Single-cell RNA-Seq reveals the heterogeneity of fibroblasts within the tympanojugular paraganglioma microenvironment.

Tympanojugular paragangliomas (TJP) originate from the parasympathetic ganglia in the lateral base of the skull. Although the cellular composition and oncogenic mechanisms of paragangliomas have been evaluated, a comprehensive transcriptomic atlas specific to TJP remains to be established to facilitate further investigations. In this study, single-cell RNA sequencing and whole-exome sequencing were conducted on six surgically excised TJP samples to determine their cellular composition and intratumoral heterogeneity. Fibroblasts were sub-classified into two distinct groups: myofibroblasts and fibroblasts associated with bone remodeling. Additionally, an elaborate regulatory and cell-cell communication network was determined, highlighting the multifaceted role of fibroblasts, which varies depending on expression transitions. The Kit receptor (KIT) signaling pathway mediated interactions between fibroblasts and mast cells, whereas robust connections with endothelial and Schwann cell-like cells were facilitated through the platelet-derived growth factor signaling pathway. These findings establish a foundation for studying the mechanisms underlying protumor angiogenesis and the specific contributions of fibroblasts within the TJP microenvironment. IL6 signaling pathway of fibroblasts interacting with macrophages and endothelial cells may be involved in tumor regrowth. These results enhance our understanding of fibroblast functionality and provide a resource for future therapeutic targeting of TJP.

[Endothelial cells and fibroblasts mediate the microenvironmental regulatory network of carotid body paraganglioma].

Objective:To explore the gene expression characteristics of endothelial cells and fibroblasts in the microenvironment of SDHD-mutated carotid body tumors（SDHD-CBT）, to fine the functional enrichment of each subcluster, and to further explore the network of cell-cell interactions in the microenvironment of SDHD-CBT. Methods:The bioinformatics analysis was used to download and reanalyze the single-nuclear RNA sequencing data of SDHD-CBT, SDHB mutated thoracic and abdominal paraganglioma（SDHB-ATPGL）, SDHB-CBT, and normal adrenal medulla（NAM）, to clarify the information of cell populations of the samples. We focused on exploring the gene expression profiles of endothelial cells and fibroblasts subclusters, and performed functional enrichment analysis based on Gene Ontology（GO） resources. CellChat was used to compare the cell-cell interactions networks of different clinical samples and predict significant signaling pathways in SDHD-CBT. Results:A total of 7 cell populations were profiled. The main subtypes of endothelial cells in SDHD-CBT are arterial and venous endothelial cells, and the main subtypes of fibroblasts are myofibroblasts and pericytes. Compared to NAM, SDHB-CBT and SDHB-ATPGL, cell communication involving endothelial cells and fibroblasts in SDHD-CBT is more abundant, with significant enrichment in pathways such as FGF, PTN, WNT, PROS, PERIOSTIN, and TGFb. Conclusion:Endothelial cells and fibroblasts in SDHD-CBT are heterogeneous and involved in important cellular interactionprocesses, in which the discovery of FGF，PTN，WNT，PROS，PERIOSTIN and TGFb signals may play an important role in the regulation of microenvironment of SDHD-CBT.

Obstructive Sleep Apnea Syndrome Exacerbates NASH Progression via Selective Autophagy-Mediated Eepd1 Degradation.

Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non-alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH-exposed mice, which deviates from human responses. To address this issue, a pair-feeding investigation with CIH-exposed and normoxia-exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome-wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver-specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH-induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH-mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH-mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS.

EEG Emotion Recognition Network Based on Attention and Spatiotemporal Convolution.

