BRD4L cooperates with MYC to block local tumor invasion via suppression of S100A10.

Targeted therapy based on BRD4 and MYC shows promise due to their well-researched oncogenic functions in cancer, but their tumor-suppressive roles are less understood. In this study, we employ a systematic approach to delete exons that encode the low-complexity domain (LCD) of BRD4L in cells by using CRISPR-Cas9. In particular, the deletion of exon 14 (BRD4-E14) results in cellular morphological changes towards spindle-shaped and loosely packed. BRD4-E14 deficient cells show increased cell migration and reduced cell adhesion. The expression of S100A10 was significantly increased in cells lacking E14. BRD4L binds with MYC via the E14-encoded region of the LCD to inhibit the expression of S100A10. In cancer tissues, there is a positive correlation between BRD4 and MYC, while both of these proteins are negatively associated with S100A10 expression. Finally, knocking out the BRD4-E14 region or MYC promotes tumor growth in vivo. Together, these data support a tumor-suppressive role of BRD4L and MYC in some contexts. This discovery emphasizes the significance of a discreetly design and precise patient recruitment in clinical trials that testing cancer therapy based BRD4 and MYC.

In Situ Infrared Spectroscopic Evidence of Enhanced Electrochemical CO2 Reduction and C-C Coupling on Oxide-Derived Copper.

The reaction mechanism of CO2 electroreduction on oxide-derived copper has not yet been unraveled even though high C2+ Faradaic efficiencies are commonly observed on these surfaces. In this study, we aim to explore the effects of copper anodization on the adsorption of various CO2RR intermediates using in situ surface-enhanced infrared absorption spectroscopy (SEIRAS) on metallic and mildly anodized copper thin films. The in situ SEIRAS results show that the preoxidation process can significantly improve the overall CO2 reduction activity by (1) enhancing CO2 activation, (2) increasing CO uptake, and (3) promoting C-C coupling. First, the strong *COO- redshift indicates that the preoxidation process significantly enhances the first elementary step of CO2 adsorption and activation. The rapid uptake of adsorbed *COatop also illustrates how a high *CO coverage can be achieved in oxide-derived copper electrocatalysts. Finally, for the first time, we observed the formation of the *COCHO dimer on the anodized copper thin film. Using DFT calculations, we show how the presence of subsurface oxygen within the Cu lattice can improve the thermodynamics of C2 product formation via the coupling of adsorbed *CO and *CHO intermediates. This study advances our understanding of the role of surface and subsurface conditions in improving the catalytic reaction kinetics and product selectivity of CO2 reduction.

Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion.

Although the transcriptional regulation of the programmed death ligand 1 (PD-L1) promoter has been extensively studied, the transcription factor residing in the PD-L1 super-enhancer has not been comprehensively explored. Through saturated CRISPR-Cas9 screening of the core region of the PD-L1 super-enhancer, we have identified a crucial genetic locus, referred to as locus 22, which is essential for PD-L1 expression. Locus 22 is a potential binding site for NFE2:MAF transcription factors. Although genetic silencing of NRF2 (NFE2L2) did not result in a reduction of PD-L1 expression, further analysis reveals that MAFG and NFE2L1 (NRF1) play a critical role in the expression of PD-L1. Importantly, lipopolysaccharides (LPS) as the major component of intratumoral bacteria could greatly induce PD-L1 expression, which is dependent on the PD-L1 super-enhancer, locus 22, and NFE2L1/MAFG. Mechanistically, genetic modification of locus 22 and silencing of MAFG greatly reduce BRD4 binding and loop formation but have minimal effects on H3K27Ac modification. Unlike control cells, cells with genetic modification of locus 22 and silencing of NFE2L1/MAFG failed to escape T cell-mediated killing. In breast cancer, the expression of MAFG is positively correlated with the expression of PD-L1. Taken together, our findings demonstrate the critical role of locus 22 and its associated transcription factor NFE2L1/MAFG in super-enhancer- and LPS-induced PD-L1 expression. Our findings provide new insight into understanding the regulation of PD-L1 transcription and intratumoral bacteria-mediated immune evasion.

N4BP1 regulates keratinocytes development and plays protective role in burn- and adhesive-related skin injury via MMP9.

