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Ling-Yun Bao,* Xin-Yue Dao,* Kun Du Department of Neonate, Kun Ming Children’s Hospital, Yunnan, 650021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun Du, Department of Neonate, Kun Ming Children’s Hospital, No. 28 of Shulin Road, Yunnan, 650021, People’s Republic of China, Tel +86 15388843393, Email kdidljtdr_09@outlook.comAbstract: Neonatal respiratory distress syndrome (NRDS) is a common critical disease in neonates. Early diagnosis and timely treatment are crucial. Historically, X-ray imaging was the primary method for diagnosing NRDS. However, this method carries radiation exposure risks, making it unsuitable for dynamic lung condition monitoring. In addition, neonates who are critically ill require bedside imaging, but diagnostic delays are often unavoidable due to equipment transportation and positioning limitations. These challenges have been resolved with the introduction of lung ultrasound (LUS) in neonatal intensive care. The diagnostic efficacy and specificity of LUS for NRDS is superior to that of X-ray. The non-invasive, dynamic, and real-time benefits of LUS also allow for real-time monitoring of lung changes throughout treatment for NRDS, yielding important insights for guiding therapy. In this paper, we examine the ultrasonographic characteristics of NRDS and the recent progress in the application of ultrasound in the diagnosis and treatment of NRDS while aiming to promote wider adoption of this method.Keywords: dynamic monitoring, lung ultrasound, neonates, respiratory distress syndrome, NRDS, point of care ultrasound

Abstract Host organisms use different innate immune mechanisms to defend against pathogenic infections, while tight control of innate immunity is essential for proper immune induction and balance. Here, we reported that apoptotic induction or caspase-3 overexpression caused dramatic reduction of differently triggered cytokine signalings in human cells, murine primary cells and mouse model, while the loss of caspase-3 or inhibiting apoptosis markedly enhances these immune signalings. Furthermore, caspase-3 can mediate the cleavage of NF-κB members p65/RelA, RelB, and c-Rel via its protease activity. And the caspase-3-resistant p65/RelA, RelB, or c-Rel mutant mostly restored the caspase-3-induced suppression of cytokine production. Interestingly, we further uncovered that apoptotic induction also dramatically inhibited Toll immune signaling in Drosophila, and the Drosophila effector caspases, drICE and DCP-1, also mediated the degradation of DIF, the NF-κB of Toll signaling. Together, our findings demonstrate apoptotic effector caspases, including mammalian caspase-3 and fly drICE/DCP-1, can function as repressors of NF-κB-mediated innate immune signalings.

Summary: RNA interference (RNAi) is a well-established antiviral immunity. However, for mammalian somatic cells, antiviral RNAi becomes evident only when viral suppressors of RNAi (VSRs) are disabled by mutations or VSR-targeting drugs, thereby limiting its scope as a mammalian immunity. We find that a wild-type alphavirus, Semliki Forest virus (SFV), triggers the Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs) in both mammalian somatic cells and adult mice. These SFV-vsiRNAs are located at a particular region within the 5′ terminus of the SFV genome, Argonaute loaded, and active in conferring effective anti-SFV activity. Sindbis virus, another alphavirus, also induces vsiRNA production in mammalian somatic cells. Moreover, treatment with enoxacin, an RNAi enhancer, inhibits SFV replication dependent on RNAi response in vitro and in vivo and protects mice from SFV-induced neuropathogenesis and lethality. These findings show that alphaviruses trigger the production of active vsiRNA in mammalian somatic cells, highlighting the functional importance and therapeutic potential of antiviral RNAi in mammals.

Rubella virus (RuV) is the infectious agent of a series of birth defect diseases termed congenital rubella syndrome, which is a major public health concern all around the world. RNA interference (RNAi) is a crucial antiviral defense mechanism in eukaryotes, and numerous viruses have been found to encode viral suppressors of RNAi (VSRs) to evade antiviral RNAi response. However, there is little knowledge about whether and how RuV antagonizes RNAi. In this study, we identified that the RuV capsid protein is a potent VSR that can efficiently suppress shRNA- and siRNA-induced RNAi in mammalian cells. Moreover, the VSR activity of the RuV capsid is dependent on its dimerization and double-stranded RNA (dsRNA)-binding activity. In addition, ectopic expression of the RuV capsid can effectively rescue the replication defect of a VSR-deficient virus or replicon, implying that the RuV capsid can act as a VSR in the context of viral infection. Together, our findings uncover that RuV encodes a VSR to evade antiviral RNAi response, which expands our understanding of RuV–host interaction and sheds light on the potential therapeutic target against RuV.