Human emotions are complex psychological and physiological responses to external stimuli. Correctly identifying and providing feedback on emotions is an important goal in human-computer interaction research. Compared to facial expressions, speech, or other physiological signals, using electroencephalogram (EEG) signals for the task of emotion recognition has advantages in terms of authenticity, objectivity, and high reliability; thus, it is attracting increasing attention from researchers. However, the current methods have significant room for improvement in terms of the combination of information exchange between different brain regions and time-frequency feature extraction. Therefore, this paper proposes an EEG emotion recognition network, namely, self-organized graph pesudo-3D convolution (SOGPCN), based on attention and spatiotemporal convolution. Unlike previous methods that directly construct graph structures for brain channels, the proposed SOGPCN method considers that the spatial relationships between electrodes in each frequency band differ. First, a self-organizing map is constructed for each channel in each frequency band to obtain the 10 most relevant channels to the current channel, and graph convolution is employed to capture the spatial relationships between all channels in the self-organizing map constructed for each channel in each frequency band. Then, pseudo-three-dimensional convolution combined with partial dot product attention is implemented to extract the temporal features of the EEG sequence. Finally, LSTM is employed to learn the contextual information between adjacent time-series data. Subject-dependent and subject-independent experiments are conducted on the SEED dataset to evaluate the performance of the proposed SOGPCN method, which achieves recognition accuracies of 95.26% and 94.22%, respectively, indicating that the proposed method outperforms several baseline methods.

ST-TGR: Spatio-Temporal Representation Learning for Skeleton-Based Teaching Gesture Recognition.

Teaching gesture recognition is a technique used to recognize the hand movements of teachers in classroom teaching scenarios. This technology is widely used in education, including for classroom teaching evaluation, enhancing online teaching, and assisting special education. However, current research on gesture recognition in teaching mainly focuses on detecting the static gestures of individual students and analyzing their classroom behavior. To analyze the teacher's gestures and mitigate the difficulty of single-target dynamic gesture recognition in multi-person teaching scenarios, this paper proposes skeleton-based teaching gesture recognition (ST-TGR), which learns through spatio-temporal representation. This method mainly uses the human pose estimation technique RTMPose to extract the coordinates of the keypoints of the teacher's skeleton and then inputs the recognized sequence of the teacher's skeleton into the MoGRU action recognition network for classifying gesture actions. The MoGRU action recognition module mainly learns the spatio-temporal representation of target actions by stacking a multi-scale bidirectional gated recurrent unit (BiGRU) and using improved attention mechanism modules. To validate the generalization of the action recognition network model, we conducted comparative experiments on datasets including NTU RGB+D 60, UT-Kinect Action3D, SBU Kinect Interaction, and Florence 3D. The results indicate that, compared with most existing baseline models, the model proposed in this article exhibits better performance in recognition accuracy and speed.

Deletion of speA and aroC genes impacts the pathogenicity of Vibrio anguillarum in spotted sea bass.

Vibrio anguillarum is one of the major pathogens responsible for bacterial infections in marine environments, causing significant impacts on the aquaculture industry. The misuse of antibiotics leads to bacteria developing multiple drug resistances, which is detrimental to the development of the fisheries industry. In contrast, live attenuated vaccines are gradually gaining acceptance and widespread recognition. In this study, we constructed a double-knockout attenuated strain, V. anguillarum ΔspeA-aroC, to assess its potential for preparing a live attenuated vaccine. The research results indicate a significant downregulation of virulence-related genes, including Type VI secretion system, Type II secretion system, biofilm synthesis, iron uptake system, and other related genes, in the mutant strain. Furthermore, the strain lacking the genes exhibited a 67.47% reduction in biofilm formation ability and increased sensitivity to antibiotics. The mutant strain exhibited significantly reduced capability in evading host immune system defenses and causing in vivo infections in spotted sea bass (Lateolabrax maculatus), with an LD50 that was 13.93 times higher than that of the wild-type V. anguillarum. Additionally, RT-qPCR analysis of immune-related gene expression in spotted sea bass head kidney and spleen showed a weakened immune response triggered by the knockout strain. Compared to the wild-type V. anguillarum, the mutant strain caused reduced levels of tissue damage. The results demonstrate that the deletion of speA and aroC significantly reduces the biosynthesis of biofilms in V. anguillarum, leading to a decrease in its pathogenicity. This suggests a crucial role of biofilms in the survival and invasive capabilities of V. anguillarum.

