circMTO1/miR-30c-5p/SOCS3 axis alleviates oral submucous fibrosis through inhibiting fibroblast-myofibroblast transition.

BACKGROUND: circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF. METHODS: Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH). RESULTS: circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002. CONCLUSION: circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF.

Factors related to microimplant-assisted rapid palatal expansion in teenagers and young adults: A cone-beam computed tomography study.

INTRODUCTION: For patients with maxillary transverse deficiency, selecting an appropriate therapeutic method is important for the treatment effect and prognosis. Our study aimed to explore factors related to microimplant-assisted rapid palatal expansion (MARPE) in teenagers and young adults using cone-beam computed tomography. METHODS: Twenty-five patients who underwent MARPE were included in this retrospective study from February 2014 to June 2019. Midpalatal suture density (MPSD) ratio, midpalatal suture maturation (MPSM), bone effect, dentoalveolar effect, and dental effect in maxillary first molar were evaluated using cone-beam computed tomography. Spearman correlation analysis was used to analyze the correlation between the MPSD ratio, MPSM, age, and the expansion amount generated by MARPE. RESULTS: Twenty-five patients (mean age, 19.84 ± 3.96 years; range, 15-29 years) with maxillary transverse deficiency were analyzed. Age was negatively correlated with bone expansion, alveolar expansion, and alveolar change (all P <0.05). There was a negative correlation between MPSM and nasal cavity variation, bone expansion, and alveolar change (all P <0.05). The bone expansion was negatively correlated with MPSD ratio 3 (r = -0.417; P <0.05) and MPSD ratio 4 (all P <0.05). CONCLUSIONS: Age, MPSM, and MPSD ratio were significantly related to the MARPE effect. Age, MPSM, and MPSD ratio should be considered when choosing MARPE.

Computer science skills across China, India, Russia, and the United States.

We assess and compare computer science skills among final-year computer science undergraduates (seniors) in four major economic and political powers that produce approximately half of the science, technology, engineering, and mathematics graduates in the world. We find that seniors in the United States substantially outperform seniors in China, India, and Russia by 0.76-0.88 SDs and score comparably with seniors in elite institutions in these countries. Seniors in elite institutions in the United States further outperform seniors in elite institutions in China, India, and Russia by ∼0.85 SDs. The skills advantage of the United States is not because it has a large proportion of high-scoring international students. Finally, males score consistently but only moderately higher (0.16-0.41 SDs) than females within all four countries.

RAB-10 Promotes EHBP-1 Bridging of Filamentous Actin and Tubular Recycling Endosomes.

EHBP-1 (Ehbp1) is a conserved regulator of endocytic recycling, acting as an effector of small GTPases including RAB-10 (Rab10). Here we present evidence that EHBP-1 associates with tubular endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] enriched membranes through an N-terminal C2-like (NT-C2) domain, and define residues within the NT-C2 domain that mediate membrane interaction. Furthermore, our results indicate that the EHBP-1 central calponin homology (CH) domain binds to actin microfilaments in a reaction that is stimulated by RAB-10(GTP). Loss of any aspect of this RAB-10/EHBP-1 system in the C. elegans intestinal epithelium leads to retention of basolateral recycling cargo in endosomes that have lost their normal tubular endosomal network (TEN) organization. We propose a mechanism whereby RAB-10 promotes the ability of endosome-bound EHBP-1 to also bind to the actin cytoskeleton, thereby promoting endosomal tubulation.

Role of Xeroderma Pigmentosum Group D in Cell Cycle and Apoptosis in Cutaneous Squamous Cell Carcinoma A431 Cells.

BACKGROUND Cutaneous squamous cell carcinoma (cSCC) is the second most widespread cancer in humans and its incidence is rising. Novel therapy with better efficacy is needed for clinical treatment of cSCC. Many studies have shown the importance of DNA repair pathways during the development of cancer. A key nucleotide excision repair (NER) protein, xeroderma pigmentosum group D (XPD), is responsible for the excision of a large variety of bulky DNA lesions. MATERIAL AND METHODS To explore the role of XPD in A431 cells, we overexpressed XPD in A431 cells and performed MTT assay, flow cytometry, and Western blot analysis to examine cell proliferation, cell apoptosis, and genes expression. RESULTS We found that the overexpression of XPD suppressed cell viability, induced cell cycle arrest at G1 phase, and promoted cell apoptosis. Additionally, XPD blocked the expression of c-myc, cdc25A, and cdk2, and improved the levels of HIPK2 and p53. CONCLUSIONS These results provide new evidence to reveal the role of XPD in cSCC A431 cells and suggest that XPD may serve as an anti-oncogene during cSCC development.