The present study is proposed based on two important practical issues. First, brand image is one essential aspect of building the brand of a business. Second, with the development of the internet, social media has become a revolution for people worldwide to communicate, connect, create, and share their content and opinions in a dynamic and flexible way. Customers use their social networks to discuss online their reviews, and recommendations regarding product quality and customer service of a brand. Based on these two practical issues, the present study employs Netnography as the research method to explore aspects of the brand image of Cocoon from customers’ perspectives, with the following objectives: (1) explore aspects of Cocoon’s brand image, (2) describe customers’ perspective of these aspects, and (3) propose suggestions for Cocoon to improve its brand image from the viewpoint of customers. The study is conducted by combining in-depth interview data and Netnography data. Then the thematic analysis is undertaken as an approach to Analysing data. The research findings result from the interviews with 07 customers and Netnography data from 49 posts on 08 communities on Facebook. Among 15 explored aspects of Cocoon’s brand, there are 08 aspects of Cocoon, which are reviewed and discussed frequently, including quality, reputation, price, packaging, brand aspects, usefulness, influencer marketing, and seeding. Based on the research findings, several solutions are proposed to improve its brand image for Cocoon.

Background: It is challenging to correctly identify and diagnose breast nonmass lesions. This study aimed to explore the multimodal ultrasound features associated with malignant breast nonmass lesions (NMLs), and evaluate their combined diagnostic performance., Methods: This retrospective analysis was conducted on 573 breast NMLs, including 309 were benign and 264 were malignant, their multimodal ultrasound features (B-mode, color Doppler and strain elastography) were assessed by two experienced radiologists. Univariate and multivariate logistic regression analysises were used to explore multimodal ultrasound features associated with malignancy, and a nomogram was developed. Diagnostic performance and clinical utility were evaluated and validated by the receiver operating characteristic (ROC) curve, calibration curve and decision curve in the training and validation cohorts., Results: Multimodal ultrasound features including linear (odds ratio [OR] = 4.69) or segmental distribution (OR = 7.67), posterior shadowing (OR = 3.14), calcification (OR = 7.40), hypovascularity (OR = 0.38), elasticity scored 4 (OR = 7.00) and 5 (OR = 15.77) were independent factors associated with malignant breast NMLs. The nomogram based on these features exhibited diagnostic performance in the training and validation cohorts were comparable to that of experienced radiologists, with superior specificity (89.4%, 89.5% vs. 81.2%) and positive predictive value (PPV) (89.2%, 90.4% vs. 82.4%). The nomogram also demonstrated good calibration in both training and validation cohorts (all P > 0.05). Decision curve analysis indicated that interventions guided by the nomogram would be beneficial across a wide range of threshold probabilities (0.05-1 in the training cohort and 0.05-0.93 in the validation cohort)., Conclusions: The combined use of linear or segmental distribution, posterior shadowing, calcification, hypervascularity and high elasticity score, displayed as a nomogram, demonstrated satisfied diagnostic performance for malignant breast NMLs, which may contribute to the imaging interpretation and clinical management of tumors., (© 2024. The Author(s).)

Background: Automated Breast Ultrasound (AB US) has shown good application value and prospects in breast disease screening and diagnosis. The aim of the study was to explore the ability of AB US to detect and diagnose mammographically Breast Imaging Reporting and Data System (BI-RADS) category 4 microcalcifications., Methods: 575 pathologically confirmed mammographically BI-RADS category 4 microcalcifications from January 2017 to June 2021 were included. All patients also completed AB US examinations. Based on the final pathological results, analyzed and summarized the AB US image features, and compared the evaluation results with mammography, to explore the detection and diagnostic ability of AB US for these suspicious microcalcifications., Results: 250 were finally confirmed as malignant and 325 were benign. Mammographic findings including microcalcifications morphology (61/80 with amorphous, coarse heterogeneous and fine pleomorphic, 13/14 with fine-linear or branching), calcification distribution (189/346 with grouped, 40/67 with linear and segmental), associated features (70/96 with asymmetric shadow), higher BI-RADS category with 4B (88/120) and 4 C (73/38) showed higher incidence in malignant lesions, and were the independent factors associated with malignant microcalcifications. 477 (477/575, 83.0%) microcalcifications were detected by AB US, including 223 malignant and 254 benign, with a significantly higher detection rate for malignant lesions (x 2  = 12.20, P < 0.001). Logistic regression analysis showed microcalcifications with architectural distortion (odds ratio [OR] = 0.30, P = 0.014), with amorphous, coarse heterogeneous and fine pleomorphic morphology (OR = 3.15, P = 0.037), grouped (OR = 1.90, P = 0.017), liner and segmental distribution (OR = 8.93, P = 0.004) were the independent factors which could affect the detectability of AB US for microcalcifications. In AB US, malignant calcification was more frequent in a mass (104/154) or intraductal (20/32), and with ductal changes (30/41) or architectural distortion (58/68), especially with the both (12/12). BI-RADS category results also showed that AB US had higher sensitivity to malignant calcification than mammography (64.8% vs. 46.8%)., Conclusions: AB US has good detectability for mammographically BI-RADS category 4 microcalcifications, especially for malignant lesions. Malignant calcification is more common in a mass and intraductal in AB US, and tend to associated with architectural distortion or duct changes. Also, AB US has higher sensitivity than mammography to malignant microcalcification, which is expected to become an effective supplementary examination method for breast microcalcifications, especially in dense breasts., (© 2024. The Author(s).)