Unexpected enhancement of sulfuric acid-driven new particle formation by alcoholic amines: The role of ion-induced nucleation.

New particle formation (NPF) contributes more than half of the global aerosol. Diethanolamine (DEA) and methyldiethanolamine (MDEA) are the most common amines used to remove CO2 and H2S, which are lost to the atmosphere from CO2 chemical absorbers, livestock and consumer products and are involved in sulfuric acid (SA)-driven NPF. Ion-induced nucleation (IIN) is an important nucleation pathway for NPF. We investigated the role of IIN on DEA and MDEA enhancing SA-driven NPF using density functional method (DFT), molecular dynamics (MD) simulation and atmospheric cluster dynamics code (ACDC). The effects of SO42-, H3O+, NH4+, HSO4-, NO3-, ammonia, methylamine, dimethylamine, trimethylamine and water (W) on the nucleation of SA-DEA were further investigated. The enhancement ability of DEA is greater than that of dimethylamine (DMA) and MDEA. Participation in SA-based NPF is a removal pathway for DEA and MDEA. DEA-SA clusters are generated that not only aggregate DEA and SA molecules, but also increase further growth of atmospheric ions. The very low Gibbs formation free energy highlights the importance of ion-induced nucleation for SA-based NPF. The order of the ability of common atmospheric ions to increase the (SA)(DEA) cluster nucleation is SO42- > H3O+ > NH4+ > HSO4- > NO3-. The addition of 20 water molecules increases the (SA)(DEA)9 cluster from 1.882 nm to 2.053 nm, promoting SA-based NPF. The atmospheric ions accelerate the aggregation rate of the (SA)5(DEA)5 cluster within 15 ns?

Effect of adipose tissue-derived stem cells therapy on clinical response in patients with primary Sjogren's syndrome.

The purpose of this trial was to clinically assess the effect and safety of Adipose Tissue-derived Stem Cells (ADSCs) treatment on primary Sjogren's Syndrome (pSS). In this 6-month randomized, triple-blind, placebo-controlled clinical trial, pSS patients were randomly assigned to two groups. After demographic characteristics and clinical examination were achieved, local injection of ADSCs into bilateral glands was performed with patients in ADSCs group (n = 35) and placebo solution was used for another group (n = 39) at three time points. Patients were followed up at 1-, 3- and 6-month. At each visit, studies of clinical and laboratory outcomes, as well as subjective symptoms, were conducted. A total of 74 subjects who met the including criteria were allocated in two groups and eventually 64 subjects (86.5%) completed the treatments and the follow-up assessments. Secretion of salivary and lachrymal glands were significantly improved in 3-month (P < 0.05). A great improvement of European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) was found after ADSCs treatment with intergroup comparison from baseline to follow-up (P < 0.05). There is also a significant difference of European Alliance of Associations for Rheumatology SS Patient Reported Index (ESSPRI) between the two groups in the follow-up (P < 0.05). A significant abatement of IgG, IgM, C3, C4 and ESR between two groups was observed in part of follow-up time points (P < 0.05). The ADSCs therapy can provide relief of oral and eye's dryness in our trial in a short time and has potential improvement of subjective and systemic syndromes of pSS.

Adenoid lymphocyte heterogeneity in pediatric adenoid hypertrophy and obstructive sleep apnea.

Introduction: Adenoid hypertrophy is the main cause of obstructive sleep apnea in children. Previous studies have suggested that pathogenic infections and local immune system disorders in the adenoids are associated with adenoid hypertrophy. The abnormalities in the number and function of various lymphocyte subsets in the adenoids may play a role in this association. However, changes in the proportion of lymphocyte subsets in hypertrophic adenoids remain unclear. Methods: To identify patterns of lymphocyte subsets in hypertrophic adenoids, we used multicolor flow cytometry to analyze the lymphocyte subset composition in two groups of children: the mild to moderate hypertrophy group (n = 10) and the severe hypertrophy group (n = 5). Results: A significant increase in naïve lymphocytes and a decrease in effector lymphocytes were found in severe hypertrophic adenoids. Discussion: This finding suggests that abnormal lymphocyte differentiation or migration may contribute to the development of adenoid hypertrophy. Our study provides valuable insights and clues into the immunological mechanism underlying adenoid hypertrophy.