Basolateral Endocytic Recycling Requires RAB-10 and AMPH-1 Mediated Recruitment of RAB-5 GAP TBC-2 to Endosomes.

The small GTPase RAB-5/Rab5 is a master regulator of the early endosome, required for a myriad of coordinated activities, including the degradation and recycling of internalized cargo. Here we focused on the recycling function of the early endosome and the regulation of RAB-5 by GAP protein TBC-2 in the basolateral C. elegans intestine. We demonstrate that downstream basolateral recycling regulators, GTPase RAB-10/Rab10 and BAR domain protein AMPH-1/Amphiphysin, bind to TBC-2 and help to recruit it to endosomes. In the absence of RAB-10 or AMPH-1 binding to TBC-2, RAB-5 membrane association is abnormally high and recycling cargo is trapped in early endosomes. Furthermore, the loss of TBC-2 or AMPH-1 leads to abnormally high spatial overlap of RAB-5 and RAB-10. Taken together our results indicate that RAB-10 and AMPH-1 mediated down-regulation of RAB-5 is an important step in recycling, required for cargo exit from early endosomes and regulation of early endosome-recycling endosome interactions.

Genome-wide gene expression profiling of tongue squamous cell carcinoma by RNA-seq.

OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is significantly more malignant than other type of oral squamous cell carcinoma (OSCC). In this study, we aimed to identify specific global gene expression signatures of TSCC to investigate the more invasive behavior of the deeply infiltrating cancer. METHODS: Using RNA-seq technology, we detected gene expression of 20 TSCCs, 20 matched paratumor tissues, and 10 healthy normal mucosa tissues. Enrichment analysis of gene ontology (GO) and pathway was conducted using online tools DAVID for the dysregulated genes. Additionally, we performed the quantitative real-time RT-PCR (qRT-PCR) to validate the findings of RNA-Seq in 10 samples of TSCC, matched paratumor, and normal mucosa, respectively. RESULTS: We detected 252 differentially expressed genes (DEGs) between TSCC and matched paratumor tissue, including 117 up-regulated and 135 down-regulated genes. For comparison between TSCC and normal mucosa, 234 DEGS were identified, consisting of 67 up-regulated and 167 down-regulated genes. For both two comparisons, GO categories of muscle contraction (GO: 0006936), epidermis development (GO: 0008544), epithelial cell differentiation (GO: 0030855), and keratinization (GO: 0031424) were commonly enriched. Altered gene expression affected some cancer-related pathways, such as tight junction. The qRT-PCR validation showed that gene expression patterns of FOLR1, NKX3-1, TFF3, PIGR, NEFL, MMP13, and HMGA2 were fully in concordance with RNA-Seq results. CONCLUSION: Findings in this study demonstrated the genetic and molecular alterations associated with TSCC, providing new clues for understanding the molecular mechanisms of TSCC pathogenesis.

Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-ß-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12-/- mice. SMCs from P2ry12-/- mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.

Association of MMP-2 gene haplotypes with thoracic aortic dissection in chinese han population.

BACKGROUND: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and MMP-2 is involved in TAD pathogenesis. Our purpose is to systematically evaluate the association of the MMP-2 gene with TAD risk in Chinese Han population. METHODS: In our case-control study, we recruited 755 unrelated participants: 315 case participants with TAD and 440 controls. Twenty-two tag SNPs were selected from MMP-2 gene and were genotyped. Genotype data were analyzed by logistic regression. RESULTS: Although we did not find any significant association for MMP-2 SNPs using single-marker analysis, we identified many windows with haplotype frequencies significantly different between case participants and control participants using a variable-sized sliding-window strategy. In particular, the most significant association was shown by a 2-SNP window consisting of rs2241145 and rs9928731 (omnibus test: asymptotic Pasym = 7.48 × 10 (-5) and empirical Pemp = 0.001867). There were two protective haplotypes: CT (Pasym = 0.00303; odds ratio [OR], 0.403) and GC (Pasym = 0.000976; OR, 0.448). CONCLUSIONS: MMP-2 haplotypes are associated with genetic susceptibility to thoracic aortic dissection in Chinese Han population.

