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Supplementary Table from Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation

Supplementary Figure from Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients’ survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

With the development of additive manufacturing, the advantages of this type implant devices in the treatment of acetabular defects and reconstruction are becoming more and more prominent. The number of registration and declaration of such products is increasing day by day. According to the relevant requirements of the National Medical Products Administration for registration and application documents, combined with the characteristics of acetabular reconstruction implant products made of additive manufacturing, this study analyzes and summarizes the relevant requirements on raw material control, product performance research, product manufacturing, clinical evaluation, et al. We should pay more attention to in the registration and application materials submitted by the applicant. Provide opinions and suggestions for the next registration applicant to standardize product RD and registration application documents, in order to help them optimize product RD process, improve product quality and registration application efficiency.

The ‘plainification of materials’ has been conceptualized to promote the sustainable development of materials. This perspective, for the first time in the field of biomaterials, proposes and defines ‘plain metallic biomaterials (PMBs)’ with demonstrated research and application case studies of pure titanium with high strength and toughness, and biodegradable, fine-grained and high-purity magnesium. Then, after discussing the features, benefits and opportunities of PMBs, the challenges are analyzed from both technical and regulatory aspects. Regulatory perspectives on PMB-based medical devices are also provided for the benefit of future research, development and commercialization.

Exploring efficient control strategies for heterogeneously congested urban networks remains a big research challenge. The theory of macroscopic fundamental diagram (MFD) provides a new perspective for network-wide congestion control decisions. This paper proposes a coordinated perimeter control strategy for multiregion heterogeneous networks based on optimized transfer flows. First, a two-layer network partitioning method is presented to capture spatial heterogeneity dynamics of urban networks. For this partition, traffic flow equilibrium model based on MFD and multiagent based hierarchical traffic management scheme are built. Then, an improved multinomial logit model is developed for deriving optimized transfer flows among multiple congested regions. A coordinated perimeter control strategy using model predictive control is further proposed, which is aimed at tracking desired accumulations of each congested region. As a case study, the proposed control strategy is applied to the downtown network of Jinan, China, using simulation analysis. The results demonstrate that it can achieve balanced network flow distribution and increased mobility.

Congestion is a kind of expression of instability of traffic network. Traffic signal control keeping traffic network stable can reduce the congestion of urban traffic. In order to improve the efficiency of urban traffic network, this study proposes a decentralized traffic signal control strategy based on backpressure algorithm used in Wi-Fi mesh networks for packets routing. Backpressure based traffic signal control algorithm can stabilize urban traffic network and achieve maximum throughput. Based on original backpressure algorithm, the variant parameter and penalty function are considered to balance the queue differential and capacity of downstream links in urban traffic network. For each traffic phase of intersections, phase weight is computed using queue differential and capacity of downstream links, which fixed the deficiency of infinite queue capacity in original backpressure algorithm. It is proved that the extended backpressure traffic signal control algorithm can maintain stability of urban traffic network, and also can prevent queue spillback, so as to improve performance of whole traffic network. Simulations are carried out in Vissim using Vissim COM programming interface and Visual Studio development tools. Evaluation results illuminate that it can get better performance than the backpressure algorithm just based on queue length differential in average queue length and delay of traffic network.

This study assessed the effects of different electric current densities on the calcification and photosynthetic physiology of a massive, colonial stony coral species. Coral survivorship, calcification rate, and photosynthetic parameters (zooxanthellae density and chlorophyll fluorescence) were measured to determine the physiological and photosynthetic performance of Galaxea fascicularis after exposure to different electric current densities. After 60 days of treatment, survival of G. fascicularis was higher at low electric current density (10 mA m−2) than in the control and at high electric current density (100 mA m−2). Electric current did not alter zooxanthellae densities, but did enhance the photosynthetic processes (e.g. maximum electron transport rates (rETRm), and maximum quantum yield (Fv/Fm)) within 45 days. Coral calcification rate increased in response to low electric current density up to 30 days, but the effects of the electric current were not significant after a longer period of treatment. Overall, our results indicated that mineral accretion technology with appropriate electric current density conditions was somewhat helpful in enhancing coral growth, and thus this technique may be used in the restoration and management of massive stony coral reefs.