Introduction: Whether lung ultrasound (LUS) can be used for pathogenic diagnosis remains controversial. This study was conducted to clarify whether ultrasound has diagnostic value for etiology., Methods: A total of 135 neonatal pneumonia patients with an identified pathogen were enrolled from the newborn intensive care units of 10 tertiary hospitals in China. The study ran from November 2020 to December 2021. The infants were divided into various groups according to pathogens, time of infection, gestational age, and disease severity. The distribution of pleural line abnormalities, B-line signs, and pulmonary consolidation, as well as the incidence of air bronchogram and pleural effusion based on LUS, were compared between these groups., Results: There were significant differences in pulmonary consolidation. The sensitivity and specificity of the diagnosis of severe pneumonia based on the extent of pulmonary consolidation were 83.3% and 85.2%, respectively. The area under the receiver operating characteristic curve for the identification of mild or severe pneumonia based on the distribution of pulmonary consolidation was 0.776., Conclusion: LUS has good performance in diagnosing and differentiating the severity of neonatal pneumonia but cannot be used for pathogenic identification in the early stages of pneumonia., (© 2022 Wiley Periodicals LLC.)

Background: Long non-coding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Abnormally expressed lncRNA can be used as a diagnostic marker for cancer. In this study, we aim to investigate the clinical significance of MIR99AHG expression in lung adenocarcinoma (LUAD), and its biological roles in LUAD progression., Methods: The relative expression of MIR99AHG in LUAD tissues and cell lines was analyzed using public databases and RT-qPCR. The biological functions of MIR99AHG were investigated using a loss-of-function approach. The effect of MIR99AHG on lung fibrosis was assessed by scratch assay, invasion assay and lung fibrosis rat model. FISH, luciferase reporter assay and immunofluorescence were performed to elucidate the underlying molecular mechanisms., Results: LncRNA MIR99AHG expression level was downregulated in LUAD tissues and cell lines. Low MIR99AHG levels were associated with poorer patient overall survival. Functional analysis showed that MIR99AHG is associated with the LUAD malignant phenotype in vitro and in vivo. Further mechanistic studies showed that, MIR99AHG functions as a competitive endogenous RNA (ceRNA) to antagonize miR-136-5p-mediated ubiquitin specific protease 4 (USP4) degradation, thereby unregulated the expression of angiotensin-converting enzyme 2 (ACE2), a downstream target gene of USP4, which in turn affected alveolar type II epithelial cell fibrosis and epithelial-mesenchymal transition (EMT). In summary, the MIR99AHG/miR-136-5p/USP4/ACE2 signalling axis regulates lung fibrosis and EMT, thus inhibiting LUAD progression., Conclusion: This study showed that downregulated MIR99AHG leads to the development of pulmonary fibrosis. Therefore, overexpression of MIR99AHG may provide a new approach to preventing LUAD progression., (© 2022. The Author(s).)