Extensive studies have demonstrated critical roles of Regnase-1 in skin inflammation; however the role of N4BP1, a member of Regnase-1 family, in skin is largely unexplored. Here, we found that N4BP1 was highly expressed in skin and its expression was further increased upon skin injury. Compared to wildtype mice, N4BP1 deficient mice showed severe skin injury upon tape-stripping and burns. Overexpression of N4BP1 in HaCaT cells caused more cuboidal with higher cell-to-cell packing, while reduced expression of N4BP1 made cells become more spindle shaped and loosely packed. Overexpression of N4BP1 promoted cell migration, while silence of N4BP1 reduced migration. N4BP1 deficient HaCaT cells were more sensitive to heats compared to control cells. RNA profiling in N4BP1 genetically modified cells demonstrated that N4BP1 broadly affects cellular behaviors such as epithelium development. RNA profiling, RT-PCR verification, WB analysis and RNA immunoprecipitation demonstrated that MMP9 was one of N4BP1 targets that significantly increased in N4BP1 deficient HaCaT cells and skin tissues. Collectively, our results demonstrate a protective role of N4BP1 in skin injury through broadly affecting cellular behaviors of keratinocytes. Furthermore, we identified MMP9 is a target of N4BP1 in keratinocytes. Our findings provide new insight to understand how N4BP1 protects skin under injury.

A novel dictionary learning-based approach for Ultrasound Elastography denoising.

Ultrasound Elastography is a late-model Ultrasound imaging technique mainly used to diagnose tumors and diffusion diseases that can't be detected by traditional Ultrasound imaging. However, artifact noise, speckle noise, low contrast and low signal-to-noise ratio in images make disease diagnosing a challenging task. Medical images denoising, as the first step in the follow-up processing of medical images, has been concerned by many people. With the widespread use of deep learning technique in the research field, dictionary learning method are once again receiving attention. Dictionary learning, as a traditional machine learning method, requires less sample size, has high training efficiency, and can describe images well. In this work, we present a novel strategy based on K-clustering with singular value decomposition (K-SVD) and principal component analysis (PCA) to reduce noise in Ultrasound Elastography images. At this stage of dictionary training, we implement a PCA method to transform the way dictionary atoms are updated in K-SVD. Finally, we reconstructed the image based on the dictionary atoms and sparse coefficients to obtain the denoised image. We applied the presented method on datasets of clinical Ultrasound Elastography images of lung cancer from Nanjing First Hospital, and compared the results of the presented method and the original method. The experimental results of subjective and objective evaluation demonstrated that presented approach reached a satisfactory denoising effect and this research provides a new technical reference for computer aided diagnosis.

Identification of Nine M6A-Related Long Noncoding RNAs as Prognostic Signatures Associated with Oxidative Stress in Oral Cancer Based on Data from The Cancer Genome Atlas.

Objective: Although the expression of long noncoding RNAs (lncRNAs) and N6-methyladenosine (M6A) is correlated with different tumors, it remains unclear how M6A-related lncRNA functioning affects the initiation and progression of oral squamous cell carcinoma (OSCC). Materials and Methods: Gene expression and clinical data were retrieved from The Cancer Genome Atlas. The prognostic value of M6A-related lncRNAs was determined using univariate Cox regression analyses. Gene set enrichment analysis of OSCC patient clusters revealed the pathways that elucidate the mechanism. Furthermore, a risk-based model was established. The difference in the overall survival (OS) between groups, including low-/high-risk groups, was determined by Kaplan-Meier analysis. Relationships among immune cells, clusters, clinicopathological characteristics, and risk scores were explored. Results: Among 1,080 M6A-related lncRNAs, 36 were prognosis-related. Patients with OSCC were divided into two clusters. T stage and the pathological grade were noticeably lower in cluster 2 than in cluster 1. Epithelial-mesenchymal transition showed greater enrichment in cluster 1. Nine hub M6A-related lncRNAs were identified for the model of risk score for predicting OSCC prognosis. The OS was longer in patients with a low-risk score than in patients with a high-risk score. The risk score was an independent prognostic factor of OSCC and was associated with the infiltration of different immune cells. T stages and the American Joint Committee on Cancer (AJCC) stages were more advanced in the high-risk score group than in the low-risk score group. Finally, expression correlation analysis showed that the risk score is associated with the expression of oxidative stress markers. Conclusion: M6A-related lncRNAs play an important role in OSCC progression. Immune cell infiltration was related to the risk score model in OSCC and could accurately predict OSCC prognosis.