RAB-10-GTPase-mediated regulation of endosomal phosphatidylinositol-4,5-bisphosphate.

Caenorhabditis elegans RAB-10 and mammalian Rab10 are key regulators of endocytic recycling, especially in the basolateral recycling pathways of polarized epithelial cells. To understand better how RAB-10 contributes to recycling endosome function, we sought to identify RAB-10 effectors. One RAB-10-binding partner that we identified, CNT-1, is the only C. elegans homolog of the mammalian Arf6 GTPase-activating proteins ACAP1 and ACAP2. Arf6 is known to regulate endosome-to-plasma membrane transport, in part through activation of type I phophatidylinositol-4-phosphate 5 kinase. Here we show that CNT-1 binds to RAB-10 through its C-terminal ankyrin repeats and colocalizes with RAB-10 and ARF-6 on recycling endosomes in vivo. Furthermore, we find that RAB-10 is required for the recruitment of CNT-1 to endosomal membranes in the intestinal epithelium. Consistent with negative regulation of ARF-6 by RAB-10 and CNT-1, we found overaccumulation of endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in cnt-1 and rab-10 mutants and reduced endosomal PI(4,5)P2 levels in arf-6 mutants. These mutants produced similar effects on endosomal recruitment of the PI(4,5)P2-dependent membrane-bending proteins RME-1/Ehd and SDPN-1/Syndapin/Pacsin and resulted in endosomal trapping of specific recycling cargo. Our studies identify a RAB-10-to-ARF-6 regulatory loop required to regulate endosomal PI(4,5)P2, a key phosphoinositide in membrane traffic.

CED-10/Rac1 regulates endocytic recycling through the RAB-5 GAP TBC-2.

Rac1 is a founding member of the Rho-GTPase family and a key regulator of membrane remodeling. In the context of apoptotic cell corpse engulfment, CED-10/Rac1 acts with its bipartite guanine nucleotide exchange factor, CED-5/Dock180-CED-12/ELMO, in an evolutionarily conserved pathway to promote phagocytosis. Here we show that in the context of the Caenorhabditis elegans intestinal epithelium CED-10/Rac1, CED-5/Dock180, and CED-12/ELMO promote basolateral recycling. Furthermore, we show that CED-10 binds to the RAB-5 GTPase activating protein TBC-2, that CED-10 contributes to recruitment of TBC-2 to endosomes, and that recycling cargo is trapped in recycling endosomes in ced-12, ced-10, and tbc-2 mutants. Expression of GTPase defective RAB-5(Q78L) also traps recycling cargo. Our results indicate that down-regulation of early endosome regulator RAB-5/Rab5 by a CED-5, CED-12, CED-10, TBC-2 cascade is an important step in the transport of cargo through the basolateral recycling endosome for delivery to the plasma membrane.

Association of the polymorphisms of MMP-9 and TIMP-3 genes with thoracic aortic dissection in Chinese Han population.

AIM: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and a shifted balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is involved in TAD pathogenesis. The aim of this study was to evaluate the association of 4 single-nucleotide polymorphisms (SNPs) in MMP-9 and TIMP-3 genes with TAD risk in Chinese Han population. METHODS: A total of 206 Chinese patients with TAD and 180 controls were included in this study. Four SNPs (rs3918249, rs2274756, rs9609643 and rs8136803) were genotyped using high-throughput MALDI-TOF mass spectrometry. Allele and genotype association analyses were conducted using PLINK. RESULTS: All the 4 SNPs resulted in Hardy-Weinberg equilibrium in patients and controls. The G allele frequency for the MMP-9 SNP rs2274756 was significantly higher in female TAD patients than in female controls (P=0.0099). Moreover, after adjusting for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes and smoking habit), the rs2274756 polymorphism (odds ratio: 0.30; 95% confidence interval: 0.11 to 0.79, P=0.015) resulted in an independent susceptibility factor for TAD in females. No associations were found between the other SNPs and TAD. CONCLUSION: The results provide strong evidence for an association between MMP-9 SNP rs2274756 and female TAD risk in Chinese Han population.