The present study investigated the influence of heating and honey addition on the appearance, chemical component content, and pharmacological activity of Codonopsis Radix decoction pieces in the honey-frying process, and explored the processing mechanism of honey-fried Codonopsis Radix. The color, sweetness, and content of macromolecular components(e.g., oligosaccharides and polysaccharides) and small molecular components(e.g., lobetyolin and atractylenolide Ⅲ) of raw Codonopsis Radix, fried Codonopsis Radix, honey-mixed Codonopsis Radix, and honey-fried Codonopsis Radix were determined, and the antioxidant activities in vitro of their water extract, polysaccharide extract, and oligosaccharide extract were compared. The results showed that in terms of color and sweetness, compared with the raw Codonopsis Radix, the fried Codonopsis Radix slightly changed, the honey-mixed Codonopsis Radix changed significantly, and the honey-fried Codonopsis Radix changed with high significance. In terms of the content of lobetyolin, atractylenolide Ⅲ, and polysaccharides, the samples were ranked as raw Codonopsis Radix &gt; fried Codonopsis Radix &gt; honey-mixed Codonopsis Radix &gt; honey-fried Codonopsis Radix, which indicated that heating and honey addition could reduce the content of these three components. In terms of the content of oligosaccharides, the samples were ranked as honey-fried Codonopsis Radix ≈ honey-mixed Codonopsis Radix &gt; fried Codonopsis Radix ≈ raw Codonopsis Radix, indicating that honey addition could increase the content of oligosaccharides. In terms of antioxidant activity in vitro, ABTS radical scavenging ability of water extract, polysaccharides, and oligosaccharides of honey-fried Codonopsis Radix was most potent, while the change of antioxidant activity in vitro of each extract in the other three processed products was different. In short, both heating and honey addition can affect the appearance, chemical component content, and antioxidant activity in vitro of Codonopsis Radix decoction pieces, but the effect of the combination of the two factors is the best. The comprehensive analysis of the effects of heating and honey addition on Codonopsis Radix decoction pieces indicates that honey addition followed by heating at high temperature is the necessary condition for honey-fried Codonopsis Radix to enhance its activity.

Photoredox/transition-metal dual catalysis could efficiently construct C-N bonds by a cross-coupling reaction. The limitations of low recovery, low utilization rate and high cost have hindered the application and development of low-cost and efficient transition metal catalytic cycles. The integration of heterogeneous metal and transition metal catalysis is an appealing alternative to realize the oxidation state modulation of active species. With the support of density functional theory (DFT) calculation, we have explored the mechanistic details of Ni-catalyzed C-N cross-coupling of aryl bromide and cyclic amine assisted by zinc powder. Zinc successfully regulates the oxidation state of Ni II → Ni I , thus achieving the Ni I -Ni III -Ni I catalytic cycle in the absence of light. In comparison, when the Ni(0) complex is employed as the initial catalyst, organic zinc reagents can still be involved in the transmetalation process to accelerate the cross-coupling reaction. We hope that such computational studies can provide theoretical reference for the design and development of low-cost and efficient catalytic systems for C-N cross-couplings.

Bladder cancer (BLCA) is one of the common malignant tumors of the urinary system. The poor prognosis of BLCA patients is due to the lack of early diagnosis and disease recurrence after treatment. Increasing evidence suggests that gene products of the nuclear factor of activated T-cells (NFAT) family are involved in BLCA progression and subsequent interaction(s) with immune surveillance. In this study, we carried out a pan-cancer analysis of the NFAT family and found that NFAT2 is an independent prognostic factor for BLCA. We then screened for differentially expressed genes (DEGs) and further analyzed such candidate gene loci using gene ontology enrichment to curate the KEGG database. We then used Lasso and multivariate Cox regression to identify 4 gene loci (FER1L4, RNF128, EPHB6, and FN1) which were screened together with NFAT2 to construct a prognostic model based on using Kaplan-Meier analysis to predict the overall survival of BLCA patients. Moreover, the accuracy of our proposed model is supported by deposited datasets in the Gene Expression Omnibus (GEO) database. Finally, a nomogram of this prognosis model for BLCA was established which could help to provide better disease management and treatment.

Background: Foxp3 + CD4 + regulatory T cells (Treg) constitutes a key event in autoimmune diseases. STAT5b is the critical link between the IL-2/15 and FOXP3, the master regulator of Treg cells., Methods: The CD3 + T cell and Foxp3 + CD4 + regulatory T cells were overexpressioned or knockdown MKL-1 and STAT5a and tested for Treg cell development and function. Direct interaction of MKL-1 and STAT5a were analyzed by coimmunoprecipitation assays, Luciferase assay, Immunofluoresence Staining and Yeast two-hybrid screening. The effect of MKL-1 and STAT5a on the Treg genes expression was analyzed by qPCR and western blotting and Flow cytometry., Results: However, the molecular mechanisms mediating STAT5b-dependent Treg genes expression and Treg cell phenotype and function in autoimmune diseases are not well defined. Here, we report that the MKL-1 is a coactivator for the major Treg genes transcription factor STAT5b, which is required for human Treg cell phenotype and function. The N terminus of STAT5b, which contains a basic coiled-coil protein-protein interaction domain, binds the C-terminal activation domain of MKL-1 and enhances MKL-1 mediated transcriptional activation of Treg-specific, CArG containing promoters, including the Treg-specific genes Foxp3. Suppression of endogenous STAT5b expression by specific small interfering RNA attenuates MKL-1 transcriptional activation in cultured human cells. The STAT5b-MKL-1 interaction identifies a role of Treg-specific gene regulation and regulated mouse Treg cell development and function and suggests a possible mechanism for the protective effects of autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP)., Conclusions: Our studies demonstrate for the first time that MKL-1 is a coactivator for STAT5b, the regulator of Treg cell development and function. Video abstract.

