositis (IBM) is a progressive muscle disease affecting patients over the age of 40, with distinctive clinical and histopathological features. The typical clinical phenotype is characterized by prominent involvement of deep finger flexors and quadriceps muscles. Less common presentations include isolated dysphagia, asymptomatic hyper-CKemia, and axial or limb weakness beyond the typical pattern. IBM is associated with marked morbidity as majority of patients eventually become wheelchair dependent with limited use of their hands and marked dysphagia. Furthermore, IBM mildly affects longevity with aspiration pneumonia and respiratory complications being the most common cause of death. On muscle biopsy, IBM is characterized by a peculiar combination of endomysial inflammation, rimmed vacuoles, and protein aggregation. These histopathological features are reflective of the complexity of underlying disease mechanisms. No pharmacological treatment is yet available for IBM. Monitoring for swallowing and respiratory complications, exercise, and addressing mobility issues are the mainstay of management. Further research is needed to better understand disease pathogenesis and identify novel therapeutic targets.
PubMed: 36237625
DOI: 10.3389/fneur.2022.1020113 -
Maedica Dec 2022Patients with sarcoidosis are known to have peripheral blood eosinophilia (PBE). However, most of them had PBE slightly above the upper limit of the normal range. Few...
Patients with sarcoidosis are known to have peripheral blood eosinophilia (PBE). However, most of them had PBE slightly above the upper limit of the normal range. Few patients had increased eosinophils in the bronchoalveolar lavage fluid (BALF), and eosinophilia in BALF enough to be diagnosed as eosinophilic pneumonia (EP) was extremely rare. We present herein a sarcoidosis case with PBE. There were fluctuations in peripheral eosinophils consistent with sarcoidosis disease activity, and peripheral blood eosinophils increased up to 50%, 12500/mm3, although the patient was affected by cough variant asthma and multimodal therapies for breast cancer. Some case reports showed EP in patients with sarcoidosis. To our best knowledge, however, no sarcoidosis patient presented with such a high level of PBE. In this report, we would like to emphasize that there might be patients with sarcoidosis who have a marked increase in peripheral blood eosinophils.
PubMed: 36818266
DOI: 10.26574/maedica.2022.17.4.990 -
Frontiers in Genetics 2021Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes,...
Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes, pathways, and molecular processes implicated in visceral fat deposition in dairy cows. Data from 172 genotyped Holstein cows classified at slaughterhouse as having low ( = 77; omental fold 5 mm in thickness and minimum fat deposition in omentum) or high ( = 95; omental fold 20 mm in thickness and marked fat deposition in omentum) omental fat were analyzed. The identification of regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as , , and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects. These regions harbor genes , and that are directly implicated in adipocyte differentiation, lipid metabolism, and insulin sensitivity. The gene-set analysis revealed functional terms related to cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, and membrane permeability, among other functions. We further evaluated the genetic link between visceral fat and two metabolic disorders, ketosis, and displaced abomasum. For this, we analyzed 28k records of incidence of metabolic disorders from 14k cows across lactations using a single-step genomic BLUP approach. Notably, the region on BTA20 significantly associated with visceral fat deposition was also associated with the incidence of displaced abomasum. Overall, our findings suggest that visceral fat deposition in dairy cows is controlled by both additive and non-additive effects. We detected at least one region with marked pleiotropic effects affecting both visceral fat accumulation and displaced abomasum.
PubMed: 35058972
DOI: 10.3389/fgene.2021.803216 -
Microorganisms Feb 2022The year 2021 marked the thirty-fifth anniversary of the discovery of microbial hemoglobins by Dale Webster and his colleagues [...].
The year 2021 marked the thirty-fifth anniversary of the discovery of microbial hemoglobins by Dale Webster and his colleagues [...].
PubMed: 35208833
DOI: 10.3390/microorganisms10020379 -
PloS One 2023Two experiments (N = 112) were conducted to examine preschoolers' concern for the truth when transmitting information. A first experiment (Pilot Experiment) revealed...
Two experiments (N = 112) were conducted to examine preschoolers' concern for the truth when transmitting information. A first experiment (Pilot Experiment) revealed that 4-year-olds, but not 3-year-olds, selectively transmitted information marked as true versus information marked as false. The second experiment (Main Experiment) showed that 4-year-olds selectively transmitted true information regardless of whether their audience lacked knowledge (Missing Knowledge Context) or information (Missing Information Context) about the subject matter. Children selected more true information when choosing between true versus false information (Falsity Condition) and when choosing between true information versus information the truth of which was undetermined (Bullshit Condition). The Main Experiment also revealed that 4-year-olds shared information more spontaneously, i.e., before being prompted, when it was knowledge, rather than information, the audience was seeking. The findings add to the field's growing understanding of young children as benevolent sharers of knowledge.
Topics: Child, Preschool; Humans; Knowledge; Communication
PubMed: 37104267
DOI: 10.1371/journal.pone.0284694