Valuation and comparison of the actual and optimal control strategy in an emerging infectious disease: Implication from a COVID-19 transmission model.

To effectively combat emerging infectious diseases like COVID-19, it is crucial to adopt strict prevention and control measures promptly to effectively contain the spread of the epidemic. In this paper, we propose a transmission model to investigate the influence of two control strategies: reducing contact numbers and improving medical resources. We examine these strategies in terms of constant control and time-varying control. Through sensitivity analysis on two reproduction numbers of the model with constant control, we demonstrate that reducing contact numbers is more effective than improving medical resources. Furthermore, these two constant controls significantly influence the peak values and timing of infections. Specifically, intensifying control measures can reduce peak values, albeit at the expense of delaying the peak time. In the model with time-varying control, we initially explore the corresponding optimal control problem and derive the characteristic expression of optimal control. Subsequently, we utilize real data from January 10th to April 12th, 2020, in Wuhan city as a case study to perform parameter estimation by using our proposed improved algorithm. Our findings illustrate that implementing optimal control measures can effectively reduce infections and deaths, and shorten the duration of the epidemic. Then, we numerically explore that implementing control measures promptly and increasing intensity to reduce contact numbers can make actual control be more closer to optimized control. Finally, we utilize the real data from October 31st to November 18th, 2021, in Hebei province as a second case study to validate the feasibility of our proposed suggestions.

Synthesis and characterization of 3-in-1 multifunctional lipiodol-doped Fe3O4@Poly (diallyl isophthalate) microspheres for arterial embolization, chemotherapy, and imaging.

Transcatheter arterial embolization plays a pivotal role in treating various diseases. However, the efficacy of embolization therapy in cancer treatment can be limited by several factors, such as inevitable incomplete or non-target embolization, and the tumor recurrence and metastasis caused by the hypoxic microenvironment. Moreover, it is essential to explore simpler, more economical, and efficient methods for microsphere synthesis. Herein, we achieved one-step photocatalytic synthesis of lipiodol-doped Fe3O4@Poly (diallyliso-phthalate) multifunctional microspheres (IFeD MS) for arterial embolization, chemotherapy, and imaging. The prepared microspheres are in the shape of dried plums, with a particle size of 100-300 µm. Lipiodol demonstrates a certain degree of chemotherapeutic activity, and the incorporation of Fe3O4enables the microspheres to exhibit magnetothermal response and magnetic resonance imaging capabilities. Furthermore, the radiopaque characteristics of both agents provide the microspheres with promising potential for computed tomography and digital radiography imaging. The renal embolization experiment in rabbits demonstrated that IFeD MS achieved significant embolization and chemotherapeutic effects. Biocompatibility experiments revealed that this embolic agent did not induce tissue damage or inflammation beyond the treatment area. Additionally, IFeD MS exhibited promising imaging potential. The results of this study imply that the developed multifunctional embolic agent IFeD MS may have significant potential in transforming tumors previously only suitable for palliative cares into resectable radical treatments.

DP-GAN+B: A lightweight generative adversarial network based on depthwise separable convolutions for generating CT volumes.

X-rays, commonly used in clinical settings, offer advantages such as low radiation and cost-efficiency. However, their limitation lies in the inability to distinctly visualize overlapping organs. In contrast, Computed Tomography (CT) scans provide a three-dimensional view, overcoming this drawback but at the expense of higher radiation doses and increased costs. Hence, from both the patient's and hospital's standpoints, there is substantial medical and practical value in attempting the reconstruction from two-dimensional X-ray images to three-dimensional CT images. In this paper, we introduce DP-GAN+B as a pioneering approach for transforming two-dimensional frontal and lateral lung X-rays into three-dimensional lung CT volumes. Our method innovatively employs depthwise separable convolutions instead of traditional convolutions and introduces vector and fusion loss for superior performance. Compared to prior models, DP-GAN+B significantly reduces the generator network parameters by 21.104 M and the discriminator network parameters by 10.82 M, resulting in a total reduction of 31.924 M (44.17%). Experimental results demonstrate that our network can effectively generate clinically relevant, high-quality CT images from X-ray data, presenting a promising solution for enhancing diagnostic imaging while mitigating cost and radiation concerns.