Background Deep learning (DL) algorithms are gaining extensive attention for their excellent performance in image recognition tasks. DL models can automatically make a quantitative assessment of complex medical image characteristics and achieve increased accuracy in diagnosis with higher efficiency. Purpose To determine the feasibility of using a DL approach to predict clinically negative axillary lymph node metastasis from US images in patients with primary breast cancer. Materials and Methods A data set of US images in patients with primary breast cancer with clinically negative axillary lymph nodes from Tongji Hospital (974 imaging studies from 2016 to 2018, 756 patients) and an independent test set from Hubei Cancer Hospital (81 imaging studies from 2018 to 2019, 78 patients) were collected. Axillary lymph node status was confirmed with pathologic examination. Three different convolutional neural networks (CNNs) of Inception V3, Inception-ResNet V2, and ResNet-101 architectures were trained on 90% of the Tongji Hospital data set and tested on the remaining 10%, as well as on the independent test set. The performance of the models was compared with that of five radiologists. The models' performance was analyzed in terms of accuracy, sensitivity, specificity, receiver operating characteristic curves, areas under the receiver operating characteristic curve (AUCs), and heat maps. Results The best-performing CNN model, Inception V3, achieved an AUC of 0.89 (95% confidence interval [CI]: 0.83, 0.95) in the prediction of the final clinical diagnosis of axillary lymph node metastasis in the independent test set. The model achieved 85% sensitivity (35 of 41 images; 95% CI: 70%, 94%) and 73% specificity (29 of 40 images; 95% CI: 56%, 85%), and the radiologists achieved 73% sensitivity (30 of 41 images; 95% CI: 57%, 85%; P = .17) and 63% specificity (25 of 40 images; 95% CI: 46%, 77%; P = .34). Conclusion Using US images from patients with primary breast cancer, deep learning models can effectively predict clinically negative axillary lymph node metastasis. Artificial intelligence may provide an early diagnostic strategy for lymph node metastasis in patients with breast cancer with clinically negative lymph nodes. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Bae in this issue.

Qingxuan Jiangya Decoction (QXJYD), prescribed by academician Ke-ji Chen, has long been used as a Traditional Chinese Medicine formula in blood pressure control and has achieved good clinical outcomes in hypertensive patients. Qingda granules (QDGs), which is a formula simplified from QXJYD, might serve as a novel anti-hypertensive pharmaceutical. However, the functional mechanism of QDGs remains unclear. This study aimed to evaluate the effect of QDGs against the elevation of blood pressure, systemic inflammation and brain injury in Ang II-mediated hypertensive mice. Ang II-mediated hypertensive mice were treated with 28.63mg QDG of per mouse every day. The blood pressure of all mice was measured on days 0, 1, 3, 5, 7, 14 and 28 by using the tail-cuff plethysmograph method. Following 28 days of treatment, the mice were sacrificed and their whole blood and brain tissues were used for analysis. The results showed that QDGs significantly decreased elevated systolic and diastolic blood pressure in Ang II-mediated hypertensive mice while body weight did not change, which demonstrated anti-hypertensive activities of QDGs without obvious toxicity. QDGs significantly attenuated the level of serum cytokines (IL-6, TNF-a) and chemokines (MCP-1, MIP-1a, RANTES) in the Ang II-mediated hypertensive mice. Moreover, pathological staining showed that QDGs significantly ameliorated cerebral histopathology changes, reduced the loss of neurons and activations of astrocytes. Additionally, QDGs inhibited neuronal apoptosis by down-regulation of Bax expression and up-regulation of Bcl-2 expression. These results suggested that QDGs exhibited excellent anti-hypertensive properties by preventing systemic inflammation and providing neuroprotective effects against Ang II-mediated hypertension.