Background Fibronectin type III domain containing 3B (FNDC3B) acts as an oncogene in various cancers, and abnormal expression of FNDC3B has been found in colorectal cancer (CRC). Our study aimed to illustrate the role of FNDC3B in CRC development. Methods Through RT-qPCR and western blotting assays, the mRNA and protein expressions of target genes were measured. CCK-8 and MTT methods were used to detect cell proliferation. Invasion ability was determined using Transwell assay. TargetScan platform and luciferase reporter gene assay were performed to predict and validate the bindings between FNDC3B and miR-125a-5p or miR-217. Besides, the expression correlation was measured by Pearson's Correlation analysis. Results We found that FNDC3B was significantly upregulated in CRC tissues and tumor cell lines, and high expression of FNDC3B predicted a poor survival outcome. The bindings between FNDC3B and miR-125a-5p and miR-217 were respectively at the motifs of CUCAGGG and AUGCAGU. MiR-125a-5p and miR-217 were downregulated in CRC tissues, and both were negatively correlated with FNDC3B expression. Subsequently, the downregulated miR-125a-5p and miR-217 were confirmed as contributors FNDC3B upregulation in CRC. A loss-of-function assay demonstrated that FNDC3B knockdown inhibited the proliferation of CRC cells, while FNDC3B overexpression promoted the proliferation and invasion of tumor cells. Besides, we validated that PI3K/mTOR signaling was involved in the regulation of FNDC3B on the proliferation and invasion of CRC cells. Conclusion Generally, our findings demonstrated that FNDC3B facilitated cell proliferation and invasion via PI3K/mTOR signaling, and further promoted CRC progression. The novel miR-125a-5p/FNDC3B and miR-217/FNDC3B axes might be new targets for CRC prognosis and therapy.

Pancreatic cancer ranks fourth among cancer-related deaths, with a 5-years overall survival rate being below 10%. Gemcitabine (dFdC) has been considered the first-line drug for patients with pancreatic cancer. However, the clinical effectiveness is less than 20% due to drug resistance. Most importantly, overwhelming evidence suggested c-Myc and PD-L1 were generally highly expressed in pancreatic cancer patients. However, whether dFdC-resistant pancreatic cancer is associated with c-Myc and PD-L1 has not been elucidated. In our present study, we found that the expression of c-Myc and PD-L1 was markedly increased in pancreatic tumor tissues compared with adjacent tissues. Similarly, c-Myc and PD-L1 expression were also remarkably elevated in dFdC-resistant Panc-1 cells compared with parental cells. In addition, dFdC sensitivity was enhanced by the combination of dFdC and c-Myc inhibitors in Panc-1 cells. Interestingly, its sensitivity was reduced when c-Myc was overexpressed. Moreover, PD-L1 protein expression was dramatically down-regulated when treated with c-Myc inhibitors. Furthermore, artesunate (ARTS) screened from 18 compounds could reverse dFdC resistance in combination with dFdC in dFdC-resistant Panc-1 cells in vitro and suppressed DMBA-induced pancreatic cancer in vivo. In summary, our data revealed that the mechanism of dFdC resistance may be that c-Myc overexpression contributed to increased PD-L1 expression, and ARTS could overcome dFdC-resistant pancreatic cancer by inhibiting c-Myc and PD-L1. Our findings not only suggest c-Myc and PD-L1 as novel prognostic biomarkers in dFdC-resistant pancreatic cancer, but also provide ARTS as a promising candidate for overcoming dFdC resistance.

The effects of a simulated climate change scenario, i.e., increased ultraviolet radiation (UVR) and dissolved organic carbon (DOC), on the growth and photosynthesis of tropical coastal phytoplankton were evaluated in Sanya Bay, northern South China Sea, in summer. Microcosm experiments were conducted at two contrasting stations (Stns S1 and S2) with three different UVR treatments and two DOC addition treatments. Our results showed that natural sunlight UVR or increased UV-B did not affect phytoplankton biomass and primary production. However, increased UV-B significantly decreased the proportion of picophytoplankton and the efficiency of carbon fixation at Stn S2. DOC enhancement caused negative effects on primary production under natural sunlight UVR only at Stn S1. Interactive effects of UVR and DOC addition on phytoplankton biomass and primary production were detected at Stn S1, due to the negative effects of DOC being eliminated under the increased UV-B condition. The lack of interactive effects at Stn S2 were likely due to the differences with Stn S1 in terms of light acclimation and biological interaction. In summary, this future climate change scenario will probably not affect the photosynthetic CO2 fixation and biomass of natural phytoplankton in Sanya Bay.