MicroRNA-125a-3p participates in odontoblastic differentiation of dental pulp stem cells by targeting Fyn.

Fyn is a member of the protein tyrosine kinase family and its overexpression is associated with various types of inflammation. MicroRNAs can regulate the expression of target genes and play an important role in varied physiological and pathological processes. Based on the important role of Fyn and microRNA-125a-3p (miR-125a-3p) in inflammation, and combined with the bioinformatics studies, we performed in this study and chose miR-125a-3p as the focus of our research. During the progression of inflammation, we found that the expression of miR-125a-3p was decreased while the expression of Fyn was up-regulated. Fyn formed a complex with Neuropilin-1, which inhibited odontoblastic differentiation and expanded inflammatory responses through nuclear factor-κB signal pathways in dental pulp stem cells (DPSCs). These findings suggested that miR-125a-3p plays an important role in odontoblastic differentiation of DPSCs by targeting Fyn, implying its therapeutic potential in dental caries.

Spherical Metal Oxides with High Tap Density as Sulfur Host to Enhance Cathode Volumetric Capacity for Lithium-Sulfur Battery.

Effective hosts of sulfur are essential for the application of lithium-sulfur batteries. However, various refined nanomaterials or carbon-based hosts possess low density, high surface area, and large porosity, leading to undesirable reduction on both gravimetric and volumetric energy densities. Herein, spherical metal oxides with high tap density are introduced as carbon-free hosts of sulfur for the first time. The ternary oxides show a superior synergistic effect of adsorption and electrocatalytic conversion of soluble intermediate polysulfides. Besides, oxide microspheres can build stable conductive frameworks and open channels in porous electrodes for fast transport of electrons and active diffusion of electrolyte. Such a synergistic effect and unique structural feature of porous electrodes are favorable for achieving good utilization and stable cycle performance of the sulfur cathode. Typically, the S/LiNi0.8Co0.1Mn0.1O2 composite exhibits good cycle stability with a low capacity decay rate (0.057% per cycle) during 500 cycles at 0.1 C. Importantly, due to the high tap density (1.81 g cm-3), the S/LiNi0.8Co0.1Mn0.1O2 composite delivers a larger volumetric capacity (1601.9 mAh cm-3-composite), almost 2.3 times of S/carbon composite (689.4 mAh cm-3-composite). Therefore, this work provides a feasible strategy to reach long life and high volumetric capacity of cathode based on metal oxides as sulfur hosts.

Dysfunction of MiR-148a-NRP1 Functional Axis Suppresses Osteogenic Differentiation of Periodontal Ligament Stem Cells Under Inflammatory Microenvironment.

Periodontitis is a chronic inflammatory disease that can lead to the loss of periodontal bone tissue. The osteogenic potential of periodontal ligament stem cells (PDLSCs) is significantly decreased in periodontitis microenvironment. However, the mechanism is still unclear. We used Porphyromonas gingivalis lipopolysaccharide (LPS) as a stimulator of PDLSCs to mimic the periodontal inflammatory environment. The mineralization capability was restrained in LPS-stimulated PDLSCs, and the level of miR-148a increased, while the level of Neuropilin 1 (NRP1) decreased. Downregulation of miR-148a could reverse the osteogenesis deficiency of PDLSCs under LPS treatment. In addition, the expression of miR-148a in PDLSCs was negatively correlated with the expression of NRP1. Furthermore, overexpression of NRP1 upregulated the osteogenesis ability of LPS-stimulated PDLSCs, while inhibition of NRP1 eliminated the stimulative effect of miR-148a inhibitor on osteogenic differentiation. These data illustrated that the inflammatory environment mimicked by LPS inhibits osteogenesis by upregulation of miR-148a and subsequent downregulation of NRP1. We also found, compared to healthy periodontal tissues, miR-148a level increased, while NRP1 level decreased in periodontitis tissues. These two phenomena also exist in PDLSCs that come from the upper two types of tissues. To summarize, the decline of osteogenic potential of PDLSCs under inflammatory condition of periodontitis is related to miR-148a/NRP1 functional axis. This study may provide a novel strategy in the molecular aspect for the therapy of periodontitis.