The purpose of this study was to investigate the diagnostic performance of the automated breast ultrasound system (ABUS) compared with hand-held ultrasonography (HHUS) and mammography (MG) for breast cancer in women aged 40 y or older. A total of 594 breasts in 385 patients were enrolled in the study. HHUS, ABUS and MG exams were performed for these patients. Follow-up and pathologic findings were used as the reference standard. Based on the reference standard, 519 units were benign or normal and 75 were malignant. The sensitivity, specificity, accuracy and Youden index were 97.33%, 89.79%, 90.74% and 0.87 for HHUS; 90.67%, 92.49%, 92.26% and 0.83 for ABUS; 84.00%, 92.87%, 91.75% and 0.77 for MG, respectively. The specificity of ABUS was significantly superior to that of HHUS (p = 0.024). The area under the receiver operating characteristic curve was 0.936 for HHUS, which was the highest, followed by 0.916 for ABUS and 0.884 for MG. However, the difference was not statistically significant (p > 0.05). In conclusion, the diagnostic performance of ABUS for breast cancer was equivalent to HHUS and MG and potentially can be used as an alternative method for breast cancer diagnosis., (Copyright © 2019. Published by Elsevier Inc.)

A beam-scanning terahertz (THz) radiation mechanism in a free-electron-driven grating system is proposed for THz applications. By loading a period-asynchronous rod array above the grating, the spoof surface plasmon (SSP) originally excited by the electron changes its radiation characteristics owing to the rod-induced Brillouin zone folding effect. The rod array functions as an antenna and converts the SSP into a spatial coherent THz radiation. The radiation frequency and direction can be precisely controlled by the electron energy. The field intensity of the radiation is increased approximately 20 times compared with that of the conventional Smith-Purcell radiation in the same frequency range. In addition, a microwave-band scaling prototype is fabricated and the frequency-controlled radiation is measured. Excellent agreement between the experimental and simulated results is obtained. This study paves the way for the development of on-chip THz sources for advanced communication and detection applications.

Background: Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. But the exact molecular mechanism of ERα-36 and STAT3 on metastasis is still not fully understood., Methods: MCF-7 and MDA-MB-231 human breast cancer cell lines and MCF-10A were overexpressioned or knockdown ERα-36 and STAT3 and tested for migration, invasion and proliferation assays. Direct interaction of STAT3 and ERα-36 were analyzed by coimmunoprecipitation assays. The effect of STAT3 and ERα-36 on MMP2/9 expression was analyzed by qPCR and western blotting. STAT3 phospholyation and acetylation by ERα-36 and p300 were observed and quantified by coimmunoprecipitation assays and western blotting., Results: Cross-talk between ERα-36 and STAT3 was demonstrated to mediate through a direct physical association between the two proteins. Furthermore, the interaction between ERα-36 and STAT3 was demonstrated to give rise to functional changes in their signaling events. Both MMP2 and MMP9 expression require the binding of the newly identified protein complex, ERα-36-STAT3, to its promoter, the second phase, which is more robust, depends on ERα-mediated recruitment of p300 onto the complex and the subsequent acetylation of STAT3. In addition, STAT3 is tyrosine-phosphorylated in a biphasic manner, and the late phase requires ERα-36-mediated p300-dependent acetylation. Furthermore, interference with acetylation of STAT3 by overexpression of acetylation null STAT3 mutant led to the loss of MMP2 and MMP9 expression. ChIP analysis and reporter gene assays revealed that ERα-36-STAT3 complex binding to the MMP2 and MMP9 promoter led to an enhanceosome formation and facilitated MMP2 and MMP9 expression., Conclusions: Our studies demonstrate for the first time that the function of MMP2 and MMP9 in breast cancer cell migration, which is mediated by interactions between ERα-36 and STAT3.

Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a-5p/Stat3/hnRNP-A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 expression, hnRNP-A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a-5p, which functionally targets Stat3, whereas hnRNP-A1 blocks the biogenesis of let-7a-5p to counteract its ability to downregulate the Stat3/hnRNP-A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP-A1/PKM2 by let-7a-5p is verified using a breast cancer. These results suggest that let-7a-5p, Stat3, and hnRNP-A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention., (© 2018 Wiley Periodicals, Inc.)

An unprecedented zeolite supramolecular framework featuring truncated cuboctahedral and truncated octahedral cavities was self-assembled from tetrahedral metal-organic cationic cages and tetrahedral anions. This crystalline porous material could trap iodine and organic dye molecules, and its solid state spin-crossover behavior was affected by guest encapsulation.

Four pairs of chiral supramolecular coordination cages were facilely synthesized, and they could efficiently inhibit amyloid-β (Aβ) aggregation with a high inhibition rate of 0.64-0.86. This research provides a new perspective on the design of chiral Aβ inhibitors using supramolecular metal-organic cages.