Inhibition of platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis.

PURPOSE: Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopidogrel could inhibit hypertension-induced cardiac inflammation and fibrosis. METHODS: Using a mouse model of angiotensin II (Ang II) infusion (1,500 ng/[kg·min] for 7 days), we determined the role of platelet activation in Ang II infusion-induced cardiac inflammation and fibrosis using a P2Y12 receptor inhibitor, clopidogrel (50 mg/[kg·day]). RESULTS: CD41 staining showed that platelets accumulated in Ang II-infused hearts. Clopidogrel treatment inhibited Ang II infusion-induced accumulation of α-SMA(+) myofibroblasts and cardiac fibrosis (4.17 ± 1.26 vs. 1.46 ± 0.81, p < 0.05). Infiltration of inflammatory cells, including Mac-2(+) macrophages and CD45(+)Ly6G(+) neutrophils (30.38 ± 4.12 vs. 18.7 ± 2.38, p < 0.05), into Ang II-infused hearts was also suppressed by platelet inhibition. Real-time PCR and immunohistochemical staining showed that platelet inhibition significantly decreased the expression of interleukin-1ß and transforming growth factor-ß. Acute injection of Ang II or PE stimulated platelet activation and platelet-leukocyte conjugation, which were abolished by clopidogrel treatment. CONCLUSION: Thus, inhibition of platelet activation by clopidogrel prevents cardiac inflammation and fibrosis in response to Ang II. Taken together, our results indicate Ang II infusion-induced hypertension stimulated platelet activation and platelet-leukocyte conjugation, which initiated inflammatory responses that contributed to cardiac fibrosis.

Using phonocardiography to investigate maternal cardiac reserve function in gestational hypertension and pre-eclampsia.

AIM: This study used phonocardiography to investigate maternal cardiac reserve function in gestational hypertension and pre-eclampsia. METHOD: Ninety-nine pregnant women with gestational hypertension (50 cases) and pre-eclampsia (49 cases) were included in the study; 99 normotensive pregnant women acted as controls. Using phonocardiography, cardiac reserve function parameters for all participants were recorded: heart rate, the ratio of the first heart sound magnitude to the second heart sound magnitude (S1/S2) and the ratio of the diastolic duration to the systolic duration (D/S). RESULTS: The average values for S1/S2 in the pre-eclampsia and gestational hypertension groups were 4.3±2.2 and 2.2±1.1 respectively. The average D/S of the pre-eclampsia and gestational hypertension groups were 1.1±0.3 and 1.4±0.3 respectively. Cases of postnatal adverse maternal outcomes were only observed in the pre-eclampsia group. A small proportion (2 out of 28) suffered cardiac-related complications, with one of these two patients dying from cardiac failure. Both these cases had notably poor cardiac reserve function (S1/S2>5.00 and D/S<1) before delivery. The index S1/S2 increases and the index D/S decreases with increasing severity of hypertension-complicated pregnancies. CONCLUSIONS: Our findings indicate that cardiac reserve function declines with the increasing severity of hypertension during pregnancy. Phonocardiography is a useful, convenient and clinically worthwhile technique to monitor cardiac reserve function parameters of pregnant women with pre-eclampsia.

SUnet: A multi-organ segmentation network based on multiple attention.

Organ segmentation in abdominal or thoracic computed tomography (CT) images plays a crucial role in medical diagnosis as it enables doctors to locate and evaluate organ abnormalities quickly, thereby guiding surgical planning, and aiding treatment decision-making. This paper proposes a novel and efficient medical image segmentation method called SUnet for multi-organ segmentation in the abdomen and thorax. SUnet is a fully attention-based neural network. Firstly, an efficient spatial reduction attention (ESRA) module is introduced not only to extract image features better, but also to reduce overall model parameters, and to alleviate overfitting. Secondly, SUnet's multiple attention-based feature fusion module enables effective cross-scale feature integration. Additionally, an enhanced attention gate (EAG) module is considered by using grouped convolution and residual connections, providing richer semantic features. We evaluate the performance of the proposed model on synapse multiple organ segmentation dataset and automated cardiac diagnostic challenge dataset. SUnet achieves an average Dice of 84.29% and 92.25% on these two datasets, respectively, outperforming other models of similar complexity and size, and achieving state-of-the-art results.