Mechanistic understanding of rapid H2SO4-HNO3-NH3 nucleation in the upper troposphere.

The upper troposphere (UT) nucleation is thought to be responsible for at least one-third of the global cloud condensation nuclei. Although NH3 was considered to be extremely rare in the UT, recent studies show that NH3 is convected aloft, promoting H2SO4-HNO3-NH3 rapid nucleation in the UT during the Asian monsoon. In this study, the roles of HNO3, H2SO4 (SA), and NH3 in the nucleation of SA-HNO3-NH3 were investigated by quantum chemical calculation and molecular dynamic (MD) simulations at the level of M06-2×/6-31 + G (d, p). The nucleation ability of SA-HNO3-NH3 is suppressed as the temperature increases in the UT. The results indicated that bisulfate (HSO4-), nitrate (NO3-), and ammonium (NH4+) ionized from SA, HNO3, and NH3, respectively, can significantly enhance the nucleation ability of SA-HNO3-NH3. In addition, hydrated hydrogen ion (H3O+) as well as sulfate ions (SO42-) ionized by SA can also actively participate in the process of ion-induced nucleation. The results reveal that the enhancement effect of five ions on the SA-HNO3-NH3 nucleation can be ordered as follows: SO42- > H3O+ > HSO4- > NO3- > NH4+. Many ion-induced nucleation pathways of SA-HNO3-NH3 with the Gibbs free energies of formation (ΔG) lower than -100 kcal mol-1 were energetically favorable. HNO3 and NH3 can promote the nucleation of SA-HNO3-NH3 and water (W) molecules are also beneficial to promote the new particle formation (NPF) of SA-HNO3-NH3. Under the action of H-bonds and electrostatic interaction, ion-induced nucleation could lead to the rapid nucleation of H2SO4-HNO3-NH3 in the UT.

Multifunctional Evaluation Technology for Diagnosing Malfunctions of Regional Pelvic Floor Muscles Based on Stretchable Electrode Array Probe.

The pelvic floor dysfunction (PFD) has become a serious public health problem. Accurate diagnosis of regional pelvic floor muscle (PFM) malfunctions is vitally important for the prevention and treatment of PFD. However, there is a lack of reliable diagnostic devices to evaluate and diagnose regional PFM abnormality. In this work, we developed a multifunctional evaluation technology (MET) based on a novel airbag-type stretchable electrode array probe (ASEA) for the diagnosis of malfunctions of regional PFM. The inflatable ASEA has specifically distributed 32 electrodes along the muscles, and is able to adapt to different human bodies for tight contact with the muscles. These allow synchronous collection of high-quality multi-channel surface electromyography (MC-sEMG) signals, and then are used to diagnose regional PFM malfunctions and evaluate inter-regional correlation. Clinical trial was conducted on 15 postpartum stress urinary incontinence (PSUI) patients and 15 matched asymptomatic women. Results showed that SUI patients responded slowly to the command and have symptoms of muscle strength degeneration. The results were consistent with the relevant clinical manifestations, and proved the reliability of MET for multifunctional PFM evaluation. Furthermore, the MET can diagnose malfunctions of regional PFM, which is inaccessible with existing technology. The results also showed that the dysfunction of PSUI patients is mainly located in iliococcygeus, pubococcygeus, and urethral sphincter regions, and there is a weak correlation between these specific regions and nearby regions. In conclusion, MET provides a point-of-care diagnostic method for abnormal function of regional PFM, which has a potential for the targeted point-to-point electrical stimulation treatment and PFD pathology research.

Effect of endodontic treatment on clinical outcome in type 2 diabetic patients with apical periodontitis.