Importance: The crtierion standard method for monitoring intracranial pressure (ICP) can result in complications and pain. Hence, noninvasive, repeatable methods would be valuable., Objective: To examine how ultrasonographic optic nerve sheath diameter (ONSD) correlated with noninvasive and dynamically monitored ICP changes., Design, Setting, and Participants: The ONSD was measured before the lumbar puncture (LP) in 60 patients on admission. Patients with elevated ICP were divided into group 1 (200 < LP ≤ 300 mm H2O) and group 2 (LP > 300 mm H2O). Patients underwent follow-up ONSD and LP measurements within 1 month. We analyzed the correlations between the ONSD and ICP on admission and between the changes in ONSD and ICP, which were the respective changes in ONSD and ICP from admission to follow-up., Main Outcomes and Measures: The ultrasonographic ONSD and ICP were measured on admission and follow-up. The correlations between the ONSD and ICP on admission and between the changes in ONSD and ICP were analyzed using Pearson correlation analyses., Results: For 60 patients (Han nationality; mean [SD] age, 36.2 [12.04] years; 29 [48%] female) on admission, the ONSD and ICP values were strongly correlated, with an r of 0.798 (95% CI, 0.709-0.867; P < .001). Twenty-five patients with elevated ICP who completed the follow-up were included. The mean (SD) ONSD and ICP on admission were 4.50 (0.54) mm and 302.40 (54.26) mm H2O, respectively. The ONSD and ICP values obtained on admission were strongly correlated , with an r of 0.724 (95% CI, 0.470-0.876; P < .001). The mean (SD, range) changes in ICP and ONSD were 126.64 (52.51 mm H2O, 20-210 mm H2O) (95% CI, 106.24-146.07) and 1.00 (0.512 mm, 0.418-2.37 mm) (95% CI, 0.83-1.20), respectively. The change in ONSD was strongly correlated with the change in ICP, with an r of 0.702 (95% CI, 0.425-0.870; P < .001). The follow-up evaluations revealed that the elevated ICP and dilated ONSD had returned to normal, and no evidence of difference was found in the mean ONSDs between group 1 (3.49 mm; 95% CI, 3.34-3.62 mm) and group 2 (3.51 mm; 95% CI, 3.44-3.59 mm) (P = .778) at follow-up., Conclusions and Relevance: The dilated ONSDs decreased along with the elevated ICP reduction. Ultrasonographic ONSD measurements may be a useful, noninvasive tool for dynamically evaluating ICP.

Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. Our previous study has shown that MRTF-A promote the migration of MDA-MB-231 cells and WDR1 promotes breast cancer cell migration. But the exact molecular mechanism on metastasis is still not fully understood, we now report that WDR1 enhanced the effect of MRTF-A induced-MDA-MB-231 cell migration by promoting the expression of the EMT markers and migration markers via RhoA-MRTF-A signaling pathway. Importantly, WDR1 promoted the nuclear importion of MRTF-A by affecting the expression of nuclear transport protein importin. But WDR1 did not affect the expression of MRTF-A. Interestingly, MRTF-A promoted the expression of miR-206 via its promoter CArG box but miR-206 inhibits the migration of breast cancer cells through suppressing the expression of WDR1 and MRTF-A via targeted their 3'UTR. Our data thus provide important and novel insights into MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Myocardin is regarded as a key mediator for the change of smooth muscle phenotype. The gap junction protein connexin 43 (Cx43) has been shown to be involved in vascular smooth muscle cells (VSMCs) proliferation and the development of atherosclerosis. However, the role of myocardin on gap junction of cell communication and the relation between myocardin and Cx43 in VSMC phenotypic switch has not been investigated. The goal of the present study is to investigate the molecular mechanism by which myocardin affects Cx43-regulated VSMC proliferation. Data presented in this study demonstrated that inhibition of the Cx43 activation process impaired VSMC proliferation. On the other hand, overexpression miR-206 inhibited VSMC proliferation. In additon, miR-206 silences the expression of Cx43 via targeting Cx43 3' Untranslated Regions. Importantly, myocardin can significantly promote the expression of miR-206. Cx43 regulates VSMCs' proliferation and metastasis through miR-206, which could be promoted by myocardin and used as a marker for diagnosis and a target for therapeutic intervention. Thus myocardin affected the gap junction by inhibited Cx43 and myocardin-miR-206-Cx43 formed a loop to regulate VSMC phenotypic switch., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Vascular endothelial growth factor A (VEGF-A) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and vascular smooth muscle cell (VSMC) proliferation, yet very little is known about the actual signaling events that mediate VEGF-A induced VSMC phenotypic switch. In this report, we describe the identification of an intricate VEGF-A-induced signaling cascade that involves VEGFR2, STAT3, and Myocardin. We demonstrate that VEGF-A promotes VSMC proliferation via VEGFR2/STAT3-mediated upregulating the proliferation of markers like Cyclin D1 and PCNA. Specifically, VEGF-A leads to nitrosylation of Myocardin, weakens its effect on promoting the expression of contractile markers and is unable to inhibit the activation of STAT3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for VEGF-A-induced VSMC phenotypic switch. In addition, Myocardin, GSNOR and GSNO can create a negative feedback loop to regulate the VSMC phenotypic switch. Thus, the discovery of this interactive network of signaling pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