Coronavirus disease 2019 pandemic continues globally with a growing number of infections, but there are currently no effective antibody drugs against the virus. In addition, 90% amino acid sequence identity between the S2 subunit of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV S proteins attracts us to examine S2-targeted cross-neutralizing antibodies that are not yet well defined. We therefore immunized RenMab mice with the full-length S protein and constructed a high-throughput antibody discovery method based on single-cell sequencing technology to isolate SARS-CoV-2 S-targeted neutralizing antibodies and cross-neutralizing antibodies against the S2 region of SARS-CoV-2/SARS-CoV S. Diversity of antibody sequences in RenMab mice and consistency in B-cell immune responses between RenMab mice and humans enabled screening of fully human virus-neutralizing antibodies. From all the frequency >1 paired clonotypes obtained from single-cell V(D)J sequencing, 215 antibodies with binding affinities were identified and primarily bound S2. However, only two receptor-binding domain-targeted clonotypes had neutralizing activity against SARS-CoV-2. Moreover, 5' single-cell RNA sequencing indicated that these sorted splenic B cells are mainly plasmablasts, germinal center (GC)-dependent memory B-cells and GC B-cells. Among them, plasmablasts and GC-dependent memory B-cells were considered the most significant possibility of producing virus-specific antibodies. Altogether, using a high-throughput single cell-based antibody discovery approach, our study highlighted the challenges of developing S2-binding neutralizing antibodies against SARS-CoV-2 and provided a novel direction for the enrichment of antigen-specific B-cells.

Acidification is recognized as the predominant characteristic of the tumor microenvironment (TME) and contributes to tumor progression. However, the mechanism of extracellular acidic TME directly influences intercellular pathologic responses remains unclear. Meanwhile, acidic TME is mainly ascribed to aberrant metabolism of lipids and glucose, but whether and how acidity affects metabolic reprogramming, especially for lipid metabolism, is still unknown. We found that lipid was significantly accumulated in liver cancer cells when exposed to acidic TME. Moreover, proteomic analysis showed that differentially expressed proteins were mainly clustered into fatty acid pathways. Subsequently, we found that acidification increased the expression of SCD1 by activating PI3K/AKT signaling pathway. Interestingly, we found that SCD1 directly bound to PPARα in the acidic TME, which vanished after 2-day reverse incubation in pH 7.4 medium, implying extracellular acidosis might influence intercellular function by mediating the binding affinity between SCD1 and PPARα under different pH gradients. In summary, our data revealed that acidosis could significantly trigger fatty acid synthesis to promote liver tumorigenesis by upregulating SCD1 in a PI3K/AKT activation dependent manner and simultaneously promote SCD1 binding to PPARα. Our study not only provides direct mechanistic evidence to support the vital role of acidosis in lipid metabolic reprogramming, but also provides novel insights for determining the binding affinity of functional proteins as a molecular mechanism to better understand the role of the acidic TME in tumor development. Implications: The acidic TME contributes to lipid accumulation in liver cancer by activating the PI3K/AKT signaling pathway and promoting SCD1–PPARα binding.

Tissue development deformity or tissue defect is a major clinical challenge. Tissue engineering technology provides a promising solution to these problems. Among them, functional biomaterials with regenerative abilities are one of the development trends. Polypeptide is a small molecule that can be used to modify tissue engineering materials. However, the function of a single polypeptide molecule is limited and insufficient to construct comprehensive microenvironment for tissue regeneration. Fusion peptides combining two or more polypeptide molecules with different functions were expected to achieve multiple efficacies in vivo, providing a novel solution for clinical tissue regeneration engineering applications. This paper reviews the construction methods, degradation process, and biological activities of fusion peptides, and presents recent global research progress and prospects concerning fusion peptides. It provides a reference helping to guide the future exploration and development of fusion peptide-based functional biomaterials for tissue engineering.

Although targeting DNA repair signaling pathways has emerged as a promising therapeutic for skin cancer, the relevance of DNA damage responses (DDR) in the development and survival of nonmelanoma skin cancer (NMSC), the most common type of skin cancer, remains obscure. Here, we report that Src‐associated substrate during mitosis of 68 kDa (Sam68), an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2‐transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2‐transgenic mice. Moreover, Sam68 plays a critical role in DNA damage‐induced DNA repair and nuclear factor kappa B (NF‐κB) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents. Together, our data reveal a novel function of Sam68 in regulating DDR in keratinocytes that is crucial for the growth and survival of NMSC., Here, we report that Sam68, an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2‐transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2‐transgenic mice. Moreover, Sam68 plays a critical role in DNA damage‐induced DNA repair and nuclear factor kappa B (NF‐κB) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents.