Rosuvastatin Regulates Odontoblast Differentiation by Suppressing NF-κB Activation in an Inflammatory Environment.

Rosuvastatin is a synthetic statin of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. It has pleiotropic characteristics including hepatic selectivity, minimal metabolism, inhibition of inflammation, and induction of osteoblast differentiation. In this study, dental pulp stem cells (DPSCs) were treated with lipopolysaccharide alone or with rosuvastatin. Then, we examined the accelerative effects of rosuvastatin on odontoblast differentiation and mineralized nodule formation by real-time polymerase chain reaction (RT-PCR), western blot, alizarin red S staining, and alkaline phosphatase staining. The extent of anti-inflammation was determined by RT-PCR and analysis of the expression of tumor necrosis factor α, interleukin 1ß (IL-1ß), and IL-6. Furthermore, the activation of nuclear factor kappa B (NF-κB) was determined by western blot. This study demonstrates that rosuvastatin may speed up odontoblast differentiation and rescue inflammatory reaction by suppressing the NF-κB signaling pathway. It is believed that our findings provide novel perceptions on odontogenic differentiation of DPSCs.

CKIP-1 suppresses odontoblastic differentiation of dental pulp stem cells via BMP2 pathway and can interact with NRP1.

AIM: Casein kinase 2 interacting protein-1 (CKIP-1) is a recently discovered intracellular regulator of bone formation, muscle cell differentiation, and tumor cell proliferation. Our study aims to identify the inhibition of BMP2-Smad1/5 signaling by CKIP-1 in odontoblastic differentiation of human dental pulp stem cells (DPSCs). MATERIALS AND METHODS: DPSCs infected CKIP-1 siRNA or transfected CKIP-1 full-length plasmid were cultured in odontoblastic differentiation medium or added noggin (200 ng/mL) for 21 days. We examined the effects of CKIP-1 on odontoblastic differentiation, mineralized nodules formation, and interaction by western blot, real-time polymerase chain reaction (RT-PCR), alkaline phosphatase (ALP) staining, alizarin red S staining, and immunoprecipitation. RESULTS: Firstly, we have demonstrated that CKIP-1 expression markedly decreased time-dependently along with cell odontoblastic differentiation. Indeed, the silence of CKIP-1 upregulated odontoblastic differentiation via BMP2-Smad1/5 signaling, while CKIP-1 over-expression had a negative effect on odontoblastic differentiation of DPSCs. Furthermore, CKIP-1 could interact with Neuropilin-1 (NRP1). CONCLUSIONS: This work provides data that advocates a novel perception on odontoblastic differentiation of DPSCs. Therefore, inhibiting the expression of CKIP-1 may be of great significance to the development of dental caries.

The Forkhead Box C1, a Novel Negative Regulator of Osteogenesis, Plays a Crucial Role in Odontogenic Differentiation of Dental Pulp Stem Cells.

The forkhead box C1 (Foxc1) protein, a member of the forkhead/winged helix transcription factor family, is required in stem cell developmental processes. Recently, multiple studies have indicated the crucial role of Foxc1 in mesenchymal stem cell differentiation, but the precise effects and mechanisms on dental pulp stem cells (DPSCs) remain unclear. In this study, we evaluate the role of Foxc1 on the odontogenic differentiation and proliferation of DPSCs. Our results show that Foxc1 decreases time dependently in odontogenic differentiation of DPSCs. Meanwhile, overexpression of Foxc1 could significantly inhibit the mineralization of DPSCs and the expression of odontogenic-related genes, such as runt-related transcription factor 2 (Runx2), dentin sialophosphoprote (DSPP), and dentin matrix acidic phosphoprotein 1 (DMP-1). Foxc1 overexpression does not significantly alter the proliferation of DPSCs. In addition, Foxc1 reduces the expression of p-Smad1/5, an important modulator of bone morphogenetic protein (BMP)/Smad signaling pathway, inhibiting BMP/Smad signaling pathway. In conclusion, our data demonstrated that Foxc1 inhibits odontogenic differentiation of DPSCs and odontogenic-related gene expression through the BMP/Smad signaling pathway which may be useful for the dental regeneration and repair.