Four pairs of enantiomers of water-stable tetrahedral metal-organic cages [Ni4L6](8+) were facilely synthesized. They efficiently stabilized antiparallel G-quadruplex DNA with moderate enantioselectivity, and displayed promising cytotoxicity against the human cancer cell lines HCT116, HepG2 and MCF-7. These results provide a new insight into the rational design of chiral G-quadruplex-based anticancer agents.

The JAK-STAT3 signaling pathway is one of the critical pathways regulating cell proliferation, differentiation, and apoptosis. Myocardin is regarded as a key mediator for the change of smooth muscle phenotypes. However, the relationship between STAT3 and myocardin in the vascular smooth muscle cell (VSMC) phenotypic switch has not been investigated. The goal of this study was to investigate the molecular mechanism by which STAT3 affects the myocardin-regulated VSMC phenotypic switch. Data presented in this study demonstrated that STAT3 was rapidly up-regulated after stimulation with VEGF. Inhibition of the STAT3 activation process impaired VSMC proliferation and enhanced the expression of VSMC contractile genes by increasing serum-response factor binding to the CArG-containing regions of VSMC-specific contractile genes. In contrast, the interaction between serum-response factor and its co-activator myocardin was reduced by overexpression of STAT3. In addition, treated VEGF inhibited the transcription activity of myocardin, and overexpression of STAT3 inhibited myocardin-induced up-regulation of VSMC contractile phenotype-specific genes. Although myocardin and STAT3 are negatively correlated, interestingly, both of them can enhance the expression of VEGF, suggesting a feedback loop to regulate the VSMC phenotypic switch. Taken together, these results indicate that the JAK-STAT3 signaling pathway plays a key role in controlling the phenotypic switch of VSMCs through the interactions between STAT3 and myocardin by various coordinated gene regulation pathways and feedback loops., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

In order to identify the chemical constituents of Yushu tablets comprehensively, we studied the chemical constituents of CHCl3 extract from Yushu tablets by the ultra performance liquid chromatography-electrospray ionization-ion trap-time of flight mass spectrometry (UPLC-ESI-IT-TOF/MS). It showed that there were more than 100 compounds separated, and forty-nine peaks among these were identified on the basis of high resolution mass spectrometry data and literature data reported. Determination of twelve peaks was further confirmed by standard substances. These components assigned to the different plant sources mainly included phenylpropanoids, triterpenoids, quinones and m-trihydroxybenzene compounds. By analyzing the chemical components of CHCl3 extract from compound Chinese medicine Yushu tablets comprehensively, this study provided the foundation for studying chemical components, pharmacodynamic substance and quality control of Yushu tablets.

The aim of the present study was to investigate the histopathological changes and wound healing process of rabbit corneas following conventional laser in situ keratomileusis (LASIK) with and without the complication of flap macrostriae. The right eyes of 14 rabbits underwent LASIK with the formation of flap striae (macrostriae group) and the left underwent LASIK alone (control group). Two rabbits were selected at random for sacrifice on days 1, 3, 7 and 14, and at 1, 3 and 6 months postoperatively. The histopathological characters of the corneas were compared by hematoxylin and eosin (H&E), periodic acid-Schiff (PAS) and Masson staining. In the control group, the epithelial basement membrane of the cornea exhibited microstriae and the arrangement of stromal collagen fibers was regular. The width of the microstriae in the flap was 20-40 μm one week after surgery and the microstriae were no longer visible two weeks postoperatively. In the macrostriae group, infiltration of polymorphonuclear cells occurred around the incision and irregular hyperplasia of the epithelium was observed due to undulation of the epithelial basement membrane on the first postoperative day. The collagen fibers and striae of the corneal stroma exhibited irregular undulation one month postoperatively. The area between the corneal flap and stromal bed was distinctly stained by PAS and Masson stains. Macrostriae with a width of 80-120 μm affecting two-thirds of the entire cornea remained visible six months postoperatively. In conclusion, the inflammatory reactions and clinical impact of flap macrostriae were severe. Macrostriae involving two-thirds of the entire cornea remained visible six months postoperatively. Longer-term studies are required to further elucidate the issues associated with corneal flap striae.