Network-wide traffic control strategies (e.g. perimeter control and route guidance) in urban networks have recently been mainly studied to relieve or postpone congestion based on the theory of macroscopic fundamental diagram (MFD). Nevertheless, these studies are mostly applied to the statically partitioned networks or the dynamic networks that fail to fully consider traffic state prediction, conflicting with strongly spatiotemporal variability of traffic congestion or objective of active traffic management (ATM). This paper proposes a methodology to dynamically identify critical congestion warning areas from heterogeneous urban road networks, which aids to design efficient perimeter control approaches. In the methodology, a dynamic directed weighted network is built on the base of the link connectivity and the real-time traffic loads, and a link travel time prediction method based on Kalman filter is developed to calibrate directed weight values and undirected input values for links. With the undirected link input information, a dynamic congestion warning community detection method which consists of three consecutive steps is developed. Firstly, it could capture emergence of new congestion areas based on the definition of congestion seed intersection. Secondly, expansion and regression of each congested area could be achieved with the objectives of spatial compactness and traffic condition homogeneity. Thirdly, a two-level merging algorithm of adjacent different congestion areas is designed utilizing modularity model in community detection of complex networks. The proposed methodology is validated using ground truth data from downtown network of Jinan City in China. The results show that the proposed algorithms can efficiently track congestion evolutionary processes and effectively detect congestion warning areas from the test real network.

Recent studies have indicated that various corals might have different degrees of resistance to elevated CO2 levels. However, the underlying molecular mechanism accounting for these differences is still poorly understood. In this study, RNA-seq data were analyzed to identify differentially expressed genes in two coral species (Acropora austera and Acropora cerealis) in response to high CO2 levels. The calcification rates were higher in high CO2 treatment than the control in A. austera, but was not significantly different in A. cerealis. A KEGG database search revealed that in both coral species, most Ca2+ transporters were present in the calcium signaling pathway, which could be important in the CO2 regulation of coral calcification. The gene expression levels of many CO2 and HCO3- transporters were not affected by elevated CO2. Nevertheless, high CO2 levels did have an effect on the expression of certain Ca2+ transporters. The upregulation of Ca2+ transporters likely explained the higher resistance of A. austera to high CO2 than A. cerealis.

H- and Nb-doped ZnO (HNZO) thin films were fabricated on glass substrates with radio frequency magnetron sputtering. The effect of the flow rate of H2 has been investigated by analyzing the structural, optical, and electrical properties. The incorporation of H during the deposition of Nb-incorporated ZnO films significantly improved their crystallinity, conductivity, and transmittance. The crystallites of the HNZO films were preferentially oriented in the c-axis direction; the films possess high transmittance (approximately 85%) in the visible and near-infrared regions (400 to 1400 nm). The lowest room-temperature resistivity of the HNZO films was measured as 1.28 × 10−3 Ω cm. Such optical and electrical properties along with the remarkable chemical stability of the HNZO films make them a promising candidate for applications in solar cells.

The annual sea surface temperature increased at a rate of 0.038 to 0.074 °C/year in recent decade, and pH decreased at a rate of 0.012–0.014/year in two coastal waters of the South China Sea. Therefore, a culture experiment was conducted to study the effects of acidification and warming on coral calcification rates. The calcification of three coral species were significantly reduced during the exposure to elevated CO2, while other three coral species were not significantly affected. The reef coral Pocillopora damicornis was resistant to high CO2, but was not able to survive during the exposure to 33 °C in our culture experiments. Our findings suggested that some corals might not survive in tropical areas if coral could not adapt to warming rapidly, and subtropical coastal waters with temperature of

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF

The development of society requires high-quality talents, which propels colleges and universities to cultivate graduates with both theoretical and practical abilities. As an applied undergraduate university, Beijing City University has always attached importance to cultivating students' practical ability based on theoretical teaching. In “Project Planning and Control”, a module for the major of project management, the task-driven method is used for practical training. The college aims to improve students' ability to apply the theory through practical training scenarios, real-life training tasks, assessments and other key steps. In order to test the effect of practical training, SPSS statistical software is used to perform paired sample T test and correlation analysis on the usual scores and final scores. The analysis results show that the design of practical training is reasonable, achieving good results.

Bile acids (BAs), the most important components of bile, attribute predominately to maintain metabolic homeostasis. In hepatocellular carcinoma (HCC) patients, the BAs homeostasis was seriously disturbed, especially in those patients with alcohol-intake history. However, whether alcohol consumption could promote HCC progression via influencing BAs homeostasis and the precise mechanism underlying are still unclear. In our study, by collecting HCC specimens from both alcohol-drinkers (n = 15) and non-alcohol drinkers (n = 22), we found that compared to non-alcohol intake HCC patients, BAs homeostasis was disturbed in HCC patients who drank alcohol. Furthermore, ethanol treatment was also found to promote HCC progression by markedly activating oncogenes (RAS, MYC, MET, and HER2), while remarkably suppressing tumor suppressor genes (BRCA2 and APC). We evaluated 14 key functional genes that maintain the homeostasis of BAs and found that either in alcohol-intake HCC patients (n = 15), or in ethanol-treated mice, BSEP, rate-limiting transporter governing excreting BAs from liver into bile duct, was remarkably decreased when exposed to alcohol. Moreover, by screening for changes in the epigenetic landscape of liver cancer cells exposed to alcohol, we strikingly found that histone methyltransferases (RBBP-5, Suv39h1, ASH2L, and SET7/9) were increased, and KMT3B, KMT4, and KMT7 gene expression was also elevated, while histone demethyltransferases (JARID1a, JARID1b, JARID1c) were decreased. In summary, we found that alcohol could trigger BAs disequilibrium to initiate and promote HCC progression. Our study provided a novel and supplementary mechanism to determine the important role of alcohol-intake in HCC development regarding from the perspective of BAs homeostasis.