Wedelolactone Enhances Odontoblast Differentiation by Promoting Wnt/ß-Catenin Signaling Pathway and Suppressing NF-κB Signaling Pathway.

Wedelolactone is a multitarget natural plant compound with many pharmacological activities, including anti-inflammatory, anticancer, and antiosteoporosis. In this study, dental pulp stem cells (DPSCs) were treated with or without wedelolactone. We found that wedelolactone stimulated odontoblast differentiation and mineralization. At the molecular level, wedelolactone directly promoted the nuclear accumulation of ß-catenin, and thereafter stimulated the expression of odontoblast-related marker genes containing dentin matrix protein-1 (DMP1), dentin sialophosphoprotein (DSPP), and runt-related transcription factor 2 (Runx2). Furthermore, wedelolactone upregulated the expression of IκBα and inhibited phosphonation and nuclear migration of p65. As a result, wedelolactone remarkably induced odontoblast differentiation through semaphorin 3A (Sema3A)/neuropilin-1 (NRP1) pathway-mediated ß-catenin activation and nuclear factor kappa B (NF-κB) pathway inhibition. Our findings provide novel perceptions on odontogenic differentiation of DPSCs.

The Role of Neuropilin-1-FYN Interaction in Odontoblast Differentiation of Dental Pulp Stem Cells.

Abnormal odontoblast differentiation of dental pulp stem cells (DPSCs) caused by inflammation is closely related to the development of dental caries. Neuropilin-1 (NRP1) is one of the members of neuropilin family. It can combine with disparate ligands involved in regulating cell differentiation. FYN belongs to the protein-tyrosine kinase family, which has been implicated in the control of cell growth, and the effect can be further strengthened by inflammatory factors. In our studies, we verified that NRP1 can form complexes with FYN and have the correlation changes in odontoblast differentiation of DPSCs. Therefore, we surmise that in the progress of dental caries, NRP1 interacts with FYN, by expanding inflammation and inhibition of odontoblast differentiation of DPSCs through nuclear factor kappa B (NF-κB) signaling pathway. In this subject, we first investigated the expression and interaction of NRP1 and FYN in DPSCs. And then, we researched the effect of this complex controlling downstream signal pathway in normal or inflammation stimulated DPSCs. Finally, we analyzed the relationship between this role and odontoblast differentiation of DPSCs. This research will provide the molecular mechanism of inflammation factors of dental caries through activating NF-κB signal regulating odontoblast differentiation in DPSCs for finding new potential drug targets for the clinical treatment of dental caries.

NRP1 Accelerates Odontoblast Differentiation of Dental Pulp Stem Cells Through Classical Wnt/ß-Catenin Signaling.

Neuropilin-1 (NRP1) is one of the members of neuropilin family. It can combine with disparate ligands involved in regulating cell proliferation, apoptosis, and differentiation. The binding of NRP1 to Sema3A stimulates osteoblast differentiation through the classical Wnt/ß-catenin pathway. However, the functions of NRP1 in dental pulp stem cells (DPSCs) are not clear. The aim of our study was to investigate how NRP1 controlled odontoblast differentiation in DPSCs and clarified the underlying mechanisms. NRP1 expression was increased in time-dependent manner along with cell odontoblast differentiation. Overexpression of NRP1 upregulated dentin matrix protein-1, dentin sialophosphoprotein, alkaline phosphatase protein level, and mineralization in DPSCs, while knockdown of NRP1 induced the opposite effects. SiNRP1 similar to DKK1 availably blocked classical Wnt/ß-catenin signaling and odontoblast differentiation. In summary, NRP1, as a promoter of odontoblast differentiation, regulates DPSCs via the classical Wnt/ß-catenin pathway.

Development of a novel biochar/PSF mixed matrix membrane and study of key parameters in treatment of copper and lead contaminated water.