Background: Previous research has demonstrated that poor controlled diabetic showed higher prevalence of AP compared to well-controlled patients and endodontic treatment may improve metabolic control of patients with diabetes. The purpose of this trial was to clinically assess the effects of endodontic treatment on glycemic control in patients with type 2 diabetes mellitus (T2DM) and apical periodontitis (AP). Study design: For present trial, AP + T2DM with patients insulin injection (Group1, G1,n = 65), AP + T2DM patients with hypoglycaemic agents (Group2, G2, n = 82), and AP patients without DM (Group3, G3, n = 86) were enrolled. After demographic characteristics and clinical examination were achieved, root canal treatment (RCT) was performed for each patient. Subjects were followed up at 2-week, 3- and 6-month. At each visit, blood samples were taken and clinical laboratory studies were performed. At 6-month follow-up, Periapical Index (PAI) score was used to assess the periapical status. Results: A total of 237 subjects who met the including criteria were allocated in three groups and 223 subjects (94.1%) completed the treatments and the follow-up assessments. After treatment, taking PAI into consideration, both groups showed significant improvement of AP in each group (P < 0.05). Patients in G3 had a continued significant lower concentration of fasting plasma glucose (FPG) levels at follow-up (P < 0.05). A continued reduction of hemoglobin glycation (HbA1c) was observed in most of time points (P < 0.05). Throughout the trial, there are also significant changes in inflammatory factors in short-term. Conclusion: Endodontic therapy improved AP healing, glycemic control and systemic inflammation in patients with T2DM and/or AP in each group. However, a continued reduction in inflammatory factors and decreasing of HbA1c in short-term could not be observed in this trial.

Functional Cooperation of α-Synuclein and Tau Is Essential for Proper Corticogenesis.

Alpha-synuclein (αSyn) and tau are abundant multifunctional neuronal proteins, and their intracellular deposits have been linked to many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Despite the disease relevance, their physiological roles remain elusive, as mice with knock-out of either of these genes do not exhibit overt phenotypes. To reveal functional cooperation, we generated αSyn-/-tau-/- double-knock-out mice and characterized the functional cross talk between these proteins during brain development. Intriguingly, deletion of αSyn and tau reduced Notch signaling and accelerated interkinetic nuclear migration of G2 phase at early embryonic stage. This significantly altered the balance between the proliferative and neurogenic divisions of progenitor cells, resulting in an overproduction of early born neurons and enhanced neurogenesis, by which the brain size was enlarged during the embryonic stage in both sexes. On the other hand, a reduction in the number of neural progenitor cells in the middle stage of corticogenesis diminished subsequent gliogenesis in the αSyn-/-tau-/- cortex. Additionally, the expansion and maturation of macroglial cells (astrocytes and oligodendrocytes) were suppressed in the αSyn-/-tau-/- postnatal brain, which in turn reduced the male αSyn-/-tau-/- brain size and cortical thickness to less than the control values. Our study identifies important functional cooperation of αSyn and tau during corticogenesis.SIGNIFICANCE STATEMENT Correct understanding of the physiological functions of αSyn and tau in CNS is critical to elucidate pathogenesis involved in the etiology of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. We show here that αSyn and tau are cooperatively involved in brain development via maintenance of progenitor cells. αSyn and tau double-knock-out mice exhibited an overproduction of early born neurons and accelerated neurogenesis at early corticogenesis. Furthermore, loss of αSyn and tau also perturbed gliogenesis at later embryonic stage, as well as the subsequent glial expansion and maturation at postnatal brain. Our findings provide new mechanistic insights and extend therapeutic opportunities for neurodegenerative diseases caused by aberrant αSyn and tau.

Single-Cell RNA-Seq Reveals Heterogeneity of Cell Communications between Schwann Cells and Fibroblasts within Vestibular Schwannoma Microenvironment.