Fifth-generation (5G) communication network puts forward a demanding requirement for spectrum resources. To improve spectral efficiency, a novel uplink cooperative nonorthogonal multiple access (NOMA) model is proposed. In particular, the proposed scheme enables the relay node to perform a cooperative transmission and uplink transmission simultaneously during the cooperative phase, at the expense of a slight decrease in the signal reception reliability. Moreover, the optimal power allocation strategy of relay node is given. Relay selection criteria is also presented. We analyze the outage probability and outage throughput in both ideal and non-ideal successive interference cancellation (SIC) conditions. Simulation results confirm that the proposed scheme can obtain higher throughput than other cooperative NOMA schemes.

Lung cancer has surpassed breast cancer as the leading cause of cancer death in females in developed countries and the leading cause of cancer death in males. Despite extensive research on lung cancer, the pathogenesis of lung cancer is not fully understood. ALKBH1 is a 2-oxoglutarate and Fe (II)-dependent dioxygenase responsible for the demethylation of 6-methyladenine (m6A) in RNA and is essential to multiple cellular processes in human. Numerous recent studies suggest that ALKBH1 plays a role in tumorigenesis and tumor progression, but the role of ALKBH1 in lung cancer is largely unknown. In this study, we demonstrated that the expression levels of ALKBH1 in lung cancer tissues and cells were up regulated. The invasion and migration abilities of lung cancer cells were significantly suppressed in vitro upon the silencing of ALKBH1 while they were significantly promoted upon its overexpression. We next characterized the enzyme biochemically by analyzing the contribution of essential residues Y184, H231, D233, H287, R338, and R344 to its m6A demethylation activity. Lastly, our 3.1-A crystal structure of mouse ALKBH1 revealed that the N-terminal domain of the protein forms close contacted with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. In summary, our combined cellular, biochemical, and structural results provide insight into the potential ALKBH1-based drug design for cancer therapies.

In today’s Internet era, “blended learning” is a relatively advanced and effective learning method, which is of great significance for promoting curriculum teaching reforms and improving teaching quality. This paper explores the blended teaching design method of the platform course of “Management”, clarifies the teaching objectives, overall design and unit design, and implements in teaching. A comprehensive evaluation of the teaching effect was made in three areas of the usage of the platform, analysis of students’ assessment grades and feedback of students’ questionnaire, which shows that blended teaching has achieved good results. There are still some problems in the implementation of blended teaching, including the quantity and quality of teaching resources, as well as the students’ assessment results need to be improved, and need to be improved in future research.

The intermediate filament protein keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at Krt14’s codon 373 (C373A) exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in epidermis. A proteomics screen identified 14-3-3 as K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiating Krt14 C373A keratinocytes. Residue C373 in K14, which is conserved in a subset of keratins, is revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in epidermis.

Ethnopharmacological relevance Herb-derived anti-tumor agents, such as paclitaxel and vincristine, exert significant but varied effectivenesses towards different cancer types. Similarly, Centipeda minima (CM) is a well-known traditional Chinese medicine that has been used to treat rhinitis, relieve pain and reduce swelling, and recently found to exert overwhelming anti-tumor effects against breast cancer, colon cancer, and nasopharyngeal carcinoma with different response rates. However, what is the optimizing cancer model that benefits most from CM, and what is the specific target underlying still require more exclusive and profound investigations. Aims of the study This study aimed to explore the dominant tumor model and specific target of CM by integrative pharmacology and biological experiments. Materials and methods The most predominant and specific cancer types that are sensitive to CM were screened and identified based on a combination network pharmacology and bioinformatics analysis. Compound-target network and protein-protein interaction of CM-related cancer targets were carried out to determine the most abundant active compound. Simultaneously, the priority target responsible for CM-related anti-tumor efficacy was further validated by molecular docking and in vitro experiments. Results In total, approximately 42% (8/19) of the targets were enriched in prostate cancer (p = 1.25E-09), suggesting prostate cancer would be the most sensitive tumor response to CM-related efficacy. Furthermore, we found that arnicolide D (ARD), the most abundant and representative active compound of CM, could directly bind to Src with binding energy of -7.3 kcal/mol, implying Src would be the priority target responsible for CM-related anti-tumor efficacy. Meanwhile, the results were further validated by solvent-induced protein precipitation (SIP) assay. In addition, PCR and WB results also revealed that either CM or ARD could not influence the gene expression of Src, while significantly decreased its protein expression instead, which further suggested that ARD might markedly shortene the Src protein half-life to promote Src protein degradation, thereby achieving significant anti-prostate cancer efficacy. Conclusion Our findings not only suggest CM as a promising Src-targeting candidate for prostate cancer treatment, but also bring up a strategy for understanding the personalization of herbal medicines by using integrative pharmacology.