Mixed matrix membrane (MMM) has attracted increasing attentions in various applications, such as water treatment. In this study, an innovative biochar/polysulfone (PSF) mixed matrix hollow fiber membrane was fabricated by incorporating micro-sized biochar particles in the PSF matrix. It was demonstrated that the membrane was more hydrophilic than the pure PSF membrane. Higher water flux was obtained. The adsorption of copper and lead on the MMM increased as the pH was increased with the maximum adsorption capacity observed at pH > 4.5. The adsorption equilibrium was established in 7 and 12 h for lead and copper, respectively. The adsorption kinetics and isotherm followed the intraparticle surface diffusion model and Freundlich isotherm, respectively. The presence of humic acid (HA) had a little effect on the adsorption, while the ionic strength showed an adverse effect on the removal. In addition, the feed concentration and cross flow rate significantly affected the removal efficiency in a continuous filtration mode. The increase in feed concentration and cross flow rate resulted in a reduction in the volume of treated permeate that had the copper/lead concentrations below the regulated levels for drinking water. The MMM exhibited an excellent regeneration-reuse performance in the removal of both copper and lead. Finally, our mechanism studies indicated that the uptake of heavy metals was controlled by a combination of key reactions of complexation, ion-exchange and precipitation. This study indicated that the MMM can be applied as an effective and eco-friendly material for the treatment of heavy metals contaminated water.

Renal Parenchymal Area Growth Curves for Children 0 to 10 Months Old.

PURPOSE: Low renal parenchymal area, which is the gross area of the kidney in maximal longitudinal length minus the area of the collecting system, has been associated with increased risk of end stage renal disease during childhood in boys with posterior urethral valves. To our knowledge normal values do not exist. We aimed to increase the clinical usefulness of this measure by defining normal renal parenchymal area during infancy. MATERIALS AND METHODS: In a cross-sectional study of children with prenatally detected mild unilateral hydronephrosis who were evaluated between 2000 and 2012 we measured the renal parenchymal area of normal kidney(s) opposite the kidney with mild hydronephrosis. Measurement was done with ultrasound from birth to post-gestational age 10 months. We used the LMS method to construct unilateral, bilateral, side and gender stratified normalized centile curves. We determined the z-score and the centile of a total renal parenchymal area of 12.4 cm(2) at post-gestational age 1 to 2 weeks, which has been associated with an increased risk of kidney failure before age 18 years in boys with posterior urethral valves. RESULTS: A total of 975 normal kidneys of children 0 to 10 months old were used to create renal parenchymal area centile curves. At the 97th centile for unilateral and single stratified curves the estimated margin of error was 4.4% to 8.8%. For bilateral and double stratified curves the estimated margin of error at the 97th centile was 6.6% to 13.2%. Total renal parenchymal area less than 12.4 cm(2) at post-gestational age 1 to 2 weeks had a z-score of -1.96 and fell at the 3rd percentile. CONCLUSIONS: These normal renal parenchymal area curves may be used to track kidney growth in infants and identify those at risk for chronic kidney disease progression.

Segmentation of renal parenchymal area from ultrasound images using level set evolution.

This paper presents a framework for segmentation of renal parenchymal area from ultrasound images based on a 2-step level set method. We used distance regularized level set evolution method to partition the kidney boundary, followed by region-scalable fitting energy minimization method to segment the kidney collecting system, and determined renal parenchymal area by subtracting the area of the collecting system from the gross kidney area. The proposed method demonstrated excellent validity and low inter-observer variability.

A novel level set method for segmentation of left and right ventricles from cardiac MR images.

In this paper, we propose a novel level set method for segmentation of cardiac left and right ventricles based on the distance regularized level set evolution (DRLSE) framework [7] and the distance regularized two-layer level set (DR2LS) model [17]. First, DRLSE is applied to obtain a preliminary segmentation of left and right ventricles, which is then used to initialize the endocardial contour, which is represented by the zero level contour of the level set function in our method. Then, the epi-cardial contour is represented by a different level contour of the same level set function. These two level sets are optimized by an energy minimization process to best fit the true endocardium and epicardium. In order to ensure smoothly varying distance between the two level contours, we introduce a distance regularization constraint in the energy function. With the region-scalable fitting (RSF) energy [8] as the data term, our method is able to deal with intensity inhomogeneities in the images, which is a main source of difficulty in image segmentation. Our method has been tested on cardiac MR images with promising results.