Vestibular schwannomas (VSs), which develop from Schwann cells (SCs) of the vestibular nerve, are the most prevalent benign tumors of the cerebellopontine angle and internal auditory canal. Despite advances in treatment, the cellular components and mechanisms of VS tumor progression remain unclear. Herein, single-cell RNA-sequencing was performed on clinically surgically isolated VS samples and their cellular composition, including the heterogeneous SC subtypes, was determined. Advanced bioinformatics analysis revealed the associated biological functions, pseudotime trajectory, and transcriptional network of the SC subgroups. A tight intercellular communication between SCs and tumor-associated fibroblasts via integrin and growth factor signaling was observed and the gene expression differences in SCs and fibroblasts were shown to determine the heterogeneity of cellular communication in different individuals. These findings suggest a microenvironmental mechanism underlying the development of VS.

Comprehensive Analysis of N6-Methyladenosine Regulators in the Subcluster Classification and Drug Candidates Prediction of Severe Obstructive Sleep Apnea.

Background: Obstructive sleep apnea (OSA) is the most common type of sleep apnea that impacts the development or progression of many other disorders. Abnormal expression of N6-methyladenosine (m6A) RNA modification regulators have been found relating to a variety of human diseases. However, it is not yet known if m6A regulators are involved in the occurrence and development of OSA. Herein, we aim to explore the impact of m6A modification in severe OSA. Methods: We detected the differentially expressed m6A regulators in severe OSA microarray dataset GSE135917. The least absolute shrinkage and selection operator (LASSO) and support vector machines (SVM) were used to identify the severe OSA-related m6A regulators. Receiver operating characteristic (ROC) curves were performed to screen and verify the diagnostic markers. Consensus clustering algorithm was used to identify m6A patterns. And then, we explored the character of immune microenvironment, molecular functionals, protein-protein interaction networks and miRNA-TF coregulatory networks for each subcluster. Finally, the Connectivity Map (CMap) tools were used to tailor customized treatment strategies for different severe OSA subclusters. An independent dataset GSE38792 was used for validation. Results: We found that HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1 and IGF2BP3 were dysregulated in severe OSA patients. Among them, IGF2BP3 has a high diagnostic value in both independent datasets. Furthermore, severe OSA patients can be accurately classified into three m6A patterns (subcluster1, subcluster2, subcluster3). The immune response in subcluster3 was more active because it has high M0 Macrophages and M2 Macrophages infiltration and up-regulated human leukocyte antigens (HLAs) expression. Functional analysis showed that representative genes for each subcluster in severe OSA were assigned to histone methyltransferase, ATP synthesis coupled electron transport, virus replication, RNA catabolic, multiple neurodegeneration diseases pathway, et al. Moreover, our finding demonstrated cyclooxygenase inhibitors, several of adrenergic receptor antagonists and histamine receptor antagonists might have a therapeutic effect on severe OSA. Conclusion: Our study presents an overview of the expression pattern and crucial role of m6A regulators in severe OSA, which may provide critical insights for future research and help guide appropriate prevention and treatment options.

Lis1 mutation prevents basal radial glia-like cell production in the mouse.

Human cerebral cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe perturbation of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that disruption of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.

Metabolomics and microbiome profiling as biomarkers in obstructive sleep apnoea: a comprehensive review.

INTRODUCTION: Obstructive sleep apnoea (OSA) is a common sleep disorder with a high social and economic burden. Thus, early prediction and diagnosis of OSA are important. Changes in metabolism and the microbiome may serve as biomarkers for OSA. Herein, we review the literature on the metabolomic and microbiome changes associated with OSA, and identify the metabolites and microorganisms involved. METHODS: We searched the PUBMED and EMBASE electronic databases using the following terms: "obstructive sleep apnea", "OSA", "sleep disordered breathing", "SDB", "intermittent hypoxia", "sleep fragmentation", and either "metabolomics" or "microbiome". In total, 273 papers were identified, of which 28 were included in our study. RESULTS: Changes in the levels of certain metabolites related to fatty acid, carbohydrate and amino acid metabolism were associated with the incidence of OSA. The diversity and abundance of microflora, particularly Firmicutes and Bacteroidetes, were altered in humans and rodents with OSA. CONCLUSIONS: Certain changes in metabolism and the microbiota play an integral role in the pathophysiology of OSA and OSA-induced cardiovascular complications. Metabolomic and microbiome biomarkers shed light on the pathogenesis of OSA, and facilitate early diagnosis and treatment.