In this paper, novel micro- and nano-composite Al-doped ZnO (AZO) films with broadband-gap light-trapping capacity was successfully fabricated by post-chemical-etching AZO film and re-sputtering self-textured H and Al co-doped ZnO (HAZO) film. The influence of pressure and etching time on the optical and electrical properties of HAZO, AZO, and AZO/HAZO films were systematically investigated. The performance of this novel ZnO film was increased remarkably compared to that of the post-etched AZO film or native textured HAZO film for both long and short wavelengths. Microcrystalline silicon solar cells deposited on this new type of AZO/HAZO films exhibited a strong enhancement of 13.4% in the conversion efficiency, demonstrating its wide application prospect.

A simple, low-cost, and sensitive liposome-based colorimetric aptasensor has been developed to detect ochratoxin A (OTA). Specifically, a dumbbell-shaped probe was designed, including magnetic beads (MBs), double-stranded DNA (dsDNA), and enzyme-encapsulated liposome. The dsDNA formed by the hybridization between OTA aptamer and its complementary probe. And the dsDNA was used to contact the MBs and the enzyme-encapsulated liposome. In the presence of OTA, the aptamer preferred to combine with OTA to form G-quadruplex, resulting in the release of the detection probe and the enzyme-encapsulated liposome. Each liposome contained a large amount of HRP. Thus, when the liposome was lysed by adding the mixed solution of 3,3′,5,5′-tetramethylbenzidine (TMB) and H2O2, a large number of HRP were released. HRP could catalyze the H2O2-mediated oxidation of TMB and hence resulted in the color change from colorless to blue with the OTA concentration varying, and this variation can be observed by naked eyes easily. The result showed that the absorption intensity at 652 nm enhanced with the increase of OTA concentration ranging from 0.05 to 2.0 ng mL−1, and the limit of detection was calculated to be 0.023 ng mL−1 (S/N = 3). The developed colorimetric aptasensor has been applied to detect OTA concentration in corn samples with satisfied results.

Aflatoxin B1 (AFB1) can cause great threat to human health, so the development of convenient and portable device for sensitive detection of AFB1 is highly desired. The portable pH meter has the characters of facile operation, low cost, and easy availability. Therefore, in this study, we investigate the applicability of utilizing a pH meter as the readout to develop a portable sensor for AFB1. The specific detection of AFB1 is realized via the combination of AFB1-responsive aptamer-cross-linked hydrogel. Upon the addition of AFB1, AFB1 binds to its aptamer with high affinity in lieu of aptamer/DNA complex, causing the collapse of hydrogel network and results in the releasing of urease into the solution. The released urease can catalyse the hydrolysis of urea and result in the rise of pH value. The change of pH value has a direct relationship to the concentration of AFB1 in the range of 0.2-20µM with a detection limit of 0.1µM (S/N = 3). The proposed portable device is successfully applied to assay AFB1 in the food samples with satisfied results.

Eu3+ doped LuVO4 phosphors were synthesized by a hydrothermal method. The phase and microstructure of the synthesized phosphors were confirmed by the XRD and SEM. Under the excitation at 260 nm, pure LuVO4 exhibits emission band in blue region, but Eu3+ doped LuVO4 emits emission bands locating in blue and red regions. In Eu3+ doped LuVO4 phosphors, the emission intensity and lifetime of VO4 3− group decrease with the increasing Eu3+ concentrations, which suggest the energy transfer from VO4 3− groups to Eu3+ ions.