A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma.

PURPOSE: Glutamine plays an important role in tumor metabolism and progression. This research aimed to find out how Gln exert their effects on laryngeal squamous cell carcinoma (LSCC). METHODS: Cell proliferation was measured by CCK8 and EdU assay, mitochondrial bioenergetic activity was measured by mitochondrial stress tests. Gene expression profiling was revealed by RNA sequencing and validated by RT-qPCR. In LSCC patients, protein expression in tumor and adjacent tissues was examined and scored by IHC staining. RNAi was performed by stably expressed shRNA in TU177 cells. In vivo tumor growth analysis was performed using a nude mouse tumorigenicity model. RESULTS: Gln deprivation suppressed TU177 cell proliferation, which was restored by αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. In LSCC patients, the expression of CECR2 in tumors was lower than adjacent tissues. Furthermore, deficiency of CECR2 promoted tumor cell growth both in vitro and in vivo, suggesting it has tumor suppressor effects. Besides, cell proliferation inhibited by Gln withdrawal could be restored by CECR2 depletion, and the proliferation boosted by αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG's effect on tumor growth. Transcriptomic profiling revealed CECR2 regulated the expression of a series of genes involved in tumor progression. CONCLUSION: We confirmed the Gln-αKG-CECR2 axis contributes to tumor growth in LSCC. This finding provided a potential therapeutic opportunity for the use of associated metabolites as a potential treatment for LSCC.

Circ-ITCH restrains the expression of MMP-2, MMP-9 and TNF-α in diabetic retinopathy by inhibiting miR-22.

Diabetic retinopathy (DR), the most frequent complication of diabetes mellitus, is the principal cause of acquired blindness worldwide. Although the roles of circRNAs have been extensively explored, the detailed physiological and pathological functions of circRNAs in DR are less understood. Here, we studied the biological effects of circ-ITCH in diabetic retinal pigment epithelial cells (RPEs) and explored the underlying mechanisms. As our results shown, the RNA expression of circ-ITCH was significantly lower in RPEs isolated from diabetic rats than they were in those isolated from normal rats. While diabetes induced an increase in MMP-2, MMP-9 and TNF-α in RPEs, circ-ITCH overexpression exerted an inhibitory on these increases and knockdown of circ-ITCH reversed the inhibitory. In addition, increased expression of miR-22 in RPEs correlated with diabetes and downregulation of circ-ITCH. Remarkably, in the presence of miR-22 mimics, the effects of circ-ITCH on the MMP-2 and MMP-9 were both antagonized. Collectively, our data supports a cellular signaling cascade in which circ-ITCH-inhibited miR-22 activity modulates the expression of MMP-2, MMP-9 and TNF-α in DR.

Nitric Oxide Mediates Inflammation in Type II Diabetes Mellitus through the PPARγ/eNOS Signaling Pathway.

Inflammation accounts for the process of type II diabetes mellitus (T2DM), the specific mechanism of which is still to be elucidated yet. Nitric oxide (NO), a critical inflammation regulator, the role of which is the inflammation of T2DM, is rarely reported. Therefore, our study is aimed at exploring the effect of NO on the inflammation in T2DM and the corresponding mechanism. We analyzed the NO levels in plasma samples from T2DM patients and paired healthy adults by Nitric Oxide Analyzer then measured the expression of inflammatory cytokines (C-reactive protein, heptoglobin, IL-1ß, TNF-α, IL-6) in insulin-induced HepG2 cells treated with NO donor or NO scavenger, and the PPARγ, eNOS, C-reactive protein, heptoglobin, IL-1ß, TNF-α, and IL-6 levels were detected by RT-PCR and western blot in insulin-induced HepG2 cells transfected with si-PPARγ. The results showed that excess NO increased the inflammation marker levels in T2DM, which is activated by the PPARγ/eNOS pathway. These findings will strengthen the understanding of NO in T2DM and provide a new target for the treatment of T2DM.