Being attracted by offloading local services to adjacent users, the operator allows two proximity users to build up a direct communication link, which is a new supplementary to current cellular network and called device-to-device (D2D) communication. Due to the low power radiation and occupation of the licensed band, D2D users can share the resource with cellular users fully controlled by cellular network to improve the local frequency efficiency. Due to the combinatorial and nonconvex nature of formulated problem, solving such problem optimally is a nearly impossible task. However, we propose an upper bound computation method, which can be seen as a benchmark for resource sharing scheme design. We also propose another two suboptimal schemes, i.e., suboptimal resource sharing scheme I with parallel computation structure which can achieve optimality in the most cases, and suboptimal resource sharing scheme II with relatively low complexity at the cost of acceptable performance loss. Moreover, through extensive numerical results, we find that both suboptimal resource sharing schemes can outperform the existed works. To conclude, our work actually provide a tradeoff between complexity and performance.

Dark carbon fixation (DCF) has been usually assumed to be insignificant in the study of microbial production and carbon cycling. In order to evaluate DCF distribution and its contribution to biogenic carbon flux, surface and vertical distribution of DCF, primary production (PP) and bacterial production (BP) were investigated in both offshore and coastal waters in the South China Sea (SCS). Surface DCF was ~ 0.058 μg C L−1 h−1 (~ 10% of PP), within the same order of magnitude as BP of ~ 0.047 μg C L−1 h−1 in the offshore waters. Integrated over the 1500 m water column, DCF was ~ 196 mg C m−2 h−1, corresponding to ~ 384% of PP, and represented a newly produced source of organic matter. This suggested that DCF was an important microbial metabolic pathway in the SCS, which might support ~ 83% carbon demand of heterotrophic prokaryotes. Interestingly, the DCF was higher in the deep water (~ 0.140 μg C L−1 h−1) than the surface water (~ 0.089 μg C L−1 h−1). In addition to the different microbial community, this different vertical distribution of DCF was likely due to the nutrient status, as our nutrient enrichment experiment showed that the addition of glucose, ammonium and phosphate stimulated the DCF rates, especially the addition of glucose plus ammonium.

Power distribution faulting is one of the main reasons for the unplanned outage. In terms of the distribution fault outage, cost evaluation and hotspot area recognition are beneficial for utilities to develop schemes tailored for distribution operation, maintenance and upgrading. In this study, multi-source data from marketing, distribution, and dispatching fields are effectively utilised for comprehensive information collection of medium-voltage distribution network faults. A new approach to fault fuzzy location is proposed using distribution network topology and transformer outage duration. Meanwhile, fault outage cost is evaluated based on the short-term load forecast of distribution transformers, which completely considers the impact of load transferring on multi-power supply users. Furthermore, the distribution blackout events are mapped with geography information system, and the fault hotspot areas are highlighted by geographical grid virtualisation. The method proposed in this study has been validated using practical examples. This approach has been actually applied in Jiangsu distribution maintenance management.

A highly sensitive and selective fluorescence biosensor for inorganic pyrophosphatase (PPase) activity has been developed based on special click ligation trigger hyperbranched rolling circle amplification (CLT-HRCA). Pyrophosphate ion (PPi) can coordinate with Cu2+ to form stable PPi/Cu2+ complex and Cu2+ in the complex cannot be reduced to Cu+. The addition of PPase causes the hydrolysis of PPi into orthophosphate (Pi) and therefore induces the releasing of Cu2+ from the stable PPi/Cu2+ complex, and the free Cu2+ is easily reduced to Cu+ by sodium ascorbate. Then Cu+ catalyzes the cyclization reaction between the specially designed 5′-azide and 3′-alkyne tagged padlock probes through Cu+ catalyzed azide-alkyne cycloaddition (CuAAC), which in turn initiates the hyperbranched rolling circle amplification (HRCA). Given that the CLT-HRCA products contain large amounts of double-stranded DNAs (dsDNAs), the addition of SYBR Green I resulted in the enhanced fluorescence signal. There was a linear relationship between the enhanced fluorescence intensity and the logarithm PPase activity ranging from 0.05 to 25 mU with a detection limit of 0.02 mU. Such proposed biosensor has been successfully applied to screen the potential PPase inhibitors and has accessed the related inhibit ability with high efficiency.

SummaryThe type I intermediate filament (IF) keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at codon 373 (C373A) inKrt14exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in the epidermis. A proteomics screen identified 14-3-3 as major K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiatingKrt14C373A keratinocytes. Residue C373 in K14, which is conserved in several other type I IFs, is thus revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in the epidermis.

This paper presents a suitability evaluation approach to assess whether the LTE-based wireless private network satisfies the communication needs of smart grid applications. This approach can obtain different evaluation indexes including reliability, delay and throughput when the business attributes are used as the initial inputs by analyzing the MAC and PHY layer models and coverage characteristics. Then combined with the business analysis model, the applicability of wireless private network can be evaluated according to different power business needs. In order to verify the use of the proposed evaluation method, a simulation analysis of the suitability of the LTE 1.8GHz wireless private network is conducted for the businesses of power distribution and utilization.

The accurate topology of distribution network has a significant impact on power flow calculation, reliability evaluation and system operation. However, due to frequently reconfiguration and modification of switches, the topology is hard to maintain. In this paper, a novel two-stage method is proposed to identify the connection relationships between distribution transformers and feeders. In stage 1, a new correlation indicator is adopted to screen out the unsure distribution transformers which are doubted of being incorrectly connected. In stage 2, unsure distribution transformers are assigned to the most likely feeders, and then incorrectly connected distribution transformers are found out by clustering correction. The proposed two-stage method can help operators to correct the topology errors. Cases studies in actual distribution network verified the effectiveness of the proposed method and correlation indicator.

On the foundation of the original backpressure-based traffic light control algorithm, a distributed cooperative backpressure-based traffic light control method is proposed in this paper. The urban traffic network is modeled as a smart agent-controlled queuing network, in which the intersection agents exchange the queue length information and the selected activating light phase information of neighboring intersections through communications and determine the activating light phase at each time slot according to local traffic information. The improved phase pressure computation method considers the phase state of downstream intersections instead of only the queue length of the local intersections. Light phase switching coordination among adjacent intersections is achieved using the consensus-based bundle algorithm, in which the cooperative light phase switching problem is viewed as a task assignment issue among adjacent intersections. Simulation results illustrated that the proposed cooperative backpressure-based traffic light control method obtained better performance than the original backpressure-based and fixed-time traffic control methods.

Macroscopic fundamental diagram (MFD) characterizes a unimodal and low-scatter relationship between traffic accumulation and trip completion rate for homogenous urban network, providing a new perspective for the development of regional congestion control strategies. This paper contributes to the state-of-the-art by proposing a perimeter traffic control strategy for single urban congested region with MFD model and boundary conditions. For an urban protected region, the MFD is introduced to capture network traffic dynamics and optimal capacity. When regional accumulation exceeds the optimal capacity, the restricted inflow distribution considering boundary condition constraints of real-time traffic flows and queue dynamics is used to formulate a perimeter traffic flow control strategy for adjusting traffic signal timing on the periphery of region. To proactively reduce the possibility of queue spillbacks at border links, the dynamic queue-dependent border gated points are also integrated into the proposed control method. The simulation experiment was performed using part of urban network in Jinan, China. The results demonstrate the proposed perimeter control method alleviates the issue of congestion and improves traffic performance in the protected region and at the boundaries.

A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD., Mutations in LRRK2 are linked to Parkinson's Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.

Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.

It has been shown that the deployment of device-to-device (D2D) communication in cellular systems can provide better support for local services. However, improper design of the hybrid system may cause severe interference between cellular and D2D links. In this paper, we consider transceiver design for the system employing multiple antennas to mitigate the interference. The precoder and decoder matrices are optimized in terms of sum mean squared error (MSE) and capacity, respectively. For the MSE minimization problem, we present an alternative transceiver optimization algorithm. While for the non-convex capacity maximization problem, we decompose the primal problem into a sequence of standard convex quadratic programs for efficient optimization. The evaluation of our proposed algorithms for performance enhancement of the entire D2D integrated cellular system is carried out through simulations.

In VANET (vehicular ad hoc network) environment, the successive vehicle position data actually are discrete, so the key to the moving vehicle modeling is to effectively reduce the updating frequency of the position data so as to alleviate the communication and database management load. This paper proposes vehicle position data updating strategy with packet repetition based on Kalman filter predicting. Firstly, we design a position data updating model based on Kalman filter difference predicting equations. Then, we design a packet repetition mode decision algorithm, which is applied to deliver vehicle position updating data. The model with packet repetition can not only generate position updating data according to preset threshold, but also decide packet repetition mode related to the distance of two adjacent vehicles in order to reduce data loss. Both simulated highway and realistic urban road experimental results show that vehicle position data updating frequency could be obviously reduced and the reliability of the communication is greatly improved through packet repetition mechanism by using this position updating strategy.

Highly transparent conductive F and Ga co-doped ZnO films were deposited on a glass substrate with radio frequency magnetron sputtering at various growth temperatures. Growing the films at a substrate temperature of 480 °C produced the lowest resistivity of 6.84 × 10−4 Ωcm, a carrier concentration of 2.3 × 1020 cm−3, and a mobility of 39.7 cm2/Vs. These parameters were significantly improved to 3.53 × 10−4 Ωcm, 3.08 × 1020 cm−3, and 57.5 cm2/Vs, respectively, after a rapid thermal annealing treatment. All the films showed a high average transmittance of 90% in the optical range 380–1400 nm.